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Sample records for ameliorates renal fibrosis

  1. Dahuang Fuzi Decoction Attenuates Renal Fibrosis and Ameliorates Mitochondrial Dysfunction in Chronic Aristolochic Acid Nephropathy

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    Guang-xing Shui

    2017-01-01

    Full Text Available Objectives. The effects of the traditional formula Dahuang Fuzi Decoction (DFD on chronic aristolochic acid nephropathy (AAN in mice and its underlying mechanisms were studied. Methods. Mice were randomly divided into the following six groups: the control group, the model group (AAN, the saline-treated group (AAN + vehicle, the normal dose DFD-treated group (AAN + NDFD, the high dose DFD-treated group (AAN + HDFD, and the rosiglitazone treated group (AAN + Rosi. After treating for 8 weeks, 24 h urine and blood samples were collected and the mice sacrificed to study the biochemical parameters associated with renal function. The samples were analyzed for renal fibrosis and mitochondrial dysfunction (MtD markers. To achieve that, collagen III, collagen I, mitochondrial DNA copy numbers (mtDNA, mitochondrial membrane potential (MMP, ATP content, and ROS production were evaluated. Results. Our results showed that proteinuria, kidney function, and the renal pathological characteristics were improved by DFD and rosiglitazone. The expression of collagen III and collagen I decreased after treating with either DFD or rosiglitazone. Mitochondrial dysfunction based on the increase in ROS production, decrease in mitochondrial DNA copy numbers, and reduction of MMP and ATP content was improved by DFD and rosiglitazone. Conclusions. DFD could protect against renal impairments and ameliorate mitochondrial dysfunction in chronic AAN mice.

  2. Slit2 ameliorates renal inflammation and fibrosis after hypoxia-and lipopolysaccharide-induced epithelial cells injury in vitro

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    Zhou, Xiangjun [Department of Urology, Taihe Hospital, Hubei University of Medicine, Hubei (China); Yao, Qisheng, E-mail: yymcyqs@126.com [Department of Urology, Taihe Hospital, Hubei University of Medicine, Hubei (China); Sun, Xinbo; Gong, Xiaoxin; Yang, Yong; Chen, Congbo [Department of Urology, Taihe Hospital, Hubei University of Medicine, Hubei (China); Shan, Guang [Department of Urology, Renmin Hospital of Wuhan University, Hubei (China)

    2017-03-01

    Hypoxic acute kidney injury (AKI) is often incompletely repaired and leads to chronic kidney disease (CKD), which is characterized by tubulointerstitial inflammation and fibrosis. The Slit2 family of secreted glycoproteins is expressed in the kidney, it has been shown to exert an anti-inflammatory activity and prevent ischemic renal injury in vivo. However, whether Slit2 reduces renal fibrosis and inflammation after hypoxic and inflammatory epithelial cells injury in vitro remains unknown. In this study, we aimed to evaluate whether Slit2 ameliorated fibrosis and inflammation in two renal epithelial cells line challenged with hypoxia and lipopolysaccharide (LPS). Renal epithelial cells were treated with hypoxia and LPS to induce cell injury. Hoechst staining and Western blot analysis was conducted to examine epithelial cells injury. Immunofluorescence staining and Western blot analysis was performed to evaluate tubulointerstitial fibrosis. Real-time polymerase chain reaction (PCR) tested the inflammatory factor interleukin (IL)−1β and tumor necrosis factor (TNF)-α, and Western blot analysis determined the hypoxia-inducible factor (HIF)−1α, Toll-like receptor 4 (TLR4) and nuclear factor (NF)-κB. Results revealed that hypoxia induced epithelial cells apoptosis, inflammatory factor IL-1β and TNF-α release and tubulointerstitial fibrosis. LPS could exacerbate hypoxia -induced epithelial cells apoptosis, IL-1β and TNF-α release and fibrosis. Slit2 reduced the expression of fibronectin, the rate of epithelial cell apoptosis, and the expression of inflammatory factor. Slit2 could also inhibit the expression of TLR4 and NF-κB, but not the expression of HIF-1α. Therefore, Slit2 attenuated inflammation and fibrosis after LPS- and hypoxia-induced epithelial cells injury via the TLR4/NF-κB signaling pathway, but not depending on the HIF-1α signaling pathway. - Highlights: • Slit2 ameliorates inflammation after hypoxia-and LPS-induced epithelial cells injury

  3. Elevated bilirubin levels are associated with a better renal prognosis and ameliorate kidney fibrosis.

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    Park, Sehoon; Kim, Do Hyoung; Hwang, Jin Ho; Kim, Yong-Chul; Kim, Jin Hyuk; Lim, Chun Soo; Kim, Yon Su; Yang, Seung Hee; Lee, Jung Pyo

    2017-01-01

    Bilirubin has been reported to protect against kidney injury. However, further studies highlighting the beneficial effects of bilirubin on renal fibrosis and chronic renal function decline are necessary. We assessed a prospective cohort with a reference range of total bilirubin levels. The primary outcome was a 30% reduction in the estimated glomerular filtration rate (eGFR) from baseline, and the secondary outcome was a doubling of the serum creatinine levels, halving of the eGFR and the initiation of dialysis. In addition, experiments with tubular epithelial cells and C57BL/6 mice were performed to investigate the protective effects of bilirubin on kidney fibrosis. As a result, 1,080 patients were included in the study cohort. The study group with relative hyperbilirubinemia (total bilirubin 0.8-1.2 mg/dL) showed a better prognosis in terms of the primary outcome (adjusted hazard ratio (HR) 0.33, 95% confidence interval (CI) 0.19-0.59, P bilirubin-treated mice showed less fibrosis in the unilateral ureteral obstruction (UUO) model (P bilirubin treatment decreased fibronectin expression in tubular epithelial cells in a dose-dependent manner (P bilirubin levels were associated with better renal prognosis, and bilirubin treatment induced a beneficial effect on renal fibrosis. Therefore, bilirubin could be a potential therapeutic target to delay fibrosis-related kidney disease progression.

  4. Follistatin, an Activin Antagonist, Ameliorates Renal Interstitial Fibrosis in a Rat Model of Unilateral Ureteral Obstruction

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    Akito Maeshima

    2014-01-01

    Full Text Available Activin, a member of the TGF-β superfamily, regulates cell growth and differentiation in various cell types. Activin A acts as a negative regulator of renal development as well as tubular regeneration after renal injury. However, it remains unknown whether activin A is involved in renal fibrosis. To clarify this issue, we utilized a rat model of unilateral ureteral obstruction (UUO. The expression of activin A was significantly increased in the UUO kidneys compared to that in contralateral kidneys. Activin A was detected in glomerular mesangial cells and interstitial fibroblasts in normal kidneys. In UUO kidneys, activin A was abundantly expressed by interstitial α-SMA-positive myofibroblasts. Administration of recombinant follistatin, an activin antagonist, reduced the fibrotic area in the UUO kidneys. The number of proliferating cells in the interstitium, but not in the tubules, was significantly lower in the follistatin-treated kidneys. Expression of α-SMA, deposition of type I collagen and fibronectin, and CD68-positive macrophage infiltration were significantly suppressed in the follistatin-treated kidneys. These data suggest that activin A produced by interstitial fibroblasts acts as a potent profibrotic factor during renal fibrosis. Blockade of activin A action may be a novel approach for the prevention of renal fibrosis progression.

  5. Shenqiwan Ameliorates Renal Fibrosis in Rats by Inhibiting TGF-β1/Smads Signaling Pathway

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    Hongshu Chen

    2017-01-01

    Full Text Available Epithelial-mesenchymal transition (EMT refers to the transition of epithelial cells into mesenchymal cells. Emerging evidence suggests that EMT is a key point in renal interstitial fibrosis (RIF. Traditional Chinese Medicine Shenqiwan (SQW is widely used in clinical treatment of chronic kidney disease, but the underlying mechanism remains unclear. The purpose of this study is to investigate the effect of SQW on renal fibrosis and its association with TGF-β1/Smads signaling pathway. A rat model of adenine (150 mg/kg was established and intragastrically treated with various concentrations of SQW at dose of 1.5 g/kg, 3 g/kg, and 6 g/kg. Control group and model group were given the same volume of saline. Meanwhile, the positive control group was treated with Enalapril (4 mg/kg. Animals were sacrificed on 21st day after administration. The results showed that SQW could significantly relieve renal pathological damage caused by adenine, increase gene and protein expression of E-cadherin, and decrease the expression of Vimentin in kidney samples. In addition, SQW efficiently inhibited the mRNA and protein expression of p-Smad2/3 by upregulating Smad7. These results suggest that SQW could slow down the progression of renal fibrosis, possibly by inhibiting TGF-β1/Smads signaling pathway.

  6. Perivascular radiofrequency renal denervation lowers blood pressure and ameliorates cardiorenal fibrosis in spontaneously hypertensive rats

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    Zhang, Yan; Su, Linan; Zhang, Yunrong; Wang, Qiang; Yang, Dachun; Li, De; Yang, Yongjian; Ma, Shuangtao

    2017-01-01

    Background Catheter-based renal denervation (RDN) is a promising approach to treat hypertension, but innervation patterns limit the response to endovascular RDN and the post-procedural renal artery narrowing or stenosis questions the endovascular ablation strategy. This study was performed to investigate the anti-hypertensive and target organ protective effects of perivascular RDN in spontaneously hypertensive rats (SHR). Methods SHR and normotensive Wistar-Kyoto (WKY) rats were divided into sham group (n = 10), radiofrequency ablation group (n = 20) in which rats received bilateral perivascular ablation with radiofrequency energy (2 watts), and chemical (10% phenol in 95% ethanol) ablation group (n = 12). The tail-cuff blood pressure was measured before the ablation and on day 14 and day 28 after the procedure. The plasma levels of creatinine, urea nitrogen, and catecholamines, urinary excretion of electrolytes and protein, and myocardial and glomerular fibrosis were analyzed and compared among the groups on day 28 after the procedure. Results We identified that 2-watt is the optimal radiofrequency power for perivascular RDN in rats. Perivascular radiofrequency and chemical ablation achieved roughly comparable blood pressure reduction in SHR but not in WKY on day 14 and day 28 following the procedure. Radiofrequency-mediated ablation substantially destroyed the renal nerves surrounding the renal arteries of both SHR and WKY without damaging the renal arteries and diminished the expression of tyrosine hydroxylase, the enzyme marker for postganglionic sympathetic nerves. Additionally, perivascular radiofrequency ablation also decreased the plasma catecholamines of SHR. Interestingly, both radiofrequency and chemical ablation decreased the myocardial and glomerular fibrosis of SHR, while neither increased the plasma creatinine and blood urea nitrogen nor affected the urinary excretion of electrolytes and protein when compared to sham group. Conclusions Radiofrequency

  7. Sorafenib ameliorates renal fibrosis through inhibition of TGF-β-induced epithelial-mesenchymal transition.

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    Lining Jia

    Full Text Available This study was to investigate whether sorafenib can inhibit the progression of renal fibrosis and to study the possible mechanisms of this effect.Eight-week-old rats were subjected to unilateral ureteral obstruction (UUO and were intragastrically administered sorafenib, while control and sham groups were administered vehicle for 14 or 21 days. NRK-52E cells were treated with TGF-β1 and sorafenib for 24 or 48 hours. HE and Masson staining were used to visualize fibrosis of the renal tissue in each group. The expression of α-SMA and E-cadherin in kidney tissue and NRK-52E cells were performed using immunohistochemistry and immunofluorescence. The apoptosis rate of NRK-52E cells was determined by flow cytometry analysis. The protein levels of Smad3 and p-Smad3 in kidney tissue and NRK-52E cells were detected by western blot analysis.HE staining demonstrated that kidney interstitial fibrosis, tubular atrophy, and inflammatory cell infiltration in the sorafenib-treated-UUO groups were significantly decreased compared with the vehicle-treated-UUO group (p<0.05. Masson staining showed that the area of fibrosis was significantly decreased in the sorafenib-treated-UUO groups compared with vehicle-treated-UUO group (p<0.01. The size of the kidney did not significantly increase; the cortex of the kidney was thicker and had a richer blood supply in the middle-dose sorafenib group compared with the vehicle-treated-UUO group (p<0.05. Compared with the vehicle-treated-UUO and TGF-β-stimulated NRK-52E groups, the expression of a-SMA and E-cadherin decreased and increased, respectively, in the UUO kidneys and NRK-52E cells of the sorafenib-treated groups (p<0.05. The apoptotic rate of NRK-52E cells treated with sorafenib decreased for 24 hours in a dose-dependent manner (p<0.05. Compared with the vehicle-treated UUO and TGF-β-stimulated NRK-52E groups, the ratio of p-Smad3 to Smad3 decreased in the sorafenib-treated groups (p<0.05.Our results suggest that

  8. Microvesicles derived from human Wharton's Jelly mesenchymal stem cells ameliorate ischemia-reperfusion-induced renal fibrosis by releasing from G2/M cell cycle arrest.

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    Chen, Wenxia; Yan, Yongbin; Song, Chundong; Ding, Ying; Du, Tao

    2017-12-14

    Studies have demonstrated that microvesicles (MVs) derived from human Wharton's Jelly mesenchymal stromal cells (hWJMSCs) could ameliorate renal ischemia/reperfusion injury (IRI); however, the underlying mechanisms were not clear yet. Here, MVs were isolated and injected intravenously into rats immediately after ischemia of the left kidney, and Erk1/2 activator hepatocyte growth factor (HGF) or inhibitor U0126 was administrated. Tubular cell proliferation and apoptosis were identified by Ki67 or terminal-deoxynucleotidyl transferase-mediated nick end labeling immunostaining. Masson's tri-chrome straining and alpha-smooth muscle actin staining were used for assessing renal fibrosis. The mRNA or protein expression in the kidney was measured by quantitative reverse transcription-PCR or Western blot, respectively. The total collagen concentration was also determined. In vitro , NRK-52E cells that treated with MVs under hypoxia injury and with HGF or U0126 administration were used, and cell cycle analysis was performed. The effects of hWJMSC-MVs on enhancing the proliferation and mitigating the apoptosis of renal cells, abrogating IRI-induced fibrosis, improving renal function, decreasing collagen deposition, and altering the expression levels of epithelial-mesenchymal transition and cell cycle-related proteins in IRI rats were found. In vitro experiment showed that hWJMSC-MVs could induce G2/M cell cycle arrest and decrease the expression of collagen deposition-related proteins in NRK-52E cells after 24 or 48 h. However, U0126 treatment reversed these effects. In conclusion, MVs derived from hWJMSCs ameliorate IR-induced renal fibrosis by inducing G2/M cell cycle arrest via Erk1/2 signaling. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

  9. An aqueous extract of Portulaca oleracea ameliorates diabetic nephropathy through suppression of renal fibrosis and inflammation in diabetic db/db mice.

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    Lee, An Sook; Lee, Yun Jung; Lee, So Min; Yoon, Jung Joo; Kim, Jin Sook; Kang, Dae Gill; Lee, Ho Sub

    2012-01-01

    Diabetic nephropathy is one of the most common microvascular complications of diabetes and the leading cause of end-stage renal disease. In the present study, we investigated the renoprotective effect of the aqueous extract of Portulaca oleracea (AP) on diabetic nephropathy accelerated by renal fibrosis and inflammation in type 2 diabetic db/db mice. The mice were treated with AP (300 mg/kg/day, p.o.) for ten weeks to examine the long-term effects on diabetic nephropathy and renal dysfunction. We found that AP treatment markedly lowered blood glucose to 412 ± 11.4 mg/dl and plasma creatinine level to 2.3 ± 0.8 mg/dl compared to db/db mice (p < 0.05, p < 0.01, respectively). This study also showed that treatment with AP significantly decreased water intake and urine volume in diabetic db/db mice (p < 0.05). In immunohistological study, the renal expression of transforming growth factor-β1 (TGF-β1), advanced glycation end products (AGE), and intercellular adhesion molecule (ICAM)-1 markedly increased in the renal cortex of untreated db/db mice (p < 0.01). In contrast, AP treatment significantly reduced these expressions to 50 ± 2.1%, 48 ± 2.8%, 61 ± 1.1%, respectively (p < 0.01). Furthermore, NF-κB p65 activation in renal tissues markedly increased in untreated db/db mice, which was significantly suppressed by AP treatment. Taken together, these findings suggest that AP attenuates diabetic nephropathy through inhibition of renal fibrosis and inflammation in db/db mice.

  10. Combination of active components of Xiexin decoction ameliorates renal fibrosis through the inhibition of NF-κB and TGF-β1/Smad pathways in db/db diabetic mice.

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    Jia-Sheng Wu

    Full Text Available Xiexin decoction, a herbal therapeutic agent commonly used in traditional Chinese medicine, is recognized for its beneficial effects on diabetic nephropathy exerted through the combined action of multiple components, including Rhizoma Coptidis alkaloids (A, Radix et Rhizoma Rhei polysaccharides (P, and Radix Scutellaria flavones (F. Our previous studies have shown that a combination of A, P, and F (APF exhibits renoprotective effects against diabetic nephropathy. This study was aimed at determining the effects of APF on renal fibrosis in diabetic nephropathy and elucidating the underlying molecular mechanisms. To evaluate the effects of APF, in vivo, db/db diabetic mice were orally administered a low or high dose of APF (300 or 600 mg/kg, respectively once a day for 8 weeks. We evaluated the blood and urine indices of metabolic and renal function, renal tissue histopathology, renal inflammation, and fibrosis. APF treatment significantly ameliorated glucose and lipid metabolism dysfunction, decreased urinary albumin excretion, normalized creatinine clearance, and reduced the morphological changes in renal tissue. Additionally, APF administration in db/db diabetic mice reduced the elevated levels of renal inflammation mediators such as intercellular adhesion molecule-1, monocyte chemotactic protein-1, tumor necrosis factor-α, interleukin-1β, and active nuclear factor κB (NF-κB. APF treatment also reduced type I and IV collagen, transforming growth factor-β1 (TGF-β1, and TGF-β1 type II receptor expression levels, and decreased the phosphorylation of Smad2/3 in the kidneys of db/db diabetic mice. These results suggest that APF reduces renal fibrosis in diabetic nephropathy through the NF-κB and TGF-β1/Smad signaling pathways. In vitro, APF treatment reduced cell proliferation and protein expression of α-smooth muscle actin, collagen I, TGF-β1 and NF-κB in mesangial cells cultured with high glucose concentrations. Our findings indicate

  11. Ketamine induced renal fibrosis in a ketamine addition rat model

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    Mei-Yu Jang

    2017-09-01

    Conclusion: Ketamine treatment not only induced cystitis-like syndrome, but also renal fibrosis. These renal interstitial fibrosis changes may be induced by the TGF-β pathway. These preliminary results can provide valuable information from a clinical perspective.

  12. Less contribution of mast cells to the progression of renal fibrosis in Rat kidneys with chronic renal failure.

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    Baba, Asuka; Tachi, Masahiro; Ejima, Yutaka; Endo, Yasuhiro; Toyama, Hiroaki; Saito, Kazutomo; Abe, Nozomu; Yamauchi, Masanori; Miura, Chieko; Kazama, Itsuro

    2017-02-01

    Chronic renal failure (CRF) is histopathologically characterized by tubulointerstitial fibrosis in addition to glomerulosclerosis. Although mast cells are known to infiltrate into the kidneys with chronic inflammation, we know little about their contribution to the pathogenesis of renal fibrosis associated with CRF. The aim of this study was to reveal the involvement of mast cells in the progression of renal fibrosis in CRF. Using a rat model with CRF resulting from 5/6 nephrectomy, we examined the histopathological features of the kidneys and the infiltration of mast cells into the renal interstitium. By treating the rats with a potent mast cell stabilizer, tranilast, we also examined the involvement of mast cells in the progression of renal fibrosis associated with CRF. The CRF rat kidneys were characterized by the wide staining of collagen III and increased number of myofibroblasts, indicating the progression of renal fibrosis. Compared to T-lymphocytes or macrophages, the number of tryptase-positive mast cells was much smaller within the fibrotic kidneys and they did not proliferate in situ. The mRNA expression of mast cell-derived fibroblast-activating factors was not increased in the renal cortex isolated from CRF rat kidneys. Treatment with tranilast did not suppress the progression of renal fibrosis, nor did it ameliorate the progression of glomerulosclerosis and the interstitial proliferation of inflammatory leukocytes. This study demonstrated for the first time that mast cells are neither increased nor activated in the fibrotic kidneys of CRF rats. Compared to T-lymphocytes or macrophages that proliferate in situ within the fibrotic kidneys, mast cells were less likely to contribute to the progression of renal fibrosis associated with CRF. © 2016 Asian Pacific Society of Nephrology.

  13. Serum metabonomic analysis of protective effects of Curcuma aromatica oil on renal fibrosis rats.

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    Zhao, Liangcai; Zhang, Haiyan; Yang, Yunjun; Zheng, Yongquan; Dong, Minjian; Wang, Yaqiang; Bai, Guanghui; Ye, Xinjian; Yan, Zhihan; Gao, Hongchang

    2014-01-01

    Curcuma aromatica oil is a traditional herbal medicine demonstrating protective and anti-fibrosis activities in renal fibrosis patients. However, study of its mechanism of action is challenged by its multiple components and multiple targets that its active agent acts on. Nuclear magnetic resonance (NMR)-based metabonomics combined with clinical chemistry and histopathology examination were performed to evaluate intervening effects of Curcuma aromatica oil on renal interstitial fibrosis rats induced by unilateral ureteral obstruction. The metabolite levels were compared based on integral values of serum 1H NMR spectra from rats on 3, 7, 14, and 28 days after the medicine administration. Time trajectory analysis demonstrated that metabolic profiles of the agent-treated rats were restored to control levels after 7 days of dosage. The results confirmed that the agent would be an effective anti-fibrosis medicine in a time-dependent manner, especially in early renal fibrosis stage. Targeted metabolite analysis showed that the medicine could lower levels of lipid, acetoacetate, glucose, phosphorylcholine/choline, trimethylamine oxide and raise levels of pyruvate, glycine in the serum of the rats. Serum clinical chemistry and kidney histopathology examination dovetailed well with the metabonomics data. The results substantiated that Curcuma aromatica oil administration can ameliorate renal fibrosis symptoms by inhibiting some metabolic pathways, including lipids metabolism, glycolysis and methylamine metabolism, which are dominating targets of the agent working in vivo. This study further strengthens the novel analytical approach for evaluating the effect of traditional herbal medicine and elucidating its molecular mechanism.

  14. Inhibiting aerobic glycolysis suppresses renal interstitial fibroblast activation and renal fibrosis.

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    Ding, Hao; Jiang, Lei; Xu, Jing; Bai, Feng; Zhou, Yang; Yuan, Qi; Luo, Jing; Zen, Ke; Yang, Junwei

    2017-09-01

    Chronic kidney diseases generally lead to renal fibrosis. Despite great progress having been made in identifying molecular mediators of fibrosis, the mechanism that governs renal fibrosis remains unclear, and so far no effective therapeutic antifibrosis strategy is available. Here we demonstrated that a switch of metabolism from oxidative phosphorylation to aerobic glycolysis (Warburg effect) in renal fibroblasts was the primary feature of fibroblast activation during renal fibrosis and that suppressing renal fibroblast aerobic glycolysis could significantly reduce renal fibrosis. Both gene and protein assay showed that the expression of glycolysis enzymes was upregulated in mouse kidneys with unilateral ureter obstruction (UUO) surgery or in transforming growth factor-β1 (TGF-β1)-treated renal interstitial fibroblasts. Aerobic glycolysis flux, indicated by glucose uptake and lactate production, was increased in mouse kidney with UUO nephropathy or TGF-β1-treated renal interstitial fibroblasts and positively correlated with fibrosis process. In line with this, we found that increasing aerobic glycolysis can remarkably induce myofibroblast activation while aerobic glycolysis inhibitors shikonin and 2-deoxyglucose attenuate UUO-induced mouse renal fibrosis and TGF-β1-stimulated myofibroblast activation. Furthermore, mechanistic study indicated that shikonin inhibits renal aerobic glycolysis via reducing phosphorylation of pyruvate kinase type M2, a rate-limiting glycolytic enzyme associated with cell reliance on aerobic glycolysis. In conclusion, our findings demonstrate the critical role of aerobic glycolysis in renal fibrosis and support treatment with aerobic glycolysis inhibitors as a potential antifibrotic strategy. Copyright © 2017 the American Physiological Society.

  15. Role of Receptor Tyrosine Kinase Signaling in Renal Fibrosis

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    Feng Liu

    2016-06-01

    Full Text Available Renal fibrosis can be induced in different renal diseases, but ultimately progresses to end stage renal disease. Although the pathophysiologic process of renal fibrosis have not been fully elucidated, it is characterized by glomerulosclerosis and/or tubular interstitial fibrosis, and is believed to be caused by the proliferation of renal inherent cells, including glomerular epithelial cells, mesangial cells, and endothelial cells, along with defective kidney repair, renal interstitial fibroblasts activation, and extracellular matrix deposition. Receptor tyrosine kinases (RTKs regulate a variety of cell physiological processes, including metabolism, growth, differentiation, and survival. Many studies from in vitro and animal models have provided evidence that RTKs play important roles in the pathogenic process of renal fibrosis. It is also showed that tyrosine kinases inhibitors (TKIs have anti-fibrotic effects in basic research and clinical trials. In this review, we summarize the evidence for involvement of specific RTKs in renal fibrosis process and the employment of TKIs as a therapeutic approach for renal fibrosis.

  16. Chemical chaperon 4-phenylbutyrate protects against the endoplasmic reticulum stress-mediated renal fibrosis in vivo and in vitro.

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    Liu, Shing-Hwa; Yang, Ching-Chin; Chan, Ding-Cheng; Wu, Cheng-Tien; Chen, Li-Ping; Huang, Jenq-Wen; Hung, Kuan-Yu; Chiang, Chih-Kang

    2016-04-19

    Renal tubulointerstitial fibrosis is the common and final pathologic change of kidney in end-stage renal disease. Interesting, endoplasmic reticulum (ER) stress is known to contribute to the pathophysiological mechanisms during the development of renal fibrosis. Here, we investigated the effects of chemical chaperon sodium 4-phenylbutyrate (4-PBA) on renal fibrosis in vivo and in vitro. In a rat unilateral ureteral obstruction (UUO) model, 4-PBA mimicked endogenous ER chaperon in the kidneys and significantly reduced glucose regulated protein 78 (GRP78), CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP), activating transcription factor 4 (ATF4), and phosphorylated JNK protein expressions as well as restored spliced X-box-binding protein 1 (XBP1) expressions in the kidneys of UUO rats. 4-PBA also attenuated the increases of α-smooth muscle actin (α-SMA), connective tissue growth factor (CTGF) protein expressions, tubulointerstitial fibrosis, and apoptosis in the kidneys of UUO rats. Moreover, transforming growth factor (TGF)-β markedly increased ER stress-associated molecules, profibrotic factors, and apoptotic markers in the renal tubular cells (NRK-52E), all of which could be significantly counteracted by 4-PBA treatment. 4-PBA also diminished TGF-β-increased CTGF promoter activity and CTGF mRNA expression in NRK-52E cells. Taken together, our results indicated that 4-PBA acts as an ER chaperone to ameliorate ER stress-induced renal tubular cell apoptosis and renal fibrosis.

  17. TGF-β/Smad signaling in renal fibrosis

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    Xiao-Ming eMeng

    2015-03-01

    Full Text Available TGF-β (transforming growth factor-β is well identified as a central mediator in renal fibrosis. TGF-β initiates canonical and non-canonical pathways to exert multiple biological effects. Among them, Smad signaling is recognized as a major pathway of TGF- signaling in progressive renal fibrosis. During fibrogenesis, Smad3 is highly activated, which is associated with the down-regulation of an inhibitory Smad7 via an ubiquitin E3-ligases-dependent degradation mechanism. The equilibrium shift between Smad3 and Smad7 leads to accumulation and activation of myofibroblasts, overproduction of ECM (extracellular matrix, and reduction in ECM degradation in the diseased kidney. Therefore, overexpression of Smad7 has been shown to be a therapeutic agent for renal fibrosis in various models of kidney diseases. In contrast, another downstream effecter of TGF-β/Smad signaling pathway, Smad2, exerts its renal protective role by counter-regulating the Smad3. Furthermore, recent studies demonstrated that Smad3 mediates renal fibrosis by down-regulating miR-29 and miR-200 but up-regulating miR-21 and miR-192. Thus, overexpression of miR-29 and miR-200 or down-regulation of miR-21 and miR-192 is capable of attenuating Smad3-mediated renal fibrosis in various mouse models of chronic kidney diseases. Taken together, TGF-/Smad signaling plays an important role in renal fibrosis. Targeting TGF-β/Smad3 signaling may represent a specific and effective therapy for chronic kidney diseases associated with renal fibrosis.

  18. Erhuang Formula ameliorates renal damage in adenine-induced chronic renal failure rats via inhibiting inflammatory and fibrotic responses.

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    Zhang, Chun-Yan; Zhu, Jian-Yong; Ye, Ying; Zhang, Miao; Zhang, Li-Jun; Wang, Su-Juan; Song, Ya-Nan; Zhang, Hong

    2017-11-01

    The present study aimed to evaluate the protective effects of Erhuang Formula (EHF) and explore its pharmacological mechanisms on adenine-induced chronic renal failure (CRF). The compounds in EHF were analyzed by HPLC/MS. Adenine-induced CRF rats were administrated by EHF. The effects were evaluated by renal function examination and histology staining. Immunostaining of some proteins related cell adhesion was performedin renal tissues, including E-cadherin, β-catenin, fibronectin and laminin. The qRT-PCR was carried out determination of gene expression related inflammation and fibrosis including NF-κB, TNF-α, TGF-β1, α-SMA and osteopontin (OPN). Ten compounds in EHF were identified including liquiritigenin, farnesene, vaccarin, pachymic acid, cycloastragenol, astilbin, 3,5,6,7,8,3',4'-heptemthoxyflavone, physcion, emodin and curzerene. Abnormal renal function and histology had significant improvements by EHF treatment. The protein expression of β-catenin, fibronectin and laminin were significantly increased and the protein expression of E-cadherin significantly decreased in CRF groups. However, these protein expressions were restored to normal levels in EHF group. Furthermore, low expression of PPARγ and high expression of NF-κB, TNF-α, TGF-β1, α-SMA and OPN were substantially restored by EHF treatment in a dose-dependent manner. EHF ameliorated renal damage in adenine-induced CRF rats, and the mechanisms might involve in the inhibition of inflammatory and fibrotic responses and the regulation of PPARγ, NF-κB and TGF-β signaling pathways. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  19. Connective tissue growth factor regulates fibrosis-associated renal lymphangiogenesis

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    Kinashi, Hiroshi; Falke, Lucas L.; Nguyen, Tri Q.; Bovenschen, Niels; Aten, Jan; Leask, Andrew; Ito, Yasuhiko; Goldschmeding, Roel

    2017-01-01

    Lymphangiogenesis is correlated with the degree of renal interstitial fibrosis. Pro-fibrotic transforming growth factor beta induces VEGF-C production, the main driver of lymphangiogenesis. Connective tissue growth factor (CTGF) is an important determinant of fibrotic tissue remodeling, but its

  20. Connective tissue growth factor regulates fibrosis-associated renal lymphangiogenesis

    NARCIS (Netherlands)

    Kinashi, Hiroshi; Falke, Lucas L.; Nguyen, Tri Q.; Bovenschen, Niels; Aten, Jan; Leask, Andrew; Ito, Yasuhiko; Goldschmeding, Roel

    2017-01-01

    Lymphangiogenesis is correlated with the degree of renal interstitial fibrosis. Pro-fibrotic transforming growth factor β induces VEGF-C production, the main driver of lymphangiogenesis. Connective tissue growth factor (CTGF) is an important determinant of fibrotic tissue remodeling, but its

  1. Nephrogenic systemic fibrosis symptoms alleviated by renal transplantation

    DEFF Research Database (Denmark)

    Hansen, Jesper Melchior

    2011-01-01

    are limited. Anecdotal reports have shown partial or complete resolution of NSF following successful renal transplantation early in the course of NSF. In this report, we describe alleviation of NSF symptoms in two women following successful renal transplantation more than 3 years after onset of NSF.......Nephrogenic systemic fibrosis (NSF) is a rare, serious, and life-threatening disease of patients with severe renal impairment. Gadolinium-containing contrast agents have been shown to be the crucial trigger. There is no proven medical cure for the disease, and symptomatic treatment options...

  2. Inhibition of p38 MAPK attenuates renal atrophy and fibrosis in a murine renal artery stenosis model.

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    Wang, Diping; Warner, Gina M; Yin, Ping; Knudsen, Bruce E; Cheng, Jingfei; Butters, Kim A; Lien, Karen R; Gray, Catherine E; Garovic, Vesna D; Lerman, Lilach O; Textor, Stephen C; Nath, Karl A; Simari, Robert D; Grande, Joseph P

    2013-04-01

    Renal artery stenosis (RAS) is an important cause of chronic renal dysfunction. Recent studies have underscored a critical role for CCL2 (MCP-1)-mediated inflammation in the progression of chronic renal damage in RAS and other chronic renal diseases. In vitro studies have implicated p38 MAPK as a critical intermediate for the production of CCL2. However, a potential role of p38 signaling in the development and progression of chronic renal disease in RAS has not been previously defined. We sought to test the hypothesis that inhibition of p38 MAPK ameliorates chronic renal injury in mice with RAS. We established a murine RAS model by placing a cuff on the right renal artery and treated mice with the p38 inhibitor SB203580 or vehicle for 2 wk. In mice treated with vehicle, the cuffed kidney developed interstitial fibrosis, tubular atrophy, and interstitial inflammation. In mice treated with SB203580, the RAS-induced renal atrophy was reduced (70% vs. 39%, P < 0.05). SB203580 also reduced interstitial inflammation and extracellular matrix deposition but had no effect on the development of hypertension. SB203580 partially blocked the induction of CCL2, CCL7 (MCP-3), CC chemokine receptor 2 (CCR2), and collagen 4 mRNA expression in the cuffed kidneys. In vitro, blockade of p38 hindered both TNF-α and TGF-β-induced CCL2 upregulation. Based on these observations, we conclude that p38 MAPK plays a critical role in the induction of CCL2/CCL7/CCR2 system and the development of interstitial inflammation in RAS.

  3. Grape seed extract ameliorates bleomycin-induced mouse pulmonary fibrosis.

    Science.gov (United States)

    Liu, Qi; Jiang, Jun-Xia; Liu, Ya-Nan; Ge, Ling-Tian; Guan, Yan; Zhao, Wei; Jia, Yong-Liang; Dong, Xin-Wei; Sun, Yun; Xie, Qiang-Min

    2017-05-05

    Pulmonary fibrosis is common in a variety of inflammatory lung diseases, such as interstitial pneumonia, chronic obstructive pulmonary disease, and silicosis. There is currently no effective clinical drug treatment. It has been reported that grape seed extracts (GSE) has extensive pharmacological effects with minimal toxicity. Although it has been found that GSE can improve the lung collagen deposition and fibrosis pathology induced by bleomycin in rat, its effects on pulmonary function, inflammation, growth factors, matrix metalloproteinases and epithelial-mesenchymal transition remain to be researched. In the present study, we studied whether GSE provided protection against bleomycin (BLM)-induced mouse pulmonary fibrosis. ICR strain mice were treated with BLM in order to establish pulmonary fibrosis models. GSE was given daily via intragastric administration for three weeks starting at one day after intratracheal instillation. GSE at 50 or 100mg/kg significantly reduced BLM-induced inflammatory cells infiltration, proinflammatory factor protein expression, and hydroxyproline in lung tissues, and improved pulmonary function in mice. Additionally, treatment with GSE also significantly impaired BLM-induced increases in lung fibrotic marker expression (collagen type I alpha 1 and fibronectin 1) and decreases in an anti-fibrotic marker (E-cadherin). Further investigation indicated that the possible molecular targets of GSE are matrix metalloproteinases-9 (MMP-9) and TGF-β1, given that treatment with GSE significantly prevented BLM-induced increases in MMP-9 and TGF-β1 expression in the lungs. Together, these results suggest that supplementation with GSE may improve the quality of life of lung fibrosis patients by inhibiting MMP-9 and TGF-β1 expression in the lungs. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Targeting of the pulmonary capillary vascular niche promotes lung alveolar repair and ameliorates fibrosis.

    Science.gov (United States)

    Cao, Zhongwei; Lis, Raphael; Ginsberg, Michael; Chavez, Deebly; Shido, Koji; Rabbany, Sina Y; Fong, Guo-Hua; Sakmar, Thomas P; Rafii, Shahin; Ding, Bi-Sen

    2016-02-01

    Although the lung can undergo self-repair after injury, fibrosis in chronically injured or diseased lungs can occur at the expense of regeneration. Here we study how a hematopoietic-vascular niche regulates alveolar repair and lung fibrosis. Using intratracheal injection of bleomycin or hydrochloric acid in mice, we show that repetitive lung injury activates pulmonary capillary endothelial cells (PCECs) and perivascular macrophages, impeding alveolar repair and promoting fibrosis. Whereas the chemokine receptor CXCR7, expressed on PCECs, acts to prevent epithelial damage and ameliorate fibrosis after a single round of treatment with bleomycin or hydrochloric acid, repeated injury leads to suppression of CXCR7 expression and recruitment of vascular endothelial growth factor receptor 1 (VEGFR1)-expressing perivascular macrophages. This recruitment stimulates Wnt/β-catenin-dependent persistent upregulation of the Notch ligand Jagged1 (encoded by Jag1) in PCECs, which in turn stimulates exuberant Notch signaling in perivascular fibroblasts and enhances fibrosis. Administration of a CXCR7 agonist or PCEC-targeted Jag1 shRNA after lung injury promotes alveolar repair and reduces fibrosis. Thus, targeting of a maladapted hematopoietic-vascular niche, in which macrophages, PCECs and perivascular fibroblasts interact, may help to develop therapy to spur lung regeneration and alleviate fibrosis.

  5. Targeting of the pulmonary capillary vascular niche promotes lung alveolar repair and ameliorates fibrosis

    Science.gov (United States)

    Cao, Zhongwei; Lis, Raphael; Ginsberg, Michael; Chavez, Deebly; Shido, Koji; Rabbany, Sina Y.; Fong, Guo-Hua; Sakmar, Thomas P.; Rafii, Shahin; Ding, Bi-Sen

    2016-01-01

    Although the lung can undergo self-repair after injury, fibrosis in chronically injured or diseased lungs can occur at the expense of regeneration. Here we study how a hematopoietic-vascular niche regulates alveolar repair and lung fibrosis. Using intratracheal injection of bleomycin or hydrochloric acid in mice, we show that repetitive lung injury activates pulmonary capillary endothelial cells (PCECs) and perivascular macrophages, impeding alveolar repair and promoting fibrosis. Whereas the chemokine receptor CXCR7, expressed on PCECs, acts to prevent epithelial damage and ameliorate fibrosis after a single round of treatment with bleomycin or hydrochloric acid, repeated injury leads to suppression of CXCR7 expression and recruitment of vascular endothelial growth factor receptor 1 (VEGFR1)-expressing perivascular macrophages. This recruitment stimulates Wnt/β-catenin–dependent persistent upregulation of the Notch ligand Jagged1 (encoded by Jag1) in PCECs, which in turn stimulates exuberant Notch signaling in perivascular fibroblasts and enhances fibrosis. Administration of a CXCR7 agonist or PCEC-targeted Jag1 shRNA after lung injury promotes alveolar repair and reduces fibrosis. Thus, targeting of a maladaptbed hematopoietic-vascular niche, in which macrophages, PCECs and perivascular fibroblasts interact, may help to develop therapy to spur lung regeneration and alleviate fibrosis. PMID:26779814

  6. Spironolactone ameliorates transplant vasculopathy in renal chronic transplant dysfunction in rats

    NARCIS (Netherlands)

    Waanders, Femke; Rienstra, Heleen; Boer, Mark Walther; Zandvoort, Andre; Rozing, Jan; Navis, Gerjan; van Goor, Harry; Hillebrands, Jan-Luuk

    Waanders F, Rienstra H, Walther Boer M, Zandvoort A, Rozing J, Navis G, van Goor H, Hillebrands JL. Spironolactone ameliorates transplant vasculopathy in renal chronic transplant dysfunction in rats. Am J Physiol Renal Physiol 296: F1072-F1079, 2009. First published February 25, 2009;

  7. Nebulized hyaluronan ameliorates lung inflammation in cystic fibrosis mice.

    Science.gov (United States)

    Gavina, Manuela; Luciani, Alessandro; Villella, Valeria R; Esposito, Speranza; Ferrari, Eleonora; Bressani, Ilaria; Casale, Alida; Bruscia, Emanuela M; Maiuri, Luigi; Raia, Valeria

    2013-08-01

    Chronic lung inflammation with increased susceptibility to bacterial infections cause much of the morbidity and mortality in patients with cystic fibrosis (CF), the most common severe, autosomal recessively inherited disease in the Caucasian population. Exogenous inhaled hyaluronan (HA) can exert a protective effect against injury and beneficial effects of HA have been shown in experimental models of chronic respiratory diseases. Our objective was to examine whether exogenous administration of nebulized HA might interfere with lung inflammation in CF. F508del homozygous mice (Cftr(F508del) ) and transgenic mice overexpressing the ENaC channel β-subunit (Scnn1b-Tg) were treated with nebulized HA (0.5 mg/mouse/day for 7 days). Tumor necrosis factor-alpha (TNFα), macrophage inflammatory protein-2 (MIP-2), myeloperoxidase (MPO) levels, and macrophage infiltration were assessed on lung tissues. IB3-1 and CFBE41o-epithelial cell lines were cultured with HA (24 hr, 100 µg/ml) and Reactive Oxygen Species (ROS), Tissue Transglutaminase (TG2) SUMOylation and Peroxisome Proliferator Activated Receptor gamma (PPARγ) and phospho-p42/p44 levels were measured by dichlorodihydrofluorescein assay, or fluorescence resonance energy transfer (FRET) microscopy or immunoblots. Nebulized HA reduced TNFα expression (P < 0.005); TNFα, MIP-2, and MPO protein levels (P < 0.05); MPO activity (P < 0.05); and CD68+ cells counts (P < 0.005) in lung tissues of Cftr(F508del) and Scnn1b-Tg mice, compared with saline-treated mice. HA reduced ROS, TG2 SUMOylation, TG2 activity, phospho-p42-44, and increased PPARγ protein in both IB3-1 and CFBE41o cells (P < 0.05). Nebulized HA is effective in controlling inflammation in vivo in mice CF airways and in vitro in human airway epithelial cells. We provide the proof of concept for the use of inhaled HA as a potential anti-inflammatory drug in CF therapy. Copyright © 2012 Wiley Periodicals, Inc.

  8. A mouse model for inherited renal fibrosis associated with endoplasmic reticulum stress

    Directory of Open Access Journals (Sweden)

    Sian E. Piret

    2017-06-01

    Full Text Available Renal fibrosis is a common feature of renal failure resulting from multiple etiologies, including diabetic nephropathy, hypertension and inherited renal disorders. However, the mechanisms of renal fibrosis are incompletely understood and we therefore explored these by establishing a mouse model for a renal tubular disorder, referred to as autosomal dominant tubulointerstitial kidney disease (ADTKD due to missense uromodulin (UMOD mutations (ADTKD-UMOD. ADTKD-UMOD, which is associated with retention of mutant uromodulin in the endoplasmic reticulum (ER of renal thick ascending limb cells, is characterized by hyperuricemia, interstitial fibrosis, inflammation and renal failure, and we used targeted homologous recombination to generate a knock-in mouse model with an ADTKD-causing missense cysteine to arginine uromodulin mutation (C125R. Heterozygous and homozygous mutant mice developed reduced uric acid excretion, renal fibrosis, immune cell infiltration and progressive renal failure, with decreased maturation and excretion of uromodulin, due to its retention in the ER. The ER stress marker 78 kDa glucose-regulated protein (GRP78 was elevated in cells expressing mutant uromodulin in heterozygous and homozygous mutant mice, and this was accompanied, both in vivo and ex vivo, by upregulation of two unfolded protein response pathways in primary thick ascending limb cells from homozygous mutant mice. However, this did not lead to an increase in apoptosis in vivo. Thus, we have developed a novel mouse model for renal fibrosis, which will be a valuable resource to decipher the mechanisms linking uromodulin mutations with ER stress and renal fibrosis.

  9. Mesenchymal stem cell-derived microparticles ameliorate peritubular capillary rarefaction via inhibition of endothelial-mesenchymal transition and decrease tubulointerstitial fibrosis in unilateral ureteral obstruction.

    Science.gov (United States)

    Choi, Hoon Young; Lee, Hyun Gyu; Kim, Beom Seok; Ahn, Sun Hee; Jung, Ara; Lee, Mirae; Lee, Jung Eun; Kim, Hyung Jong; Ha, Sung Kyu; Park, Hyeong Cheon

    2015-03-11

    Microparticles (MPs) derived from kidney-derived mesenchymal stem cells (KMSCs) have recently been reported to ameliorate rarefaction of peritubular capillaries (PTC) in ischemic kidneys via delivery of proangiogenic effectors. This study aimed to investigate whether KMSC-derived MPs show anti-fibrotic effects by ameliorating endothelial-to-mesenchymal transition (EndoMT) in human umbilical vein endothelial cells (HUVEC) in vitro and by preserving PTC in kidneys with unilateral ureteral obstruction (UUO) in vivo. MPs isolated from the supernatants of KMSC were co-cultured with HUVEC to assess their in vitro biologic effects on endothelial cells. Mice were treated with MPs via the tail vein after UUO injury to assess their anti-fibrotic and PTC sparing effects. Renal tubulointerstitial damage and inflammatory cell infiltration were examined with Masson's trichrome, F4/80 and α-smooth muscle actin (α-SMA) staining and PTC rarefaction index was determined by CD31 staining. KMSC-derived MPs significantly ameliorated EndoMT and improved in vitro proliferation of TGF-β1 treated HUVEC. In vivo administration of KMSC-derived MPs significantly inhibited EndoMT of PTC endothelial cells and improved PTC rarefaction in UUO kidneys. Furthermore, administration of KMSC-derived MPs inhibited inflammatory cell infiltration as well as tubulointerstitial fibrosis in UUO mice as demonstrated by decreased F4/80 and α-SMA-positive cells and Masson's trichrome staining, respectively. Our results suggest that KMSC-derived MPs ameliorate PTC rarefaction via inhibition of EndoMT and protect against progression of renal damage by inhibiting tubulointerstitial fibrosis.

  10. Protocatechuic aldehyde ameliorates experimental pulmonary fibrosis by modulating HMGB1/RAGE pathway

    International Nuclear Information System (INIS)

    Zhang, Liang; Ji, Yunxia; Kang, Zechun; Lv, Changjun; Jiang, Wanglin

    2015-01-01

    An abnormal high mobility group box 1 (HMGB1) activation and a decrease in receptor for advanced glycation end-product (RAGE) play a key role in the pathogenesis of pulmonary fibrosis. Protocatechuic aldehyde (PA) is a naturally occurring compound, which is extracted from the degradation of phenolic acids. However, whether PA has anti-fibrotic functions is unknown. In this study, the effects of PA on the transforming growth factor-β1 (TGF-β1)-mediated epithelial–mesenchymal transition (EMT) in A549 cells, on the apoptosis of human type I alveolar epithelial cells (AT I), on the proliferation of human lung fibroblasts (HLF-1) in vitro, and on bleomycin (BLM)-induced pulmonary fibrosis in vivo were investigated. PA treatment resulted in a reduction of EMT in A549 cells with a decrease in vimentin and HMGB, an increase of E-cadherin and RAGE, a reduction of HLF-1 proliferation with a decrease of fibroblast growth factor 2 (FGF-2) and platelet-derived growth factor (PDGF). Apoptosis of AT I was attenuated with an increase of RAGE. PA ameliorated BLM-induced pulmonary fibrosis in rats with a reduction of histopathological scores and collagen deposition, and a lower FGF-2, PDGF, α-smooth muscle actin (α-SMA) and HMGB1 expression, whereas higher RAGE was found in BLM-instilled lungs. Through the decrease of HGMB1 and the regulation of RAGE, PA reversed the EMT, inhibited HLF-1 proliferation as well as reduced apoptosis in AT I, and prevented pulmonary fibrosis in vivo. Collectively, our results demonstrate that PA prevents experimental pulmonary fibrosis by modulating HMGB1/RAGE pathway. - Highlights: • PA prevents EMT, reduces the apoptosis of AT1 in vitro. • PA decreases proliferation of HLF-1, reduces PDGF and FGF expression in vitro. • PA prevents experimental pulmonary fibrosis by modulating the HMGB1/RAGE pathway

  11. Protocatechuic aldehyde ameliorates experimental pulmonary fibrosis by modulating HMGB1/RAGE pathway

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Liang, E-mail: countryspring@sina.com; Ji, Yunxia, E-mail: 413499057@qq.com; Kang, Zechun, E-mail: davidjiangwl@163.com; Lv, Changjun, E-mail: Lucky_lcj@sina.com; Jiang, Wanglin, E-mail: jwl518@163.com

    2015-02-15

    An abnormal high mobility group box 1 (HMGB1) activation and a decrease in receptor for advanced glycation end-product (RAGE) play a key role in the pathogenesis of pulmonary fibrosis. Protocatechuic aldehyde (PA) is a naturally occurring compound, which is extracted from the degradation of phenolic acids. However, whether PA has anti-fibrotic functions is unknown. In this study, the effects of PA on the transforming growth factor-β1 (TGF-β1)-mediated epithelial–mesenchymal transition (EMT) in A549 cells, on the apoptosis of human type I alveolar epithelial cells (AT I), on the proliferation of human lung fibroblasts (HLF-1) in vitro, and on bleomycin (BLM)-induced pulmonary fibrosis in vivo were investigated. PA treatment resulted in a reduction of EMT in A549 cells with a decrease in vimentin and HMGB, an increase of E-cadherin and RAGE, a reduction of HLF-1 proliferation with a decrease of fibroblast growth factor 2 (FGF-2) and platelet-derived growth factor (PDGF). Apoptosis of AT I was attenuated with an increase of RAGE. PA ameliorated BLM-induced pulmonary fibrosis in rats with a reduction of histopathological scores and collagen deposition, and a lower FGF-2, PDGF, α-smooth muscle actin (α-SMA) and HMGB1 expression, whereas higher RAGE was found in BLM-instilled lungs. Through the decrease of HGMB1 and the regulation of RAGE, PA reversed the EMT, inhibited HLF-1 proliferation as well as reduced apoptosis in AT I, and prevented pulmonary fibrosis in vivo. Collectively, our results demonstrate that PA prevents experimental pulmonary fibrosis by modulating HMGB1/RAGE pathway. - Highlights: • PA prevents EMT, reduces the apoptosis of AT1 in vitro. • PA decreases proliferation of HLF-1, reduces PDGF and FGF expression in vitro. • PA prevents experimental pulmonary fibrosis by modulating the HMGB1/RAGE pathway.

  12. Shikonin ameliorates isoproterenol (ISO)-induced myocardial damage through suppressing fibrosis, inflammation, apoptosis and ER stress.

    Science.gov (United States)

    Yang, Jun; Wang, Zhao; Chen, Dong-Lin

    2017-09-01

    Shikonin, isolated from the roots of herbal plant Lithospermum erythrorhizon, is a naphthoquinone. It has been reported to exert beneficial anti-inflammatory effects and anti-oxidant properties in various diseases. Isoproterenol (ISO) has been widely used to establish cardiac injury in vivo and in vitro. However, shikonin function in ISO-induced cardiac injury remains uncertain. In our study, we attempted to investigate the efficiency and possible molecular mechanism of shikonin in cardiac injury treatment induced by ISO. In vivo, C57BL6 mice were subcutaneously injected with 5mg/kg ISO to induce heart failure. And mice were given a gavage of shikonin (2 or 4mg/kg/d, for four weeks). Cardiac function, fibrosis indices, inflammation response, apoptosis and endoplasmic reticulum (ER) stress were calculated. Pathological alterations, fibrosis-, inflammation-, apoptosis- and ER stress-related molecules were examined. In ISO-induced cardiac injury, shikonin significantly ameliorated heart function, decreased myocardial fibrosis, suppressed inflammation, attenuated apoptosis and ER stress through impeding collagen accumulation, Toll like receptor 4/nuclear transcription factor κB (TLR4/NF-κB), Caspase-3 and glucose-regulated protein 78 (GRP78) signaling pathways activity, relieving heart failure in vivo. Also, in vitro, shikonin attenuated ISO-induced cardiac muscle cells by reducing fibrosis, inflammation, apoptosis and ER stress. Our findings indicated that shikonin treatment attenuated ISO-induced heart injury, providing an effective therapeutic strategy for heart failure treatment for future. Copyright © 2017. Published by Elsevier Masson SAS.

  13. Renal Denervation Findings on Cardiac and Renal Fibrosis in Rats with Isoproterenol Induced Cardiomyopathy

    Science.gov (United States)

    Liu, Qian; Zhang, Qi; Wang, Kai; Wang, Shengchan; Lu, Dasheng; Li, Zhenzhen; Geng, Jie; Fang, Ping; Wang, Ying; Shan, Qijun

    2015-12-01

    Cardio-renal fibrosis plays key roles in heart failure and chronic kidney disease. We sought to determine the effects of renal denervation (RDN) on cardiac and renal fibrosis in rats with isoproterenol induced cardiomyopathy. Sixty male Sprague Dawley rats were randomly assigned to Control (n = 10) and isoproterenol (ISO)-induced cardiomyopathy group (n = 50). At week 5, 31 survival ISO-induced cardiomyopathy rats were randomized to RDN (n = 15) and Sham group (n = 16). Compared with Control group, ejection fraction was decreased, diastolic interventricular septal thickness and left atrial dimension were increased in ISO-induced cardiomyopathy group at 5 week. After 10 weeks, cardio-renal pathophysiologic results demonstrated that the collagen volume fraction of left atrio-ventricular and kidney tissues reduced significantly in RDN group compared with Sham group. Moreover the pro-fibrosis factors (TGF-β1, MMP2 and Collagen I), inflammatory cytokines (CRP and TNF-α), and collagen synthesis biomarkers (PICP, PINP and PIIINP) concentration significantly decreased in RDN group. Compared with Sham group, RDN group showed that release of noradrenaline and aldosterone were reduced, angiotensin-converting enzyme (ACE)/angiotensin II (Ang II)/angiotensin II type-1 receptor (AT1R) axis was downregulated. Meanwhile, angiotensin-converting enzyme 2 (ACE2)/angiotensin-1-7 (Ang-(1-7))/mas receptor (Mas-R) axis was upregulated. RDN inhibits cardio-renal fibrogenesis through multiple pathways, including reducing SNS over-activity, rebalancing RAAS axis.

  14. Unilateral Renal Ischemia as a Model of Acute Kidney Injury and Renal Fibrosis in Cats.

    Science.gov (United States)

    Schmiedt, C W; Brainard, B M; Hinson, W; Brown, S A; Brown, C A

    2016-01-01

    The objectives of this study were to define the acute and chronic effects of 1-hour unilateral in vivo renal ischemia on renal function and histology in cats. Twenty-one adult purpose-bred research cats were anesthetized, and 1 kidney underwent renal artery and vein occlusion for 1 hour. Serum creatinine and urea concentrations, urine protein:creatinine ratio, urine-specific gravity, glomerular filtration rate, hematocrit, platelet concentration and function, and white blood cell count were measured at baseline and variable time points after ischemia. Renal histopathology was evaluated on days 3, 6, 12, 21, 42, and 70 postischemia; changes in smooth muscle actin and interstitial collagen were examined. Following ischemia, whole animal glomerular filtration rate was significantly reduced (57% of baseline on day 6; P < .05). At the early time points, the ischemic kidneys exhibited severe acute epithelial necrosis accompanied by evidence of regeneration of tubules predominantly within the corticomedullary junction. At later periods, postischemic kidneys had evidence of tubular atrophy and interstitial inflammation with significantly more smooth muscle actin and interstitial collagen staining and interstitial fibrosis when compared with the contralateral control kidneys. This study characterizes the course of ischemic acute kidney injury in cats and demonstrates that ischemic acute kidney injury triggers chronic fibrosis, interstitial inflammation, and tubular atrophy in feline kidneys. These late changes are typical of those observed in cats with naturally occurring chronic kidney disease. © The Author(s) 2015.

  15. Role of bone morphogenetic protein-7 in renal fibrosis

    Directory of Open Access Journals (Sweden)

    Rui Xi eLi

    2015-04-01

    Full Text Available Renal fibrosis is final common pathway of end stage renal disease. Irrespective of the primary cause, renal fibrogenesis is a dynamic process which involves a large network of cellular and molecular interaction, including pro-inflammatory cell infiltration and activation, matrix-producing cell accumulation and activation, and secretion of profibrogenic factors that modulate extracellular matrix (ECM formation and cell-cell interaction. Bone morphogenetic protein-7 is a protein of the TGF-β super family and increasingly regarded as a counteracting molecule against TGF-β. A large variety of evidence shows an anti-fibrotic role of BMP-7 in chronic kidney disease, and this effect is largely mediated via counterbalancing the profibrotic effect of TGF-β. Besides, BMP-7 reduced ECM formation by inactivating matrix-producing cells and promoting mesenchymal-to-epithelial transition (MET. BMP-7 also increased ECM degradation. Despite these observations, the anti-fibrotic effect of BMP-7 is still controversial such that fine regulation of BMP-7 expression in vivo might be a great challenge for its ultimate clinical application.

  16. Role of bone morphogenetic protein-7 in renal fibrosis

    Science.gov (United States)

    Li, Rui Xi; Yiu, Wai Han; Tang, Sydney C. W.

    2015-01-01

    Renal fibrosis is final common pathway of end stage renal disease. Irrespective of the primary cause, renal fibrogenesis is a dynamic process which involves a large network of cellular and molecular interaction, including pro-inflammatory cell infiltration and activation, matrix-producing cell accumulation and activation, and secretion of profibrogenic factors that modulate extracellular matrix (ECM) formation and cell-cell interaction. Bone morphogenetic protein-7 is a protein of the TGF-β super family and increasingly regarded as a counteracting molecule against TGF-β. A large variety of evidence shows an anti-fibrotic role of BMP-7 in chronic kidney disease, and this effect is largely mediated via counterbalancing the profibrotic effect of TGF-β. Besides, BMP-7 reduced ECM formation by inactivating matrix-producing cells and promoting mesenchymal-to-epithelial transition (MET). BMP-7 also increased ECM degradation. Despite these observations, the anti-fibrotic effect of BMP-7 is still controversial such that fine regulation of BMP-7 expression in vivo might be a great challenge for its ultimate clinical application. PMID:25954203

  17. Defects in MAP1S-mediated autophagy turnover of fibronectin cause renal fibrosis.

    Science.gov (United States)

    Xu, Guibin; Yue, Fei; Huang, Hai; He, Yongzhong; Li, Xun; Zhao, Haibo; Su, Zhengming; Jiang, Xianhan; Li, Wenjiao; Zou, Jing; Chen, Qi; Liu, Leyuan

    2016-05-01

    Excessive deposition of extracellular matrix proteins in renal tissues causes renal fibrosis and renal function failure. Mammalian cells primarily use the autophagy-lysosome system to degrade misfolded/aggregated proteins and dysfunctional organelles. MAP1S is an autophagy activator and promotes the biogenesis and degradation of autophagosomes. Previously, we reported that MAP1S suppresses hepatocellular carcinogenesis in a mouse model and predicts a better prognosis in patients suffering from clear cell renal cell carcinomas. Furthermore, we have characterized that MAP1S enhances the turnover of fibronectin, and mice overexpressing LC3 but with MAP1S deleted accumulate fibronectin and develop liver fibrosis because of the synergistic impact of LC3-induced over-synthesis of fibronectin and MAP1S depletion-caused impairment of fibronectin degradation. Here we show that a suppression of MAP1S in renal cells caused an impairment of autophagy clearance of fibronectin and an activation of pyroptosis. Depletion of MAP1S in mice leads to an accumulation of fibrosis-related proteins and the development of renal fibrosis in aged mice. The levels of MAP1S were dramatically reduced and levels of fibronectin were greatly elevated in renal fibrotic tissues from patients diagnosed as renal atrophy and renal failure. Therefore, MAP1S deficiency may cause the accumulation of fibronectin and the development of renal fibrosis.

  18. Dual effect of chemokine CCL7/MCP-3 in the development of renal tubulointerstitial fibrosis

    NARCIS (Netherlands)

    Gonzalez, Julien; Mouttalib, Sofia; Delage, Christine; Calise, Denis; Maoret, Jean-Jose; Pradere, Jean-Philippe; Klein, Julie; Buffin-Meyer, Benedicte; Van der Veen, Betty; Charo, Israel F.; Heeringa, Peter; Duchene, Johan; Bascands, Jean-Loup; Schanstra, Joost-Peter

    2013-01-01

    Most end-stage renal disease kidneys display accumulation of extracellular matrix (ECM) in the renal tubular compartment (tubular interstitial fibrosis - TIF) which is strongly correlated with the future loss of renal function. Although inflammation is a key event in the development of TIF, it can

  19. C-type natriuretic peptide ameliorates pulmonary fibrosis by acting on lung fibroblasts in mice.

    Science.gov (United States)

    Kimura, Toru; Nojiri, Takashi; Hino, Jun; Hosoda, Hiroshi; Miura, Koichi; Shintani, Yasushi; Inoue, Masayoshi; Zenitani, Masahiro; Takabatake, Hiroyuki; Miyazato, Mikiya; Okumura, Meinoshin; Kangawa, Kenji

    2016-02-19

    , indicating that CNP suppresses fibroblast differentiation into myofibroblasts. Furthermore, human lung fibroblasts from patients with or without interstitial lung disease substantially expressed GC-B receptor mRNA. These data suggest that CNP ameliorates bleomycin-induced pulmonary fibrosis by suppressing TGF-β signaling and myofibroblastic differentiation in lung fibroblasts. Therefore, we propose consideration of CNP for clinical application to pulmonary fibrosis treatment.

  20. Periostin-Binding DNA Aptamer Treatment Ameliorates Peritoneal Dialysis-Induced Peritoneal Fibrosis

    Directory of Open Access Journals (Sweden)

    Bo Young Nam

    2017-06-01

    Full Text Available Peritoneal fibrosis is a major complication in peritoneal dialysis (PD patients, which leads to dialysis discontinuation. Periostin, increased by transforming growth factor β1 (TGF-β1 stimulation, induces the expression of extracellular matrix (ECM genes. Aberrant periostin expression has been demonstrated to be associated with PD-related peritoneal fibrosis. Therefore, the effect of periostin inhibition by an aptamer-based inhibitor on peritoneal fibrosis was evaluated. In vitro, TGF-β1 treatment upregulated periostin, fibronectin, α-smooth muscle actin (α-SMA, and Snail expression and reduced E-cadherin expression in human peritoneal mesothelial cells (HPMCs. Periostin small interfering RNA (siRNA treatment ameliorated the TGF-β1-induced periostin, fibronectin, α-SMA, and Snail expression and restored E-cadherin expression in HPMCs. Similarly, the periostin-binding DNA aptamer (PA also attenuated fibronectin, α-SMA, and Snail upregulation and E-cadherin downregulation in TGF-β1-stimulated HPMCs. In mice treated with PD solution for 4 weeks, the expression of periostin, fibronectin, α-SMA, and Snail was significantly increased in the peritoneum, whereas E-cadherin expression was significantly decreased. The thickness of the submesothelial layer and the intensity of Masson’s trichrome staining in the PD group were significantly increased compared to the untreated group. These changes were significantly abrogated by the intraperitoneal administration of PA. These findings suggest that PA can be a potential therapeutic strategy for peritoneal fibrosis in PD patients.

  1. Cordyceps sinensis attenuates renal fibrosis and suppresses BAG3 induction in obstructed rat kidney.

    Science.gov (United States)

    Du, Feng; Li, Si; Wang, Tian; Zhang, Hai-Yan; Zong, Zhi-Hong; Du, Zhen-Xian; Li, De-Tian; Wang, Hua-Qin; Liu, Bo; Miao, Jia-Ning; Bian, Xiao-Hui

    2015-01-01

    BAG3 regulates a number of cellular processes, including cell proliferation, apoptosis, adhesion and migration, and epithelial-mesenchymal transition (EMT). However, the role of BAG3 in renal tubular EMT and renal interstitial fibrosis remains elusive. This study aimed to examine the dynamic expression of BAG3 during renal fibrosis, and to investigate the efficacy of Cordyceps sinensis (C. sinensis) on renal fibrosis. A rat model of unilateral ureteral obstruction (UUO) was established, and the expression of BAG3 and α-SMA, and the efficacy of C. sinensis on renal fibrosis induced by UUO were examined. The results showed that UUO led to collagen accumulation, which was significantly suppressed by C. sinensis. UUO increased the expression of BAG3 and α-SMA, a mesenchymal marker, while UUO induced BAG3 and α-SMA expression was significantly inhibited by C. sinensis. In addition, immunohistochemical staining demonstrated that BAG3 immunoreactivity was restricted to tubular epithelium. In conclusion, BAG3 is a potential target for the prevention and/or treatment of renal fibrosis, and C. Sinensis is a promising agent for renal fibrosis.

  2. Inhibition mechanism of compound ethanol extracts from wuweizi (fructus schisandrae chinensis) on renal interstitial fibrosis in diabetic nephropathy model mice.

    Science.gov (United States)

    Zhang, Yanqiu; Zhang, Daning; Zhang, Mianzhi

    2012-12-01

    To evaluate inhibition effect and mechanism of compound ethanol extracts from Wuweizi (Fructus Schisandrae Chinensis), Chuanxiong (Rhizoma Chuanxiong) and Muli (Cocha Ostreae) (FRC) on glomerular and tubular interstitial fibrosis in streptozocin (STZ)-induced diabetic nephropathy (ND) model mice. Twenty-seven male C57BL/6 mice were divided randomly into 3 groups: nondibetic (ND), STZ-induced diabetic (D), and STZ-induced diabetic that were treated with 5 g x kg(-1) x day(-1) of FRC by oral gavage (D(FRC)), with 9 in each group. The protein expressions of E-cadherin, alpha-smooth muscle actin (alpha-SMA), Plasminogen Activator Inhibitor-1 (PAL-1) in renal tissues were investigated by Western blotting. The expressions of fibronectin (FN) and alpha-SMA were detected by immunohistochemical method. The morphological changes of renal tissues were observed under a microscope. Renal tissues in the D(FRC) group showed a lessened degree of fibrosis. Meanwhile, the expressions of FN, alpha-SMA and PAI-1 were significantly lower in the D(FRC) group than those in the D group (all P < 0.05). FRC can ameliorate the DN in the C57BL/6 mice, and its mechanism may relate to inhibition on the epithelial to mesenchymal transdifferentiation, endothelial-myofibroblast transition and PAL-1 expression.

  3. Assessment of glomerular filtration rate and effective renal plasma flow in cystic fibrosis

    International Nuclear Information System (INIS)

    Spino, M.; Chai, R.P.; Isles, A.F.; Balfe, J.W.; Brown, R.G.; Thiessen, J.J.; MacLeod, S.M.

    1985-01-01

    A study was conducted to examine renal function in 10 healthy control subjects and eight patients with cystic fibrosis in stable condition. Sequential bolus injections of /sup 99m/Tc-DTPA and 125 I-OIH were administered to assess glomerular filtration rate and effective renal plasma flow, respectively. Blood was subsequently collected for 3 hours, and urine for 24 hours. Renal clearances of both radioisotope markers were virtually identical in patients and controls. Inasmuch as neither glomerular filtration rate nor effective renal plasma flow was enhanced in patients with cystic fibrosis, increased clearance of drugs in these patients is unlikely to be the result of enhanced glomerular filtration or tubular secretion

  4. Magnetization Transfer Magnetic Resonance Imaging Noninvasively Detects Renal Fibrosis in Swine Atherosclerotic Renal Artery Stenosis at 3.0 T.

    Science.gov (United States)

    Jiang, Kai; Ferguson, Christopher M; Woollard, John R; Zhu, Xiangyang; Lerman, Lilach O

    2017-11-01

    Renal fibrosis is a useful biomarker for diagnosis and evaluation of therapeutic interventions of renal diseases but often requires invasive testing. Magnetization transfer magnetic resonance imaging (MT-MRI), which evaluates the presence of macromolecules, offers a noninvasive tool to probe renal fibrosis in murine renal artery stenosis (RAS) at 16.4 T. In this study, we aimed to identify appropriate imaging parameters for collagen detection at 3.0 T MRI and to test the utility of MT-MRI in measuring renal fibrosis in a swine model of atherosclerotic RAS (ARAS). To select the appropriate offset frequency, an MT-MRI study was performed on a phantom containing 0% to 40% collagen I and III with offset frequencies from -1600 to +1600 Hz and other MT parameters empirically set as pulse width at 16 milliseconds and flip angle at 800 degrees. Then selected MT parameters were used in vivo on pigs 12 weeks after sham (n = 8) or RAS (n = 10) surgeries. The ARAS pigs were fed with high-cholesterol diet to induce atherosclerosis. The MT ratio (MTR) was compared with ex vivo renal fibrosis measured using Sirius-red staining. Offset frequencies at 600 and 1000 Hz were selected for collagen detection without direct saturation of free water signal, and subsequently applied in vivo. The ARAS kidneys showed mild cortical and medullary fibrosis by Sirius-red staining. The cortical and medullary MTRs at 600 and 1000 Hz were both increased. Renal fibrosis measured ex vivo showed good linear correlations with MTR at 600 (cortex: Pearson correlation coefficient r = 0.87, P 3.0 T. Therefore, MT-MRI may potentially be clinically applicable and useful for detection and monitoring of renal pathology in subjects with RAS.

  5. Angiotensin-(1-7 relieved renal injury induced by chronic intermittent hypoxia in rats by reducing inflammation, oxidative stress and fibrosis

    Directory of Open Access Journals (Sweden)

    W. Lu

    Full Text Available We aimed to study the renal injury and hypertension induced by chronic intermittent hypoxia (CIH and the protective effects mediated by angiotensin 1-7 [Ang(1-7]. We randomly assigned 32 male Sprague-Dawley rats (body weight 180-200 g to normoxia control, CIH, Ang(1-7-treated normoxia, and Ang(1-7-treated CIH groups. Systolic blood pressure (SBP was monitored at the start and end of each week. Renal sympathetic nerve activity (RSNA was recorded. CTGF and TGF-β were detected by immunohistochemistry and western blotting. Tissue parameters of oxidative stress were also determined. In addition, renal levels of interleukin-6, tumor necrosis factor-α, nitrotyrosine, and hypoxia-inducible factor-1α were determined by immunohistochemistry, immunoblotting, and ELISA. TUNEL assay results and cleaved caspase 3 and 12 were also determined. Ang(1-7 induced a reduction in SBP together with a restoration of RSNA in the rat model of CIH. Ang(1-7 treatment also suppressed the production of reactive oxygen species, reduced renal tissue inflammation, ameliorated mesangial expansion, and decreased renal fibrosis. Thus, Ang(1-7 treatment exerted renoprotective effects on CIH-induced renal injury and was associated with a reduction of oxidative stress, inflammation and fibrosis. Ang(1-7 might therefore represent a promising therapy for obstructive sleep apnea-related hypertension and renal injury.

  6. Inhaled ENaC antisense oligonucleotide ameliorates cystic fibrosis-like lung disease in mice.

    Science.gov (United States)

    Crosby, Jeff R; Zhao, Chenguang; Jiang, Chong; Bai, Dong; Katz, Melanie; Greenlee, Sarah; Kawabe, Hiroshi; McCaleb, Michael; Rotin, Daniela; Guo, Shuling; Monia, Brett P

    2017-11-01

    Epithelial sodium channel (ENaC, Scnn1) hyperactivity in the lung leads to airway surface dehydration and mucus accumulation in cystic fibrosis (CF) patients and in mice with CF-like lung disease. We identified several potent ENaC specific antisense oligonucleotides (ASOs) and tested them by inhalation in mouse models of CF-like lung disease. The inhaled ASOs distributed into lung airway epithelial cells and decreased ENaC expression by inducing RNase H1-dependent degradation of the targeted Scnn1a mRNA. Aerosol delivered ENaC ASO down-regulated mucus marker expression and ameliorated goblet cell metaplasia, inflammation, and airway hyper-responsiveness. Lack of systemic activity of ASOs delivered via the aerosol route ensures the safety of this approach. Our results demonstrate that antisense inhibition of ENaC in airway epithelial cells could be an effective and safe approach for the prevention and reversal of lung symptoms in CF and potentially other inflammatory diseases of the lung. Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

  7. Impairment of PPARα and the Fatty Acid Oxidation Pathway Aggravates Renal Fibrosis during Aging.

    Science.gov (United States)

    Chung, Ki Wung; Lee, Eun Kyeong; Lee, Mi Kyung; Oh, Goo Taeg; Yu, Byung Pal; Chung, Hae Young

    2018-04-01

    Defects in the renal fatty acid oxidation (FAO) pathway have been implicated in the development of renal fibrosis. Although, compared with young kidneys, aged kidneys show significantly increased fibrosis with impaired kidney function, the mechanisms underlying the effects of aging on renal fibrosis have not been investigated. In this study, we investigated peroxisome proliferator-activated receptor α (PPAR α ) and the FAO pathway as regulators of age-associated renal fibrosis. The expression of PPAR α and the FAO pathway-associated proteins significantly decreased with the accumulation of lipids in the renal tubular epithelial region during aging in rats. In particular, decreased PPAR α protein expression associated with increased expression of PPAR α -targeting microRNAs. Among the microRNAs with increased expression during aging, miR-21 efficiently decreased PPAR α expression and impaired FAO when ectopically expressed in renal epithelial cells. In cells pretreated with oleic acid to induce lipid stress, miR-21 treatment further enhanced lipid accumulation. Furthermore, treatment with miR-21 significantly exacerbated the TGF- β -induced fibroblast phenotype of epithelial cells. We verified the physiologic importance of our findings in a calorie restriction model. Calorie restriction rescued the impaired FAO pathway during aging and slowed fibrosis development. Finally, compared with kidneys of aged littermate controls, kidneys of aged PPAR α -/- mice showed exaggerated lipid accumulation, with decreased activity of the FAO pathway and a severe fibrosis phenotype. Our results suggest that impaired renal PPAR α signaling during aging aggravates renal fibrosis development, and targeting PPAR α is useful for preventing age-associated CKD. Copyright © 2018 by the American Society of Nephrology.

  8. Basigin/CD147 promotes renal fibrosis after unilateral ureteral obstruction.

    Science.gov (United States)

    Kato, Noritoshi; Kosugi, Tomoki; Sato, Waichi; Ishimoto, Takuji; Kojima, Hiroshi; Sato, Yuka; Sakamoto, Kazuma; Maruyama, Shoichi; Yuzawa, Yukio; Matsuo, Seiichi; Kadomatsu, Kenji

    2011-02-01

    Regardless of their primary causes, progressive renal fibrosis and tubular atrophy are the main predictors of progression to end-stage renal disease. Basigin/CD147 is a multifunctional molecule-it induces matrix metalloproteinases and hyaluronan, for example-and has been implicated in organ fibrosis. However, the relationship between basigin and organ fibrosis has been poorly studied. We investigated basigin's role in renal fibrosis using a unilateral ureteral obstruction model. Basigin-deficient mice (Bsg(-/-)) demonstrated significantly less fibrosis after surgery than Bsg(+/+) mice. Fewer macrophages had infiltrated in Bsg(-/-) kidneys. Consistent with these in vivo data, primary cultured tubular epithelial cells from Bsg(-/-) mice produced less matrix metalloproteinase and exhibited less motility on stimulation with transforming growth factor β. Furthermore, Bsg(-/-) embryonic fibro blasts produced less hyaluronan and α-smooth muscle actin after transforming growth factor β stimulation. Together, these results demonstrate for the first time that basigin is a key regulator of renal fibrosis. Basigin could be a candidate target molecule for the prevention of organ fibrosis. Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  9. Sinomenine attenuates renal fibrosis through Nrf2-mediated inhibition of oxidative stress and TGFβ signaling

    Energy Technology Data Exchange (ETDEWEB)

    Qin, Tian [School of Life Science & Technology, China Pharmaceutical University, Nanjing 210009 (China); Yin, Shasha; Yang, Jun; Zhang, Qin; Liu, Yangyang [Jiangsu Key Laboratory of Molecular Medicine, Nanjing University School of Medicine, Nanjing 210093 (China); Huang, Fengjie, E-mail: hfj@cpu.edu.cn [School of Life Science & Technology, China Pharmaceutical University, Nanjing 210009 (China); Cao, Wangsen, E-mail: wangsencao@nju.edu.cn [Jiangsu Key Laboratory of Molecular Medicine, Nanjing University School of Medicine, Nanjing 210093 (China)

    2016-08-01

    Renal fibrosis is the common feature of chronic kidney disease and mainly mediated by TGFβ-associated pro-fibrogenic signaling, which causes excessive extracellular matrix accumulation and successive loss of kidney functions. Sinomenine (SIN), an alkaloid derived from medicinal herb extensively used in treatment of rheumatoid arthritis and various inflammatory disorders, displays renal protective properties in experimental animals; however its pharmacological potency against renal fibrosis is not explored. In this study we report that SIN possesses strong anti-renal fibrosis functions in kidney cell and in mouse fibrotic kidney. SIN beneficially modulated the pro-fibrogenic protein expression in TGFβ-treated kidney cells and attenuated the renal fibrotic pathogenesis incurred by unilateral ureteral obstruction (UUO), which correlated with its activation of Nrf2 signaling - the key defender against oxidative stress with anti-fibrotic potentials. Further investigation on its regulation of Nrf2 downstream events revealed that SIN significantly balanced oxidative stress via improving the expression and activity of anti-oxidant and detoxifying enzymes, and interrupted the pro-fibrogenic signaling of TGFβ/Smad and Wnt/β-catenin. Even more impressively SIN achieved its anti-fibrotic activities in an Nrf2-dependent manner, suggesting that SIN regulation of Nrf2-associated anti-fibrotic activities constitutes a critical component of SIN's renoprotective functions. Collectively our studies have demonstrated a novel anti-fibrotic property of SIN and its upstream events and provided a molecular basis for SIN's potential applications in treatment of renal fibrosis-associated kidney disorders. - Highlights: • Sinomenine has strong potency of inhibiting renal fibrosis in UUO mouse kidney. • Sinomenine attenuates the expression of profibrogenic proteins. • Sinomenine balances renal fibrosis-associated oxidative stress. • Sinomenine mitigates profibrogenic

  10. Idiopathic retroperitoneal fibrosis involving a unilateral renal sinus: A case report and literature review

    International Nuclear Information System (INIS)

    Lee, Seul Bi; Yoon, Jung Hee; Kim, Seung Ho; Lee, Ye Daum; Kim, Suk Jung; Lim, Yun Jung; Jung, Hyun Kyung; Lee, Jin Soo

    2016-01-01

    Idiopathic retroperitoneal fibrosis (RPF) is a rare disease entity and its etiology is uncertain. We report two similar cases which showed an uncommon presentation of idiopathic RPF. A 66-year-old woman and an 80-year-old man presented with incidental findings of left renal pelvic mass-like lesions. Computed tomography revealed a soft tissue density mass replacing the left renal pelvis, which was suspicious for renal pelvic cancer, and the diagnosis of idiopathic RPF was surgically confirmed. To the best of our knowledge, a few cases of idiopathic RPF presenting with features of a localized unilateral renal pelvic mass mimicking renal pelvic cancer have been reported

  11. Idiopathic retroperitoneal fibrosis involving a unilateral renal sinus: A case report and literature review

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Seul Bi; Yoon, Jung Hee; Kim, Seung Ho; Lee, Ye Daum; Kim, Suk Jung; Lim, Yun Jung; Jung, Hyun Kyung; Lee, Jin Soo [Dept. of Radiology, Haeundae Paik Hospital, Inje University College of Medicine, Busan (Korea, Republic of)

    2016-06-15

    Idiopathic retroperitoneal fibrosis (RPF) is a rare disease entity and its etiology is uncertain. We report two similar cases which showed an uncommon presentation of idiopathic RPF. A 66-year-old woman and an 80-year-old man presented with incidental findings of left renal pelvic mass-like lesions. Computed tomography revealed a soft tissue density mass replacing the left renal pelvis, which was suspicious for renal pelvic cancer, and the diagnosis of idiopathic RPF was surgically confirmed. To the best of our knowledge, a few cases of idiopathic RPF presenting with features of a localized unilateral renal pelvic mass mimicking renal pelvic cancer have been reported.

  12. The role of Toll-like receptor 2 in inflammation and fibrosis during progressive renal injury.

    Directory of Open Access Journals (Sweden)

    Jaklien C Leemans

    Full Text Available Tissue fibrosis and chronic inflammation are common causes of progressive organ damage, including progressive renal disease, leading to loss of physiological functions. Recently, it was shown that Toll-like receptor 2 (TLR2 is expressed in the kidney and activated by endogenous danger signals. The expression and function of TLR2 during renal fibrosis and chronic inflammation has however not yet been elucidated. Therefore, we studied TLR2 expression in human and murine progressive renal diseases and explored its role by inducing obstructive nephropathy in TLR2(-/- or TLR2(+/+ mice. We found that TLR2 is markedly upregulated on tubular and tubulointerstitial cells in patients with chronic renal injury. In mice with obstructive nephropathy, renal injury was associated with a marked upregulation and change in distribution of TLR2 and upregulation of murine TLR2 danger ligands Gp96, biglycan, and HMGB1. Notably, TLR2 enhanced inflammation as reflected by a significantly reduced influx of neutrophils and production of chemokines and TGF-beta in kidneys of TLR2(-/- mice compared with TLR2(+/+ animals. Although, the obstructed kidneys of TLR2(-/- mice had less interstitial myofibroblasts in the later phase of obstructive nephropathy, tubular injury and renal matrix accumulation was similar in both mouse strains. Together, these data demonstrate that TLR2 can initiate renal inflammation during progressive renal injury and that the absence of TLR2 does not affect the development of chronic renal injury and fibrosis.

  13. Sida rhomboidea.Roxb leaf extract ameliorates gentamicin induced nephrotoxicity and renal dysfunction in rats.

    Science.gov (United States)

    Thounaojam, Menaka C; Jadeja, Ravirajsinh N; Devkar, Ranjitsinh V; Ramachandran, A V

    2010-10-28

    Sida rhomboidea.Roxb (SR) known as "Mahabala" in Ayurveda and marketed as "Shahadeyi" is used in ethnomedicine to treat ailments such as dysuria and urinary disorders. To evaluate nephroprotective potential of SR against gentamicin (GM) induced nephrotoxicity and renal dysfunction. Nephrotoxicity was induced in rats with GM (100 mg/kg bodyweight (i.p.) for 8 days) and were treated with SR extract (200 and 400 mg/kg bodyweight (p.o.) for 8 days) or 0.5% carboxymethyl cellulose (vehicle). Plasma and urine urea and creatinine, renal enzymatic and non-enzymatic antioxidants along with lipid peroxidation were evaluated in various experimental groups. GM treatment induced significant elevation (p<0.05) in plasma and urine urea, creatinine, renal lipid peroxidation along with significant decrement (p<0.05) in renal enzymatic and non-enzymatic antioxidants. SR treatment to GM treated rats (GM+SR) recorded significant decrement (p<0.05) in plasma and urine urea and creatinine, renal lipid peroxidation along with significant increment (p<0.05) in renal enzymatic and non-enzymatic antioxidants. SR leaf extract ameliorates GM induced nephrotoxicity and renal dysfunction and thus validates its ethnomedicinal use. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  14. Curcumin ameliorates hepatic fibrosis in type 2 diabetes mellitus – insights into its mechanisms of action

    Science.gov (United States)

    Stefanska, B

    2012-01-01

    A wide variety of beneficial effects have been attributed to curcumin, a major polyphenol from the golden spice Curcuma longa known as turmeric, including amelioration of severe complications of type 2 diabetes such as hepatic fibrosis, retinopathy, neuropathy and nephropathy. In the present issue of BJP, Lin and colleagues reveal new mechanisms by which curcumin inhibits the activation of hepatic stellate cells in vitro, a hallmark of non-alcoholic steatohepatitis and hepatic fibrogenesis associated with type 2 diabetes mellitus. They demonstrated that curcumin suppresses the advanced glycation end-products (AGEs)-mediated induction of the receptor for AGEs (RAGE) gene expression by increasing PPARγ activity and stimulating de novo synthesis of glutathione. As a result, downstream elements of RAGE-activated pathways are inhibited, which prevents oxidative stress, inflammation and hepatic stellate cell activation. This report suggests that curcumin may have potential as an anti-fibrotic agent in type 2 diabetes and opens the door to the evaluation of curcumin therapeutic effects in liver conditions of different aetiology and in other disorders linked to the impairment of PPARγ activity, such as obesity and atherosclerosis. LINKED ARTICLE This article is a commentary on Lin et al., pp. 2212–2227 of this issue. To view this paper visit http://dx.doi.org/10.1111/j.1476-5381.2012.01910.x PMID:22452372

  15. Curcumin ameliorates hepatic fibrosis in type 2 diabetes mellitus - insights into its mechanisms of action.

    Science.gov (United States)

    Stefanska, B

    2012-08-01

    A wide variety of beneficial effects have been attributed to curcumin, a major polyphenol from the golden spice Curcuma longa known as turmeric, including amelioration of severe complications of type 2 diabetes such as hepatic fibrosis, retinopathy, neuropathy and nephropathy. In the present issue of BJP, Lin and colleagues reveal new mechanisms by which curcumin inhibits the activation of hepatic stellate cells in vitro, a hallmark of non-alcoholic steatohepatitis and hepatic fibrogenesis associated with type 2 diabetes mellitus. They demonstrated that curcumin suppresses the advanced glycation end-products (AGEs)-mediated induction of the receptor for AGEs (RAGE) gene expression by increasing PPARγ activity and stimulating de novo synthesis of glutathione. As a result, downstream elements of RAGE-activated pathways are inhibited, which prevents oxidative stress, inflammation and hepatic stellate cell activation. This report suggests that curcumin may have potential as an anti-fibrotic agent in type 2 diabetes and opens the door to the evaluation of curcumin therapeutic effects in liver conditions of different aetiology and in other disorders linked to the impairment of PPARγ activity, such as obesity and atherosclerosis. This article is a commentary on Lin et al., pp. 2212-2227 of this issue. To view this paper visit http://dx.doi.org/10.1111/j.1476-5381.2012.01910.x. © 2012 The Author. British Journal of Pharmacology © 2012 The British Pharmacological Society.

  16. Suppression of renal fibrosis by galectin-1 in high glucose-treated renal epithelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Okano, Kazuhiro, E-mail: kaokano@kc.twmu.ac.jp; Tsuruta, Yuki; Yamashita, Tetsuri; Takano, Mari; Echida, Yoshihisa; Nitta, Kosaku

    2010-11-15

    Diabetic nephropathy is the most common cause of chronic kidney disease. We investigated the ability of intracellular galectin-1 (Gal-1), a prototype of endogenous lectin, to prevent renal fibrosis by regulating cell signaling under a high glucose (HG) condition. We demonstrated that overexpression of Gal-1 reduces type I collagen (COL1) expression and transcription in human renal epithelial cells under HG conditions and transforming growth factor-{beta}1 (TGF-{beta}1) stimulation. Matrix metalloproteinase 1 (MMP1) is stimulated by Gal-1. HG conditions and TGF-{beta}1 treatment augment expression and nuclear translocation of Gal-1. In contrast, targeted inhibition of Gal-1 expression reduces COL1 expression and increases MMP1 expression. The Smad3 signaling pathway is inhibited, whereas two mitogen-activated protein kinase (MAPK) pathways, p38 and extracellular signal-regulated kinase (ERK), are activated by Gal-1, indicating that Gal-1 regulates these signaling pathways in COL1 production. Using specific inhibitors of Smad3, ERK, and p38 MAPK, we showed that ERK MAPK activated by Gal-1 plays an inhibitory role in COL1 transcription and that activation of the p38 MAPK pathway by Gal-1 plays a negative role in MMP1 production. Taken together, two MAPK pathways are stimulated by increasing levels of Gal-1 in the HG condition, leading to suppression of COL1 expression and increase of MMP1 expression.

  17. Inhibition of G0/G1 Switch 2 Ameliorates Renal Inflammation in Chronic Kidney Disease

    Directory of Open Access Journals (Sweden)

    Naoya Matsunaga

    2016-11-01

    Full Text Available Chronic kidney disease (CKD is a global health problem, and novel therapies to treat CKD are urgently needed. Here, we show that inhibition of G0/G1 switch 2 (G0s2 ameliorates renal inflammation in a mouse model of CKD. Renal expression of chemokine (C-C motif ligand 2 (Ccl2 was increased in response to p65 activation in the kidneys of wild-type 5/6 nephrectomy (5/6Nx mice. Moreover, 5/6Nx Clk/Clk mice, which carry homozygous mutations in the gene encoding circadian locomotor output cycles kaput (CLOCK, did not exhibit aggravation of apoptosis or induction of F4/80-positive cells. The renal expression of G0s2 in wild-type 5/6Nx mice was important for the transactivation of Ccl2 by p65. These pathologies were ameliorated by G0s2 knockdown. Furthermore, a novel small-molecule inhibitor of G0s2 expression was identified by high-throughput chemical screening, and the inhibitor suppressed renal inflammation in 5/6Nx mice. These findings indicated that G0s2 inhibitors may have applications in the treatment of CKD.

  18. Chinese herbal medicine Shenqi Detoxification Granule inhibits fibrosis in adenine induced chronic renal failure rats.

    Science.gov (United States)

    Peng, Min; Cai, Pingping; Ma, Hongbo; Meng, Hongyan; Xu, Yuan; Zhang, Xiaoyi; Si, Guomin

    2014-01-01

    Progressive fibrosis accompanies all chronic renal disease, connective tissue growth factor (CTGF,) and platelet-derived growth factor-B, (PDGF-B,) play important roles in extra-cellular matrix abnormal accumulation, while endothelin-1 (ET-1) nitric oxide (NO,) are related to endothelial dysfunction, which mediates the progression of renal fibrosis. Shenqi Detoxification Granule (SDG), a traditional Chinese herbal formula, has been used for treatment of chronic renal failure in clinic for many years. In order to evaluate the efficacy, and explore the mechanism of SDG to inhibit the progression of renal fibrosis, study was carried out using the adenine-induced Wister rats as the CRF model, and losartan as postive control drug. Levels of serum creatinine [Scr], and blood urea nitrogen (BUN), albumin (ALB), 24hrs, urine protein (24hUP), triacylglycerol (TG), and cholesterol (CHO), together with ET-1, and NO were detected. Pathological changes of renal tissues were observed by HE, staining. In addition, CTGF and PDGF-B expression were analyzed by immuno-histo-chemistry. The results indicated that SDG can effectively reduce Scr, BUN, 24hUP, TG, and CHO levels, increase ALB levels, inhibit renal tissue damage in CRF rats, and the mechanism maybe reduce PDGF-B, CTGF expression and ET-1/NO. Shenqi Detoxification Granule is a beneficial treatment for chronic renal failure.

  19. GSTA3 Attenuates Renal Interstitial Fibrosis by Inhibiting TGF-Beta-Induced Tubular Epithelial-Mesenchymal Transition and Fibronectin Expression.

    Directory of Open Access Journals (Sweden)

    Yun Xiao

    Full Text Available Tubular epithelial-mesenchymal transition (EMT has been widely accepted as the underlying mechanisms of renal interstitial fibrosis (RIF. The production of reactive oxygen species (ROS plays a vital role in tubular EMT process. The purpose of this study was to investigate the involved molecular mechanisms in TGF-beta-induced EMT and identify the potential role of glutathione S-transferase alpha 3 (GSTA3 in this process. The iTRAQ screening was performed to identify protein alterations of the rats underwent unilateral-ureteral obstruction (UUO. Protein expression of GSTA3 in patients with obstructive nephropathy and UUO rats was detected by immunohistochemistry. Protein and mRNA expression of GSTA3 in UUO rats and NRK-52E cells were determined by Western blot and RT-PCR. siRNA and overexpression plasmid were transfected specifically to assess the role of GSTA3 in RIF. The generation of ROS was measured by dichlorofluorescein fluorescence analysis. GSTA3 protein and mRNA expression was significantly reduced in UUO rats. Immunohistochemical analysis revealed that GSTA3 expression was reduced in renal cortex in UUO rats and patients with obstructive nephropathy. Treating with TGF-β1 down-regulated GSTA3 expression in NRK-52E cells, which have been found to be correlated with the decreased expression in E-cadherin and megalin and increased expression in α-smooth muscle actin. Furthermore, knocking down GSTA3 in NRK-52 cells led to increased production of ROS and tubular EMT, whereas overexpressing GSTA3 ameliorated ROS production and prevented the occurrence of tubular EMT. GSTA3 plays a protective role against tubular EMT in renal fibrosis, suggesting GSTA3 is a potential therapeutic target for RIF.

  20. Amelioration of Gamma-hexachlorocyclohexane (Lindane induced renal toxicity by Camellia sinensis in Wistar rats

    Directory of Open Access Journals (Sweden)

    W. L. N. V. Vara Prasad

    2016-11-01

    Full Text Available Aim: A study to assess the toxic effects of gamma-hexachlorocyclohexane (γ-HCH (lindane and ameliorative effects of Camellia sinensis on renal system has been carried out in male Wistar rats. Materials and Methods: Four groups of rats with 18 each were maintained under standard laboratory hygienic conditions and provided feed and water ad libitum. γ-HCH was gavaged at 20 mg/kg b.wt. using olive oil as vehicle to Groups II. C. sinensis at 100 mg/kg b.wt. was administered orally in distilled water to Group IV in addition to γ-HCH 20 mg/kg b.wt. up to 45 days to study ameliorative effects. Groups I and III were treated with distilled water and C. sinensis (100 mg/kg b.wt., respectively. Six rats from each group were sacrificed at fortnight intervals. Serum was collected for creatinine estimation. The kidney tissues were collected in chilled phosphate buffer saline for antioxidant profile and in also 10% buffered formalin for histopathological studies. Results: γ-HCH treatment significantly increased serum creatinine and significantly reduced the renal antioxidative enzymes catalase, superoxide dismutase, and glutathione peroxidase. Grossly, severe congestion was noticed in the kidneys. Microscopically, kidney revealed glomerular congestion, atrophy, intertubular hemorrhages, degenerative changes in tubular epithelium with vacuolated cytoplasm, desquamation of epithelium and urinary cast formation. A significant reduction in serum creatinine levels, significant improvement in renal antioxidant enzyme activities and near to normal histological appearance of kidneys in Group IV indicated that the green tea ameliorated the effects of γ-HCH, on renal toxicity. Conclusion: This study suggested that C. sinensis extract combined with γ-HCH could enhance antioxidant/detoxification system which consequently reduced the oxidative stress thus potentially reducing γ-HCH toxicity and tissue damage.

  1. Cordyceps cicadae extracts ameliorate renal malfunction in a remnant kidney model*

    Science.gov (United States)

    Zhu, Rong; Chen, Yi-ping; Deng, Yue-yi; Zheng, Rong; Zhong, Yi-fei; Wang, Lin; Du, Lan-ping

    2011-01-01

    Background and Objectives: Chronic kidney disease (CKD) is a growing public health problem with an urgent need for new pharmacological agents. Cordyceps cicadae is widely used in traditional Chinese medicine (TCM) and has potential renoprotective benefits. The current study aimed to determine any scientific evidence to support its clinical use. Methods: We analyzed the potential of two kinds of C. cicadae extract, total extract (TE) and acetic ether extract (AE), in treating kidney disease simulated by a subtotal nephrectomy (SNx) model. Sprague-Dawley rats were divided randomly into seven groups: sham-operated group, vehicle-treated SNx, Cozaar, 2 g/(kg∙d) TE SNx, 1 g/(kg∙d) TE SNx, 92 mg/(kg∙d) AE SNx, and 46 mg/(kg∙d) AE SNx. Renal injury was monitored using urine and serum analyses, and hematoxylin and eosin (HE) and periodic acid-Schiff (PAS) stainings were used to analyze the level of fibrosis. The expression of type IV collagen (Col IV), fibronectin (FN), transforming growth factor-β1 (TGF-β1), and connective tissue growth factor (CTGF) was detected by immunohistochemistry. Results: Renal injury, reflected in urine and serum analyses, and pathological changes induced by SNx were attenuated by TE and AE intervention. The depositions of Col IV and FN were also decreased by the treatments and were accompanied by reduced expression of TGF-β1 and CTGF. In some respects, 2 g/(kg∙d) of TE produced better effects than Cozaar. Conclusions: For the first time, we have shown that C. cicadae may inhibit renal fibrosis in vivo through the TGF-β1/CTGF pathway. Therefore, we conclude that the use of C. cicadae could provide a rational strategy for combating renal fibrosis. PMID:22135152

  2. Cordyceps cicadae extracts ameliorate renal malfunction in a remnant kidney model.

    Science.gov (United States)

    Zhu, Rong; Chen, Yi-ping; Deng, Yue-yi; Zheng, Rong; Zhong, Yi-fei; Wang, Lin; Du, Lan-ping

    2011-12-01

    Chronic kidney disease (CKD) is a growing public health problem with an urgent need for new pharmacological agents. Cordyceps cicadae is widely used in traditional Chinese medicine (TCM) and has potential renoprotective benefits. The current study aimed to determine any scientific evidence to support its clinical use. We analyzed the potential of two kinds of C. cicadae extract, total extract (TE) and acetic ether extract (AE), in treating kidney disease simulated by a subtotal nephrectomy (SNx) model. Sprague-Dawley rats were divided randomly into seven groups: sham-operated group, vehicle-treated SNx, Cozaar, 2 g/(kg∙d) TE SNx, 1 g/(kg∙d) TE SNx, 92 mg/(kg∙d) AE SNx, and 46 mg/(kg∙d) AE SNx. Renal injury was monitored using urine and serum analyses, and hematoxylin and eosin (HE) and periodic acid-Schiff (PAS) stainings were used to analyze the level of fibrosis. The expression of type IV collagen (Col IV), fibronectin (FN), transforming growth factor-β1 (TGF-β1), and connective tissue growth factor (CTGF) was detected by immunohistochemistry. Renal injury, reflected in urine and serum analyses, and pathological changes induced by SNx were attenuated by TE and AE intervention. The depositions of Col IV and FN were also decreased by the treatments and were accompanied by reduced expression of TGF-β1 and CTGF. In some respects, 2 g/(kg∙d) of TE produced better effects than Cozaar. For the first time, we have shown that C. cicadae may inhibit renal fibrosis in vivo through the TGF-β1/CTGF pathway. Therefore, we conclude that the use of C. cicadae could provide a rational strategy for combating renal fibrosis.

  3. Assessment of renal fibrosis in chronic kidney disease using diffusion-weighted MRI

    International Nuclear Information System (INIS)

    Zhao, J.; Wang, Z.J.; Liu, M.; Zhu, J.; Zhang, X.; Zhang, T.; Li, S.; Li, Y.

    2014-01-01

    Aim: To assess the performance of diffusion-weighted magnetic resonance imaging (MRI) for the assessment of renal fibrosis in chronic kidney disease (CKD), with histopathology as a reference standard. Materials and methods: Forty patients with CKD and 30 healthy volunteers were recruited for the study. All participants underwent diffusion-weighted MRI. Renal biopsy was performed in 25 patients with CKD. Mean renal medullary and cortical apparent diffusion coefficient (ADC) values were compared between CKD patients and the healthy volunteers. Pearson's correlation coefficient was calculated to investigate the relationship between ADC values, serum creatinine (SCr), estimated glomerular filtration rate (eGFR), 24 h urinary protein (24h-UPRO), and renal histopathological scores. Results: Cortical and medullary ADC values in the CKD group were significantly lower compared to those in the healthy controls. In the CKD group, a significant negative correlation was found between cortical ADC values and SCr/24h-UPRO, and significant positive correlation was found between cortical ADC and eGFR. There was also a significant negative correlation between medullary ADC values and SCr. Both cortical and medullary ADC values were significantly correlated with histopathological fibrosis score. Conclusion: Renal ADC values strongly correlate with histological measures of fibrosis, and have the potential to enhance the non-invasive monitoring of chronic kidney disease. - Highlights: • Renal ADC values in the CKD patients were lower than those in controls. • Renal ADC values were strongly correlated with histological fibrosis score. • Renal ADC values have the potential to enhance the noninvasive monitoring of CKD

  4. [Autosomal-recessive renal cystic disease and congenital hepatic fibrosis: clinico-anatomic case].

    Science.gov (United States)

    Rostol'tsev, K V; Burenkov, R A; Kuz'micheva, I A

    2012-01-01

    Clinico-anatomic observation of autosomal-recessive renal cystic disease and congenital hepatic fibrosis at two fetuses from the same family was done. Mutation of His3124Tyr in 58 exon of PKHD1 gene in heterozygous state was found out. The same pathomorphological changes in the epithelium of cystic renal tubules and bile ducts of the liver were noted. We suggest that the autopsy research of fetuses with congenital abnormalities, detected after prenatal ultrasonic screening, has high diagnostic importance.

  5. Treatment with 4-methylpyrazole modulated stellate cells and natural killer cells and ameliorated liver fibrosis in mice.

    Directory of Open Access Journals (Sweden)

    Hyon-Seung Yi

    Full Text Available Accumulating evidence suggests that retinol and its metabolites are closely associated with liver fibrogenesis. Recently, we demonstrated that genetic ablation of alcohol dehydrogenase 3 (ADH3, a retinol metabolizing gene that is expressed in hepatic stellate cells (HSCs and natural killer (NK cells, attenuated liver fibrosis in mice. In the current study, we investigated whether pharmacological ablation of ADH3 has therapeutic effects on experimentally induced liver fibrosis in mice.Liver fibrosis was induced by intraperitoneal injections of carbon tetrachloride (CCl4 or bile duct ligation (BDL for two weeks. To inhibit ADH3-mediated retinol metabolism, 10 μg 4-methylpyrazole (4-MP/g of body weight was administered to mice treated with CCl4 or subjected to BDL. The mice were sacrificed at week 2 to evaluate the regression of liver fibrosis. Liver sections were stained for collagen and α-smooth muscle actin (α-SMA. In addition, HSCs and NK cells were isolated from control and treated mice livers for molecular and immunological studies.Treatment with 4-MP attenuated CCl4- and BDL-induced liver fibrosis in mice, without any adverse effects. HSCs from 4-MP treated mice depicted decreased levels of retinoic acids and increased retinol content than HSCs from control mice. In addition, the expression of α-SMA, transforming growth factor-β1 (TGF-β1, and type I collagen α1 was significantly reduced in the HSCs of 4-MP treated mice compared to the HSCs from control mice. Furthermore, inhibition of retinol metabolism by 4-MP increased interferon-γ production in NK cells, resulting in increased apoptosis of activated HSCs.Based on our data, we conclude that inhibition of retinol metabolism by 4-MP ameliorates liver fibrosis in mice through activation of NK cells and suppression of HSCs. Therefore, retinol and its metabolizing enzyme, ADH3, might be potential targets for therapeutic intervention of liver fibrosis.

  6. Identification of key metabolic changes in renal interstitial fibrosis rats using metabonomics and pharmacology.

    Science.gov (United States)

    Zhao, Liangcai; Dong, Minjian; Liao, Shixian; Du, Yao; Zhou, Qi; Zheng, Hong; Chen, Minjiang; Ji, Jiansong; Gao, Hongchang

    2016-06-03

    Renal fibrosis is one of the important pathways involved in end-stage renal failure. Investigating the metabolic changes in the progression of disease may enhance the understanding of its pathogenesis and therapeutic information. In this study, (1)H-nuclear magnetic resonance (NMR)-based metabonomics was firstly used to screen the metabolic changes in urine and kidney tissues of renal interstitial fibrotic rats induced by unilateral ureteral obstruction (UUO), at 7, 14, 21, and 28 days after operation, respectively. The results revealed that reduced levels of bioenergy synthesis and branched chain amino acids (BCAAs), as well as elevated levels of indoxyl sulfate (IS) are involved in metabolic alterations of renal fibrosis rats. Next, by pharmacological treatment we found that reduction of IS levels could prevent the renal fibrotic symptoms. Therefore, we suggested that urinary IS may be used as a potential biomarker for the diagnosis of renal fibrosis, and a therapeutic target for drugs. Novel attempt combining metabonomics and pharmacology was established that have ability to provide more systematic diagnostic and therapeutic information of diseases.

  7. New strategy for renal fibrosis: Targeting Smad3 proteins for ubiquitination and degradation.

    Science.gov (United States)

    Wang, Xin; Feng, Shaozhen; Fan, Jinjin; Li, Xiaoyan; Wen, Qiong; Luo, Ning

    2016-09-15

    Smad3 is a critical signaling protein in renal fibrosis. Proteolysis targeting chimeric molecules (PROTACs) are small molecules designed to degrade target proteins via ubiquitination. They have three components: (1) a recognition motif for E3 ligase; (2) a linker; and (3) a ligand for the target protein. We aimed to design a new PROTAC to prevent renal fibrosis by targeting Smad3 proteins and using hydroxylated pentapeptide of hypoxia-inducible factor-1α as the recognition motif for von Hippel-Lindau (VHL) ubiquitin ligase (E3). Computer-aided drug design was used to find a specific ligand targeting Smad3. Surface plasmon resonance (SPR) was used to verify and optimize screening results. Synthesized PROTAC was validated by two-stage mass spectrometry. The PROTAC's specificity for VHL (E3 ligase) was proved with two human renal carcinoma cell lines, 786-0 (VHL(-)) and ACHN (VHL(+)), and its anti-fibrosis effect was tested in renal fibrosis cell models. Thirteen small molecular compounds (SMCs) were obtained from the Enamine library using GLIDE molecular docking program. SPR results showed that #8 SMC (EN300-72284) combined best with Smad3 (KD=4.547×10(-5)M). Mass spectrometry showed that synthesized PROTAC had the correct peptide molecular weights. Western blot showed Smad3 was degraded by PROTAC with whole-cell lysate of ACHN but not 786-0. Degradation, but not ubiquitination, of Smad3 was inhibited by proteasome inhibitor MG132. The upregulation of fibronectin and Collagen I induced by TGF-β1 in both renal fibroblast and mesangial cells were inhibited by PROTAC. The new PROTAC might prevent renal fibrosis by targeting Smad3 for ubiquitination and degradation. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. Amelioration of renal lesions associated with diabetes by dietary curcumin in streptozotocin diabetic rats.

    Science.gov (United States)

    Suresh Babu, P; Srinivasan, K

    1998-04-01

    Curcumin, the coloring principle of the commonly used spice turmeric (Curcuma longa) was fed at 0.5% in the diet to streptozotocin-induced diabetic Wistar rats for 8 weeks. Renal damage was assessed by the amount of proteins excreted in the urine and the extent of leaching of renal tubular enzymes: NAG, LDH, AsAT, AlAT, alkaline and acid phosphatases. The integrity of kidney was assessed by measuring the activities of several key enzymes of the renal tissue: glucose-6-phosphate dehydrogenase, glucose-6-phosphatase, and LDH (Carbohydrate metabolism), aldose reductase and sorbitol dehydrogenase (polyol pathway), transaminases, ATPases and membrane PUFA/SFA ratio (membrane integrity). Data on enzymuria, albuminuria, activity of kidney ATPases and fatty acid composition of renal membranes in diabetic condition suggested that dietary curcumin brought about significant beneficial modulation of the progression of renal lesions in diabetes. These findings were also corroborated by histological examination of kidney sections. It is inferred that this beneficial ameliorating influence of dietary curcumin on diabetic nephropathy is possibly mediated through its ability to lower blood cholesterol levels.

  9. Interferon gamma peptidomimetic targeted to interstitial myofibroblasts attenuates renal fibrosis after unilateral ureteral obstruction in mice

    NARCIS (Netherlands)

    Poosti, Fariba; Bansal, Ruchi; Yazdani, Saleh; Prakash, Jai; Beljaars, Leonie; van den Born, Jacob; de Borst, Martin H.; van Goor, Harry; Hillebrands, Jan-Luuk; Poelstra, Klaas

    2016-01-01

    Renal fibrosis cannot be adequately treated since anti-fibrotic treatment is lacking. Interferon-gamma is a pro-inflammatory cytokine with anti-fibrotic properties. Clinical use of interferon-gamma is hampered due to inflammation-mediated systemic side effects. We used an interferon-gamma

  10. The Role of Toll-Like Receptor 2 in Inflammation and Fibrosis during Progressive Renal Injury

    NARCIS (Netherlands)

    Leemans, Jaklien C.; Butter, Loes M.; Pulskens, Wilco P. C.; Teske, Gwendoline J. D.; Claessen, Nike; van der Poll, Tom; Florquin, Sandrine

    2009-01-01

    Tissue fibrosis and chronic inflammation are common causes of progressive organ damage, including progressive renal disease, leading to loss of physiological functions. Recently, it was shown that Toll-like receptor 2 (TLR2) is expressed in the kidney and activated by endogenous danger signals. The

  11. The cytoskeleton as a novel target for treatment of renal fibrosis.

    Science.gov (United States)

    Parrish, Alan R

    2016-10-01

    The incidence of chronic kidney disease (CKD) is increasing, with an estimated prevalence of 12% in the United States (Synder et al., 2009). While CKD may progress to end-stage renal disease (ESRD), which necessitates renal replacement therapy, i.e. dialysis or transplantation, most CKD patients never reach ESRD due to the increased risk of death from cardiovascular disease. It is well-established that regardless of the initiating insult - most often diabetes or hypertension - fibrosis is the common pathogenic pathway that leads to progressive injury and organ dysfunction (Eddy, 2014; Duffield, 2014). As such, there has been extensive research into the molecular and cellular mechanisms of renal fibrosis; however, translation to effective therapeutic strategies has been limited. While a role for the disruption of the cytoskeleton, most notably the actin network, has been established in acute kidney injury over the past two decades, a role in regulating renal fibrosis and CKD is only recently emerging. This review will focus on the role of the cytoskeleton in regulating pro-fibrotic pathways in the kidney, as well as data suggesting that these pathways represent novel therapeutic targets to manage fibrosis and ultimately CKD. Copyright © 2016. Published by Elsevier Inc.

  12. Angiopoietin-like protein 2 increases renal fibrosis by accelerating transforming growth factor-β signaling in chronic kidney disease.

    Science.gov (United States)

    Morinaga, Jun; Kadomatsu, Tsuyoshi; Miyata, Keishi; Endo, Motoyoshi; Terada, Kazutoyo; Tian, Zhe; Sugizaki, Taichi; Tanigawa, Hiroki; Zhao, Jiabin; Zhu, Shunshun; Sato, Michio; Araki, Kimi; Iyama, Ken-ichi; Tomita, Kengo; Mukoyama, Masashi; Tomita, Kimio; Kitamura, Kenichiro; Oike, Yuichi

    2016-02-01

    Renal fibrosis is a common pathological consequence of chronic kidney disease (CKD) with tissue fibrosis closely associated with chronic inflammation in numerous pathologies. However, molecular mechanisms underlying that association, particularly in the kidney, remain unclear. Here, we determine whether there is a molecular link between chronic inflammation and tissue fibrosis in CKD progression. Histological analysis of human kidneys indicated abundant expression of angiopoietin-like protein 2 (ANGPTL2) in renal tubule epithelial cells during progression of renal fibrosis. Numerous ANGPTL2-positive renal tubule epithelial cells colocalized with cells positive for transforming growth factor (TGF)-β1, a critical mediator of tissue fibrosis. Analysis of M1 collecting duct cells in culture showed that TGF-β1 increases ANGPTL2 expression by attenuating its repression through microRNA-221. Conversely, ANGPTL2 increased TGF-β1 expression through α5β1 integrin-mediated activation of extracellular signal-regulated kinase. Furthermore, ANGPTL2 deficiency in a mouse unilateral ureteral obstruction model significantly reduced renal fibrosis by decreasing TGF-β1 signal amplification in kidney. Thus, ANGPTL2 and TGF-β1 positively regulate each other as renal fibrosis progresses. Our study provides insight into molecular mechanisms underlying chronic inflammation and tissue fibrosis and identifies potential therapeutic targets for CKD treatment. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

  13. Pharmacokinetics and pharmacodynamics study of rhein treating renal fibrosis based on metabonomics approach.

    Science.gov (United States)

    Sun, Hao; Luo, Guangwen; Xiang, Zheng; Cai, Xiaojun; Chen, Dahui

    2016-12-01

    The selection of effect indicators in the pharmacokinetic/ pharmacodynamic study of complex diseases to describe the relationship between plasma concentration and effect indicators is difficult. Three effect indicators of renal fibrosis were successfully determined. The relationship between pharmacokinetics and pharmacodynamics of rhein in rhubarb was elucidated. The study was a metabolomics analysis of rat plasma and pharmacokinetics/ pharmacodynamics of rhein. A sensitive and simple ultra performance liquid chromatography-tandem triple quadrupole mass spectrometry (UPLC-MS/MS) method was applied to determine the rhein plasma concentration in the rat model of renal fibrosis and rat sham-operated group after the administration of rhubarb decoction. Then, the ultra performance liquid chromatography-Micromass quadrupole-time of flight mass spectrometry (UPLC-QTOF/MS) metabolomics method was used to screen biomarkers of renal fibrosis in rat plasma. Furthermore, the relationship between the plasma concentration of rhein and the concentration of three biomarkers directly related to renal fibrosis were analyzed. The three screened biomarkers could represent the effect of rhein treatment on renal fibrosis. Increasing the plasma concentration of rhein tended to restore the concentration of the three biomarkers in the model group compared with that in the sham-operated group. Evident differences in the area under the plasma concentration-time curve (AUC) of rhein were also observed under different pathological states. The results provide valuable information for the clinical application of rhubarb. Rhein intervention could recover the physiological balance in living organisms from the pharmacokinetic/pharmacodynamic levels. New information on the pharmacokinetic/pharmacodynamic study of complex diseases is provided. Copyright © 2016 Elsevier GmbH. All rights reserved.

  14. L-Endoglin Overexpression Increases Renal Fibrosis after Unilateral Ureteral Obstruction

    Science.gov (United States)

    Arévalo, Miguel; Núñez-Gómez, Elena; Pérez-Roque, Lucía; Pericacho, Miguel; González-Núñez, María; Langa, Carmen; Martínez-Salgado, Carlos; Perez-Barriocanal, Fernando; Bernabeu, Carmelo; Lopez-Novoa, José M.

    2014-01-01

    Transforming growth factor-β (TGF-β) plays a pivotal role in renal fibrosis. Endoglin, a 180 KDa membrane glycoprotein, is a TGF-β co-receptor overexpressed in several models of chronic kidney disease, but its function in renal fibrosis remains uncertain. Two membrane isoforms generated by alternative splicing have been described, L-Endoglin (long) and S-Endoglin (short) that differ from each other in their cytoplasmic tails, being L-Endoglin the most abundant isoform. The aim of this study was to assess the effect of L-Endoglin overexpression in renal tubulo-interstitial fibrosis. For this purpose, a transgenic mouse which ubiquitously overexpresses human L-Endoglin (L-ENG+) was generated and unilateral ureteral obstruction (UUO) was performed in L-ENG+ mice and their wild type (WT) littermates. Obstructed kidneys from L-ENG+ mice showed higher amounts of type I collagen and fibronectin but similar levels of α-smooth muscle actin (α-SMA) than obstructed kidneys from WT mice. Smad1 and Smad3 phosphorylation were significantly higher in obstructed kidneys from L-ENG+ than in WT mice. Our results suggest that the higher increase of renal fibrosis observed in L-ENG+ mice is not due to a major abundance of myofibroblasts, as similar levels of α-SMA were observed in both L-ENG+ and WT mice, but to the higher collagen and fibronectin synthesis by these fibroblasts. Furthermore, in vivo L-Endoglin overexpression potentiates Smad1 and Smad3 pathways and this effect is associated with higher renal fibrosis development. PMID:25313562

  15. Inhibition of soluble epoxide hydrolase lowers portal hypertension in cirrhotic rats by ameliorating endothelial dysfunction and liver fibrosis.

    Science.gov (United States)

    Deng, Wensheng; Zhu, Yiming; Lin, Jiayun; Zheng, Lei; Zhang, Chihao; Luo, Meng

    2017-07-01

    Epoxyeicostrienoic acids (EETs) are arachidonic acid derived meditators which are catalyzed by soluble epoxide hydrolase (sEH) to less active dihydroeicostrienoics acids (DHETS). The aim of our study is to investigate the effects of sEH inhibition on hepatic and systemic hemodynamics, hepatic endothelial dysfunction, and hepatic fibrosis in CCl4 cirrhotic rats. The sEH inhibitor,trans-4-{4-[3-(4-trifluoromethoxyphenyl)-ureido]cyclohexyloxy}benzoic acid (t-TUCB) was administered to stabilize hepatic EETs by gavage at a dose of 1mg/kg/d. Our results showed that hepatic sEH expression was markedly increased in portal hypertension, and led to a lower ratio of EETs/DHETs which was effectively reversed by t-TUCB administration. t-TUCB significantly decreased portal pressure without significant changes in systemic hemodynamics, which was associated with the attenuation of intrahepatic vascular resistance (IHVR) and liver fibrosis. t-TUCB ameliorated endothelial dysfunction, increased hepatic endothelial nitric oxide synthase (eNOS) phosphorylation and nitric oxide (NO) production. In addition, t-TUCB significantly reduced alpha-Smooth Muscle Actin (α-SMA) expression and liver fibrosis, which was associated with a decrease in NF-κB signaling. Taken together, inhibition of sEH reduces portal pressure, liver fibrosis and attenuates hepatic endothelial dysfunction in cirrhotic rats. Our results indicate that sEH inhbitors may be useful in the treatment of portal hypertension in patients with cirrhosis. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Selective inhibitor of Wnt/β-catenin/CBP signaling ameliorates hepatitis C virus-induced liver fibrosis in mouse model.

    Science.gov (United States)

    Tokunaga, Yuko; Osawa, Yosuke; Ohtsuki, Takahiro; Hayashi, Yukiko; Yamaji, Kenzaburo; Yamane, Daisuke; Hara, Mitsuko; Munekata, Keisuke; Tsukiyama-Kohara, Kyoko; Hishima, Tsunekazu; Kojima, Soichi; Kimura, Kiminori; Kohara, Michinori

    2017-03-23

    Chronic hepatitis C virus (HCV) infection is one of the major causes of serious liver diseases, including liver cirrhosis. There are no anti-fibrotic drugs with efficacy against liver cirrhosis. Wnt/β-catenin signaling has been implicated in the pathogenesis of a variety of tissue fibrosis. In the present study, we investigated the effects of a β-catenin/CBP (cyclic AMP response element binding protein) inhibitor on liver fibrosis. The anti-fibrotic activity of PRI-724, a selective inhibitor of β-catenin/CBP, was assessed in HCV GT1b transgenic mice at 18 months after HCV genome expression. PRI-724 was injected intraperitoneally or subcutaneously in these mice for 6 weeks. PRI-724 reduced liver fibrosis, which was indicated by silver stain, Sirius Red staining, and hepatic hydroxyproline levels, in HCV mice while attenuating αSMA induction. PRI-724 led to increased levels of matrix metalloproteinase (MMP)-8 mRNA in the liver, along with elevated levels of intrahepatic neutrophils and macrophages/monocytes. The induced intrahepatic neutrophils and macrophages/monocytes were identified as the source of MMP-8. In conclusion, PRI-724 ameliorated HCV-induced liver fibrosis in mice. We hypothesize that inhibition of hepatic stellate cells activation and induction of fibrolytic cells expressing MMP-8 contribute to the anti-fibrotic effects of PRI-724. PRI-724 is a drug candidate which possesses anti-fibrotic effect.

  17. Lycium chinense leaves extract ameliorates diabetic nephropathy by suppressing hyperglycemia mediated renal oxidative stress and inflammation.

    Science.gov (United States)

    Olatunji, Opeyemi Joshua; Chen, Hongxia; Zhou, Yifeng

    2018-06-01

    Diabetic nephropathy is one of the most serious and most frequently encountered diabetic complication, accounting for the highest cause of end-stage renal disease. This present study was aimed at exploring the protective/attenuative effect of Lycium chinense leaf extract (MELC) on streptozotocin induced diabetic nephropathy in experimental Sprague Dawley rats. The oral administration of diabetic rats with MELC markedly ameliorated renal dysfunction as observed in the significant reduction in the serum levels of creatinine, blood urea nitrogen (BUN), albumin and TGF-β1 as compared to the untreated diabetic control rats. In addition, the elevated levels of renal oxidative stress markers and pro-inflammatory parameters (GSH, SOD, CAT, MDA, TNF-α, IL-6 and IL-1β) were significantly reduced in MELC treated diabetic rats. The results obtained in this study suggests that L. chinense leaf might have the potential as possible pharmacological agent against diabetic nephropathy by suppressing renal oxidative stress and inflammation. Copyright © 2018. Published by Elsevier Masson SAS.

  18. Deficiency of the Erc/mesothelin gene ameliorates renal carcinogenesis in Tsc2 knockout mice.

    Science.gov (United States)

    Zhang, Danqing; Kobayashi, Toshiyuki; Kojima, Tetsuo; Kanenishi, Kenji; Hagiwara, Yoshiaki; Abe, Masaaki; Okura, Hidehiro; Hamano, Yoshitomo; Sun, Guodong; Maeda, Masahiro; Jishage, Kou-ichi; Noda, Tetsuo; Hino, Okio

    2011-04-01

    Genetic crossing experiments were performed between tuberous sclerosis-2 (Tsc2) KO and expressed in renal carcinoma (Erc) KO mice to analyze the function of the Erc/mesothelin gene in renal carcinogenesis. We found the number and size of renal tumors were significantly less in Tsc2+/-;Erc-/- mice than in Tsc2+/-;Erc+/+ and Tsc2+/-;Erc+/- mice. Tumors from Tsc2+/-;Erc-/- mice exhibited reduced cell proliferation and increased apoptosis, as determined by proliferating cell nuclear antigen (Ki67) and TUNEL analysis, respectively. Adhesion to collagen-coated plates in vitro was enhanced in Erc-restored cells and decreased in Erc-suppressed cells with siRNA. Tumor formation by Tsc2-deficient cells in nude mice was remarkably suppressed by stable knockdown of Erc with shRNA. Western blot analysis showed that the phosphorylation of focal adhesion kinase, Akt and signal transducer and activator of transcription protein 3 were weaker in Erc-deficient/suppressed cells compared with Erc-expressed cells. These results indicate that deficiency of the Erc/mesothelin gene ameliorates renal carcinogenesis in Tsc2 KO mice and inhibits the phosphorylation of several kinases of cell adhesion mechanism. This suggests that Erc/mesothelin may have an important role in the promotion and/or maintenance of carcinogenesis by influencing cell-substrate adhesion via the integrin-related signal pathway. © 2011 Japanese Cancer Association.

  19. Resveratrol, an Nrf2 activator, ameliorates aging-related progressive renal injury.

    Science.gov (United States)

    Kim, Eun Nim; Lim, Ji Hee; Kim, Min Young; Ban, Tae Hyun; Jang, In-Ae; Yoon, Hye Eun; Park, Cheol Whee; Chang, Yoon Sik; Choi, Bum Soon

    2018-01-11

    Two important issues in the aging kidney are mitochondrial dysfunction and oxidative stress. An Nrf2 activator, resveratrol, is known to have various effects. Resveratrol may prevent inflammation and oxidative stress by activating Nrf2 and SIRT1 signaling. We examined whether resveratrol could potentially ameliorate the cellular condition, such as renal injury due to cellular oxidative stress and mitochondrial dysfunction caused by aging. Male 18-month-old C57BL/6 mice were used. Resveratrol (40 mg/kg) was administered to aged mice for 6 months. We compared histological changes, oxidative stress, and aging-related protein expression in the kidney between the resveratrol-treated group (RSV) and the control group (cont). We performed experiments using small-interfering RNAs (siRNAs) for Nrf2 and SIRT1 in cultured HK2 cells. Resveratrol improved renal function, proteinuria, histological changes and inflammation in aging mice. Also, expression of Nrf2-HO-1-NOQ-1 signaling and SIRT1-AMPK-PGC-1α signaling was increased in the RSV group. Transfection with Nrf2 and SIRT1 siRNA prevented resveratrol-induced anti-oxidative effect in HK2 cells in media treated with H 2 O 2 . Activation of the Nrf2 and SIRT1 signaling pathways ameliorated oxidative stress and mitochondrial dysfunction. Pharmacological targeting of Nrf2 signaling molecules may reduce the pathologic changes of aging in the kidney.

  20. Cardiac fibrosis and dysfunction in experimental diabetic cardiomyopathy are ameliorated by alpha-lipoic acid

    Directory of Open Access Journals (Sweden)

    Li Chun-jun

    2012-06-01

    Full Text Available Abstract Background Alpha-lipoic acid (ALA, a naturally occurring compound, exerts powerful protective effects in various cardiovascular disease models. However, its role in protecting against diabetic cardiomyopathy (DCM has not been elucidated. In this study, we have investigated the effects of ALA on cardiac dysfunction, mitochondrial oxidative stress (MOS, extracellular matrix (ECM remodeling and interrelated signaling pathways in a diabetic rat model. Methods Diabetes was induced in rats by I.V. injection of streptozotocin (STZ at 45 mg/kg. The animals were randomly divided into 4 groups: normal groups with or without ALA treatment, and diabetes groups with or without ALA treatment. All studies were carried out 11 weeks after induction of diabetes. Cardiac catheterization was performed to evaluate cardiac function. Mitochondrial oxidative biochemical parameters were measured by spectophotometeric assays. Extracellular matrix content (total collagen, type I and III collagen was assessed by staining with Sirius Red. Gelatinolytic activity of Pro- and active matrix metalloproteinase-2 (MMP-2 levels were analyzed by a zymogram. Cardiac fibroblasts differentiation to myofibroblasts was evaluated by Western blot measuring smooth muscle actin (α-SMA and transforming growth factor–β (TGF-β. Key components of underlying signaling pathways including the phosphorylation of c-Jun N-terminal kinase (JNK, p38 MAPK and ERK were also assayed by Western blot. Results DCM was successfully induced by the injection of STZ as evidenced by abnormal heart mass and cardiac function, as well as the imbalance of ECM homeostasis. After administration of ALA, left ventricular dysfunction greatly improved; interstitial fibrosis also notably ameliorated indicated by decreased collagen deposition, ECM synthesis as well as enhanced ECM degradation. To further assess the underlying mechanism of improved DCM by ALA, redox status and cardiac remodeling associated

  1. Cambios morfológicos, celulares y moleculares en la fibrosis renal debido al envejecimiento

    Directory of Open Access Journals (Sweden)

    Miguel Alaga

    2015-11-01

    Full Text Available En los últimos 50 años se ha registrado un aumento gradual de la tasa de envejecimiento de la población uruguaya, reflejándose en un incremento de pacientes con enfermedad renal crónica mayores de 65 años. Este fenómeno plantea la interrogante de cómo el envejecimiento tisular afecta la función del riñón y, en particular cómo contribuye al desarrollo de la fibrosis renal. Con el envejecimiento se producen cambios morfológicos y funcionales en el riñón, tales como la esclerosis glomerular y la fibrosis intersticial. Estos cambios son consecuencia de alteraciones que ocurren a nivel celular. En este trabajo se profundizará en los mecanismos celulares que desencadenan la fibrosis intersticial y la gloméruloesclerosis, describiendo el proceso de inflamación sostenida, la transformación fenotípica de las células epiteliales a miofibroblastos, así como los mecanismos de producción de matriz extracelular y la perpetuación de la fibrosis renal. Además, detallaremos las cascadas moleculares involucradas en el proceso de fibrosis, poniendo énfasis en las cascadas reguladas por TGF-β1 y sus vías de interacción, que regulan la producción factores pro- y anti-fibróticos. También veremos como el TGF-β1 modula la expresión de ARN pequeños no-codificantes (microARNs, potentes inhibidores de la expresión génica, y como el gen anti-envejecimiento Klotho inhibe el avance de la fibrosis renal. Finalmente, discutiremos terapias para frenar o enlentecer el proceso de fibrosis renal, especialmente aquellas que tengan como blanco las cascadas de señalización activadas por TGF-β1, los microRNAs y posibles terapias de activación del gen Klotho para prevenir la progresión de esta patología.

  2. Recent Advances of Curcumin in the Prevention and Treatment of Renal Fibrosis

    Directory of Open Access Journals (Sweden)

    Xuejiao Sun

    2017-01-01

    Full Text Available Curcumin, a polyphenol derived from the turmeric, has received attention as a potential treatment for renal fibrosis primarily because it is a relatively safe and inexpensive compound that contributes to kidney health. Here, we review the literatures on the applications of curcumin in resolving renal fibrosis in animal models and summarize the mechanisms of curcumin and its analogs (C66 and (1E,4E-1,5-bis(2-bromophenyl penta-1,4-dien-3-one(B06 in preventing inflammatory molecules release and reducing the deposition of extracellular matrix at the priming and activation stage of renal fibrosis in animal models by consulting PubMed and Cnki databases over the past 15 years. Curcumin exerts antifibrotic effect through reducing inflammation related factors (MCP-1, NF-κB, TNF-α, IL-1β, COX-2, and cav-1 and inducing the expression of anti-inflammation factors (HO-1, M6PRBP1, and NEDD4 as well as targeting TGF-β/Smads, MAPK/ERK, and PPAR-γ pathways in animal models. As a food derived compound, curcumin is becoming a promising drug candidate for improving renal health.

  3. Taurine Ameliorates Renal Oxidative Damage and Thyroid Dysfunction in Rats Chronically Exposed to Fluoride.

    Science.gov (United States)

    Adedara, Isaac A; Ojuade, Temini Jesu D; Olabiyi, Bolanle F; Idris, Umar F; Onibiyo, Esther M; Ajeigbe, Olufunke F; Farombi, Ebenezer O

    2017-02-01

    Excessive exposure to fluoride poses several detrimental effects to human health particularly the kidney which is a major organ involved in its elimination from the body. The influence of taurine on fluoride-induced renal toxicity was investigated in a co-exposure paradigm for 45 days using five groups of eight rats each. Group I rats received normal drinking water alone, group II rats were exposed to sodium fluoride (NaF) in drinking water at 15 mg/L alone, group III received taurine alone at a dose of 200 mg/kg group IV rats were co-administered with NaF and taurine (100 mg/kg), while group V rats were co-administered with NaF and taurine (200 mg/kg). Administration of taurine significantly reversed the fluoride-mediated decrease in absolute weight and organo-somatic index of the kidney in the exposed rats. Taurine significantly prevented fluoride-induced elevation in plasma urea and creatinine levels in the exposed rats. Moreover, taurine restored fluoride-mediated decrease in the circulatory concentrations of triiodothyronine, thyroxine, and the ratio of triiodothyronine to thyroxine. Taurine ameliorated fluoride-mediated decrease in renal antioxidant status by significantly enhancing the antioxidant enzyme activities as well as glutathione level in the exposed rats. Additionally, taurine inhibited fluoride-induced renal oxidative damage by markedly decreasing the hydrogen peroxide and malondialdehyde levels as well as improved the kidney architecture in the treated rats. Collectively, taurine protected against fluoride-induced renal toxicity via enhancement of thyroid gland function, renal antioxidant status, and histology in rats.

  4. Calcium channel blockers ameliorate iron overload-associated hepatic fibrosis by altering iron transport and stellate cell apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Ying [Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei (China); Department of Pathology, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei (China); Hebei Key Laboratory of Chinese Medicine Research on Cardio-Cerebrovascular Disease, Shijiazhuang 050200, Hebei (China); Zhao, Xin [Department of Hepatobiliary Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang 050051, Hebei (China); Chang, Yanzhong [Laboratory of Molecular Iron Metabolism, College of Life Science, Hebei Normal University, Shijiazhuang 050024, Hebei (China); Zhang, Yuanyuan [Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei (China); Chu, Xi [Department of Pharmacy, The Forth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei (China); Zhang, Xuan [Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei (China); Liu, Zhenyi; Guo, Hui [Department of Medicinal Chemistry, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei (China); Wang, Na [Department of Physiology, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei (China); Gao, Yonggang [Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei (China); Zhang, Jianping, E-mail: zhangjianping14@126.com [Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei (China); Chu, Li, E-mail: chuli0614@126.com [Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei (China); Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Shijiazhuang 050200, Hebei (China)

    2016-06-15

    Liver fibrosis is the principal cause of morbidity and mortality in patients with iron overload. Calcium channel blockers (CCBs) can antagonize divalent cation entry into renal and myocardial cells and inhibit fibrogenic gene expression. We investigated the potential of CCBs to resolve iron overload-associated hepatic fibrosis. Kunming mice were assigned to nine groups (n = 8 per group): control, iron overload, deferoxamine, high and low dose verapamil, high and low dose nimodipine, and high and low dose diltiazem. Iron deposition and hepatic fibrosis were measured in mouse livers. Expression levels of molecules associated with transmembrane iron transport were determined by molecular biology approaches. In vitro HSC-T6 cells were randomized into nine groups (the same groups as the mice). Changes in proliferation, apoptosis, and metalloproteinase expression in cells were detected to assess the anti-fibrotic effects of CCBs during iron overload conditions. We found that CCBs reduced hepatic iron content, intracellular iron deposition, the number of hepatic fibrotic areas, collagen expression levels, and hydroxyproline content. CCBs rescued abnormal expression of α1C protein in L-type voltage-dependent calcium channel (LVDCC) and down-regulated divalent metal transporter-1 (DMT-1) expression in mouse livers. In iron-overloaded HSC-T6 cells, CCBs reduced iron deposition, inhibited proliferation, induced apoptosis, and elevated expression of matrix metalloproteinase-13 (MMP-13) and tissue inhibitor of metalloproteinase-1 (TIMP-1). CCBs are potential therapeutic agents that can be used to address hepatic fibrosis during iron overload. They resolve hepatic fibrosis probably correlated with regulating transmembrane iron transport and inhibiting HSC growth. - Highlights: • Calcium channel blockers (CCBs) reduced hepatic iron content. • CCBs decreased hepatic fibrotic areas and collagen expression levels. • CCBs resolve fibrosis by regulating iron transport and

  5. Elucidation of the therapeutic role of mitochondrial biogenesis transducers NRF-1 in the regulation of renal fibrosis

    Energy Technology Data Exchange (ETDEWEB)

    Hsieh, Pei-Fang [Graduate Institute of Biomedical Science, National Sun Yat-Sen University, Kaohsiung, Taiwan (China); Graduate Institute of Medical Laboratory Science and Biotechnology, Chung Hwa University of Medical Technology, Tainan, Taiwan (China); Liu, Shu-Fen [Department of Internal Medicine, Kaohsiung Medical University Chung-Ho Memorial Hospital, Kaohsiung, Taiwan (China); Hung, Tsung-Jen [Graduate Institute of Biomedical Science, Chung Hwa University of Medical Technology, Tainan, Taiwan (China); Hung, Chien-Ya [Department of Food Nutrition, Chung Hwa University of Medical Technology, Tainan, Taiwan (China); Liu, Guo-Zheng [Graduate Institute of Medical Laboratory Science and Biotechnology, Chung Hwa University of Medical Technology, Tainan, Taiwan (China); Chuang, Lea-Yea [Department of Biochemistry, Kaohsiung Medical University, Kaohsiung, Taiwan (China); Chen, Mei-Fen [Department of Acupressure Technology, Chung Hwa University of Medical Technology, Tainan, Taiwan (China); Wang, Jue-Long [Department of Physical Medicine and Rehabilitation, Kaohsiung Veterans General Hospital, Taiwan (China); Shi, Ming-Der [Graduate Institute of Medical Laboratory Science and Biotechnology, Chung Hwa University of Medical Technology, Tainan, Taiwan (China); Department of Medical Technology, Kaohsiung Veterans General Hospital Tainan Branch, Tainan, Taiwan (China); Hsu, Chen Hung [Department of Biological Science and Technology, Chung Hwa University of Medical Technology, Tainan, Taiwan (China); Shiue, Yow-Ling, E-mail: shiue.shirley@gmail.com [Graduate Institute of Biomedical Science, National Sun Yat-Sen University, Kaohsiung, Taiwan (China); Yang, Yu-Lin, E-mail: Call0955443221@gmail.com [Graduate Institute of Medical Laboratory Science and Biotechnology, Chung Hwa University of Medical Technology, Tainan, Taiwan (China); Graduate Institute of Biomedical Science, Chung Hwa University of Medical Technology, Tainan, Taiwan (China)

    2016-11-15

    Background: Mitochondrial dysfunction is a newly established risk factor for the development of renal fibrosis. Cell survival and injury repair is facilitated by mitochondrial biogenesis. Nuclear respiratory factor 1 (NRF-1) is a transcriptional regulation factor that plays a central role in the regulation of mitochondrial biogenesis. However, the transcription factor of this process in renal fibrosis is unknown. Thus, we hereby discussed the correlations of NRF-1 and renal interstitial fibrosis. Materials and methods: In vitro fibrosis model was established by treatment with transforming growth factor-β1 (TGF-β1) in NRK-49F (Normal Rat kidney fibroblast). We investigated the ROS production, mitochondrial biogenesis and fibrogenic marker (e.q. fibronectin) during the progression of renal fibrosis by kit and Western blotting assay. Here, we used that two distinct mechanisms regulate NRF-1 activation and degradation of NRF-1. NRF-1 was transfect by pcDNA-NRF-1 overexpression gene to evaluate the NRF-1 activity of the therapeutic effect in renal fibrosis. In addition, NRF-1 was silenced by shRNA-NRF-1 to evaluate the significance of NRF-1. ELISA was used to evaluate the secreted fibronectin. Immunofluorescence staining was used to assay the in situ expression of proteins (e.g. fibronectin, NRF-1). Results: Under renal fibrosis conditions, TGF-β1 (5 ng/ml) increased ROS. Simultaneously, TGF-β1-induced extracellular fibronectin by ELISA assay. In addition, TGF-β1 decreased expression of mitochondrial biogenesis. This is the first time to demonstrate that expression of NRF-1 is significantly decreased in renal fibrosis. However, NRK49F was a transfection with pcDNA-NRF-1 (2 μg/ml) expression vector dramatically reverse TGF-β1-induced cellular fibrosis concomitantly with the suppression of fibronectin (both intracellular and extracellular fibronectin). More importantly, transfection with shRNA-NRF-1 (2 μg/ml) significantly increased the expression of fibronectin

  6. Urinary C-type natriuretic peptide excretion: a potential novel biomarker for renal fibrosis during aging.

    Science.gov (United States)

    Sangaralingham, S Jeson; Heublein, Denise M; Grande, Joseph P; Cataliotti, Alessandro; Rule, Andrew D; McKie, Paul M; Martin, Fernando L; Burnett, John C

    2011-11-01

    Renal aging is characterized by structural changes in the kidney including fibrosis, which contributes to the increased risk of kidney and cardiac failure in the elderly. Studies involving healthy kidney donors demonstrated subclinical age-related nephropathy on renal biopsy that was not detected by standard diagnostic tests. Thus there is a high-priority need for novel noninvasive biomarkers to detect the presence of preclinical age-associated renal structural and functional changes. C-type natriuretic peptide (CNP) possesses renoprotective properties and is present in the kidney; however, its modulation during aging remains undefined. We assessed circulating and urinary CNP in a Fischer rat model of experimental aging and also determined renal structural and functional adaptations to the aging process. Histological and electron microscopic analysis demonstrated significant renal fibrosis, glomerular basement membrane thickening, and mesangial matrix expansion with aging. While plasma CNP levels progressively declined with aging, urinary CNP excretion increased, along with the ratio of urinary to plasma CNP, which preceded significant elevations in proteinuria and blood pressure. Also, CNP immunoreactivity was increased in the distal and proximal tubules in both the aging rat and aging human kidneys. Our findings provide evidence that urinary CNP and its ratio to plasma CNP may represent a novel biomarker for early age-mediated renal structural alterations, particularly fibrosis. Thus urinary CNP could potentially aid in identifying subjects with preclinical structural changes before the onset of symptoms and disease, allowing for the initiation of strategies designed to prevent the progression of chronic kidney disease particularly in the aging population.

  7. Naja naja atra venom ameliorates pulmonary fibrosis by inhibiting inflammatory response and oxidative stress.

    Science.gov (United States)

    Cui, Kui; Kou, Jian-Qun; Gu, Jin-Hua; Han, Rong; Wang, Guanghui; Zhen, Xuechu; Qin, Zheng-Hong

    2014-12-02

    Naja naja atra venom (NNAV) displays diverse pharmacological actions including analgesia, anti-inflammation and immune regulation.In this study, we investigated the effects of NNAV on pulmonary fibrosis and its mechanisms of action. To determine if Naja naja atra venom (NNAV) can produce beneficial effects on pulmonary fibrosis, two marine models of pulmonary fibrosis were produced with bleomycin (BLM) and lipopolysaccharide (LPS). NNAV (30, 90, 270 μg/kg) was orally administered once a day started five days before BLM and LPS until to the end of experiment. The effects of NNAV treatment on pulmonary injury were evaluated with arterial blood gas analysis, hydroxyproline (HYP) content assessment and HE/Masson staining. The effects of NNAV treatment on inflammatory related cytokines, fibrosis related TGF-β/Smad signaling pathway and oxidative stress were examined. The results showed that NNAV improved the lung gas-exchange function and attenuated the fibrotic lesions in lung. NNAV decreased IL-1β and TNF-α levels in serum in both pulmonary fibrosis models. NNAV inhibited the activation of NF-κB in LPS-induced and TGF-β/Smad pathway in BLM-induced pulmonary fibrosis. Additionally, NNAV also increased the levels of SOD and GSH and reduced the levels of MDA in BLM-induced pulmonary fibrosis model. The present study indicates that NNAV attenuates LPS- and BLM-induced lung fibrosis. Its mechanisms of action are associated with inhibiting inflammatory response and oxidative stress. The study suggests that NNAV might be a potential therapeutic drug for treatment of pulmonary fibrosis.

  8. The Role of Butylidenephthalide in Targeting Microenvironment Contributes to the Ameliorate of Liver Fibrosis

    Directory of Open Access Journals (Sweden)

    Hong-Meng eChuang

    2016-04-01

    Full Text Available The treatment of liver fibrosis has clinical limitations because of its multiple etiologies, such as epithelial–mesenchymal transition (EMT promotion, cell regeneration and remodeling dysfunction, inflammatory cell activation, and scar tissue deposition. These factors might be considered as a new target for the fibrotic microenvironment, leading to increased fibrogenesis and liver fibrosis. Here, we investigate a small molecule named butylidenephthalide (BP and its multiple effects on liver fibrosis treatment. Thioacetamide was used in vivo to induce chronic liver fibrosis. BP was administered orally in rats for a period of 2 weeks and 4 weeks, which resulted in a significantly reduced fibrosis score (p<0.05 and (p<0.001, respectively. The inflammatory reaction of macrophage infiltration were reduced in the administration of BP, which led to the decrease in the transaminase levels. Moreover, we also found liver functions recovering (due to the increased serum albumin and reduced prothrombin time where liver cells regenerated, which can be seen in the increase of Ki-67 on Oval cell. In addition, the fibrotic scar was also reduced, along with the expression of matrix metalloprotease by hepatic stellate cell. Furthermore, regarding the mechanism/study of EMT reduced by BP, the knockdown of BMP-7, which could reduce α-SMA expression, was mediated by the regulation of TGF-β, which implies its major role on EMT. Finally, in the in vivo study, BP treatment of liver fibrosis was reduced by Bmp7 knockdown in zebrafish, suggesting that BP leads to the reduction of liver fibrosis, which also depends on BMP-7 induction. These results suggest that BP had multiple targets for treating liver fibrosis in the following ways: reduction of EMT, decreasing inflammatory reaction, and liver cell proliferation. This multiple targets approach provided a new mechanism to treat liver injury and fibrosis.

  9. Silymarin and Nigella sativa extract ameliorate paracetamol induced oxidative stress and renal dysfunction in male mice

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    Reham Zakaria Hamza

    2015-06-01

    Full Text Available Objective: To evaluate the ameliorative role of silymarin or/and Nigella sativa (N. sativa water extract against N-acetyl-p-aminophenol (APAP-induced renal function deterioration in male mice at the biochemical levels. Methods: The mice were divided into seven groups (10/group. The first group was served as control. The second group was treated with dose of APAP. The third and fourth groups were treated with silymarin alone and N. sativa water extract alone, respectively. The fifth and sixth groups were treated with combination of APAP with silymarin and APAP with N. sativa water extract, respectively. The seventh group was treated with a combination of both ameliorative compounds (silymarin and N. sativa water extract with APAP and all animals were treated for a period of 30 days. Results: Exposure to APAP at the treated dose for mice led to an alteration of kidney function parameters, increase in the level of serum urea and creatinine. Also, paracetamol administration induced oxidative stress in kidney homogenates by increasing malondialdhyde level and decreasing superoxide dismutase and catalase activities and this stress was ameliorated by administration of either silymarin or N. sativa water extract. Conclusions: Administration of silymarin or/and N. sativa water extract to APAP-treated mice alleviate the toxicity of APAP, and this appeared clearly by biochemical improvement of kidney function parameters and antioxidant parameters. But, the alleviation is more pronounced with the both antioxidants. Thus, the pronounce effect of silymarin and N. sativa water extract is most effective in reducing the toxicity induced by APAP and improving the kidney function parameters and antioxidant status of kidney of male mice.

  10. Taurine drinking ameliorates hepatic granuloma and fibrosis in mice infected with Schistosoma japonicum

    Directory of Open Access Journals (Sweden)

    Yan-Rong Yu

    2016-04-01

    Full Text Available In schistosomiasis, egg-induced hepatic granuloma formation is a cytokine-mediated, predominantly CD4+ Th2 immune response that can give rise to hepatic fibrosis. Hepatic fibrosis is the main cause of increased morbidity and mortality in humans with schistosome infection. Taurine has various physiological functions and hepatoprotective properties as well as anti-inflammatory and immunomodulatory activity. However, little is known about the role of taurine in schistosome egg-induced granuloma formation and fibrosis. We aimed to evaluate the therapeutic potential of taurine as preventative treatment for Schistosoma japonicum infection. Mice infected with S. japonicum cercariae were supplied with taurine drinking water (1% w/v for 4 weeks starting at 4 weeks post-infection. Taurine supplementation significantly improved the liver pathologic findings, reduced the serum levels of aminotransferases and area of hepatic granuloma, and prevented fibrosis progression. In addition, taurine decreased the expression of the granulomatous and fibrogenic mediators transforming growth factor β1, tumor necrosis factor α, monocyte chemotactic protein 1α and macrophage inflammatory protein 1α as well as the endoplasmic reticulum stress marker glucose-regulated protein 78. Thus, taurine can significantly attenuate S. japonicum egg-induced hepatic granuloma and fibrosis, which may depend in part on the downregulation of some relevant cytokine/chemokines and reducing the endoplasmic reticulum stress response. Keywords: Schistosomiasis, Schistosoma japonicum, Granuloma, Fibrosis, Taurine

  11. Honey Supplementation in Spontaneously Hypertensive Rats Elicits Antihypertensive Effect via Amelioration of Renal Oxidative Stress

    Directory of Open Access Journals (Sweden)

    Omotayo O. Erejuwa

    2012-01-01

    Full Text Available Oxidative stress is implicated in the pathogenesis and/or maintenance of elevated blood pressure in hypertension. This study investigated the effect of honey on elevated systolic blood pressure (SBP in spontaneously hypertensive rats (SHR. It also evaluated the effect of honey on the amelioration of oxidative stress in the kidney of SHR as a possible mechanism of its antihypertensive effect. SHR and Wistar Kyoto (WKY rats were randomly divided into 2 groups and administered distilled water or honey by oral gavage once daily for 12 weeks. The control SHR had significantly higher SBP and renal malondialdehyde (MDA levels than did control WKY. The mRNA expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2 and glutathione S-transferase (GST were significantly downregulated while total antioxidant status (TAS and activities of GST and catalase (CAT were higher in the kidney of control SHR. Honey supplementation significantly reduced SBP and MDA levels in SHR. Honey significantly reduced the activities of GST and CAT while it moderately but insignificantly upregulated the Nrf2 mRNA expression level in the kidney of SHR. These results indicate that Nrf2 expression is impaired in the kidney of SHR. Honey supplementation considerably reduces elevated SBP via amelioration of oxidative stress in the kidney of SHR.

  12. Pentraxin 3 Activates JNK Signaling and Regulates the Epithelial-To-Mesenchymal Transition in Renal Fibrosis

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    Tung-Wei Hung

    2016-12-01

    Full Text Available Background/Aims: Tubulointerstitial fibrosis can lead to end-stage renal disease. Pentraxin 3 (PTX3 is an acute phase protein produced by resident and innate immunity cells. We investigated the effect of PTX3 on cultured human proximal tubular epithelial (HK-2 cells and a rat unilateral ureteral obstruction (UUO model of renal fibrosis. Methods: Gain-of-function experiments were used to examine the effect of recombinant human PTX3 (Rh-PTX3 on HK-2 cells. Cell proliferation (MTT assay and in vitro cell migration were measured. The levels of PTX3, p-JNK, and EMT markers were measured using immunohistochemistry, RT-PCR, and western blotting in UUO rats and HK-2 cells. Results: HK-2 cells treated with Rh PTX3 did not affect cell viability, but significantly increased cell migration. Moreover, Rh-PTX3 increased the expression of snail, slug, N-cadherin, and vimentin, decreased the expression of E-cadherin, and increased the phosphorylation of JNK. SP600126 (a specific JNK inhibitor enhanced the effects of Rh-PTX3. Rats with UUO exhibited time-dependent increased levels of PTX3, p-JNK, and vimentin, and decreased expression of E-cadherin. Conclusions: Our results suggest that PTX3 induces cell migration via upregulation of EMT in a JNK-dependent mechanism, and highlight the role of PTX3 in the pathogenesis renal fibrosis.

  13. Vildagliptin ameliorates pulmonary fibrosis in lipopolysaccharide-induced lung injury by inhibiting endothelial-to-mesenchymal transition.

    Science.gov (United States)

    Suzuki, Toshio; Tada, Yuji; Gladson, Santhi; Nishimura, Rintaro; Shimomura, Iwao; Karasawa, Satoshi; Tatsumi, Koichiro; West, James

    2017-10-16

    cells or GLP-1. Inhibiting DPP-4 signaling by vildagliptin could ameliorate pulmonary fibrosis by downregulating EndMT in systemic LPS-induced lung injury.

  14. The 6-hydroxychromanol derivative SUL-109 ameliorates renal injury after deep hypothermia and rewarming in rats.

    Science.gov (United States)

    Vogelaar, Pieter C; Roorda, Maurits; de Vrij, Edwin L; Houwertjes, Martin C; Goris, Maaike; Bouma, Hjalmar; van der Graaf, Adrianus C; Krenning, Guido; Henning, Robert H

    2018-04-11

    Mitochondrial dysfunction plays an important role in kidney damage in various pathologies, including acute and chronic kidney injury and diabetic nephropathy. In addition to the well-studied ischaemia/reperfusion (I/R) injury, hypothermia/rewarming (H/R) also inflicts acute kidney injury. Substituted 6-hydroxychromanols are a novel class of mitochondrial medicines that ameliorate mitochondrial oxidative stress and protect the mitochondrial network. To identify a novel 6-hydroxychromanol that protects mitochondrial structure and function in the kidney during H/R, we screened multiple compounds in vitro and subsequently assessed the efficacy of the 6-hydroxychromanol derivatives SUL-109 and SUL-121 in vivo to protect against kidney injury after H/R in rats. Human proximal tubule cell viability was assessed following exposure to H/R for 48/4 h in the presence of various 6-hydroxychromanols. Selected compounds (SUL-109, SUL-121) or vehicle were administered to ketamine-anaesthetized male Wistar rats (IV 135 µg/kg/h) undergoing H/R at 15°C for 3 h followed by rewarming and normothermia for 1 h. Metabolic parameters and body temperature were measured throughout. In addition, renal function, renal injury, histopathology and mitochondrial fitness were assessed. H/R injury in vitro lowered cell viability by 94 ± 1%, which was counteracted dose-dependently by multiple 6-hydroxychomanols derivatives. In vivo, H/R in rats showed kidney injury molecule 1 expression in the kidney and tubular dilation, accompanied by double-strand DNA breaks and protein nitrosylation. SUL-109 and SUL-121 ameliorated tubular kidney damage, preserved mitochondrial mass and maintained cortical adenosine 5'-triphosphate (ATP) levels, although SUL-121 did not reduce protein nitrosylation. The substituted 6-hydroxychromanols SUL-109 and SUL-121 ameliorate kidney injury during in vivo H/R by preserving mitochondrial mass, function and ATP levels. In addition, both 6-hydroxychromanols

  15. Dual-Functional Nanoparticles Targeting CXCR4 and Delivering Antiangiogenic siRNA Ameliorate Liver Fibrosis.

    Science.gov (United States)

    Liu, Chun-Hung; Chan, Kun-Ming; Chiang, Tsaiyu; Liu, Jia-Yu; Chern, Guann-Gen; Hsu, Fu-Fei; Wu, Yu-Hsuan; Liu, Ya-Chi; Chen, Yunching

    2016-07-05

    The progression of liver fibrosis, an intrinsic response to chronic liver injury, is associated with hepatic hypoxia, angiogenesis, abnormal inflammation, and significant matrix deposition, leading to the development of cirrhosis and hepatocellular carcinoma (HCC). Due to the complex pathogenesis of liver fibrosis, antifibrotic drug development has faced the challenge of efficiently and specifically targeting multiple pathogenic mechanisms. Therefore, CXCR4-targeted nanoparticles (NPs) were formulated to deliver siRNAs against vascular endothelial growth factor (VEGF) into fibrotic livers to block angiogenesis during the progression of liver fibrosis. AMD3100, a CXCR4 antagonist that was incorporated into the NPs, served dual functions: it acted as a targeting moiety and suppressed the progression of fibrosis by inhibiting the proliferation and activation of hepatic stellate cells (HSCs). We demonstrated that CXCR4-targeted NPs could deliver VEGF siRNAs to fibrotic livers, decrease VEGF expression, suppress angiogenesis and normalize the distorted vessels in the fibrotic livers in the carbon tetrachloride (CCl4) induced mouse model. Moreover, blocking SDF-1α/CXCR4 by CXCR4-targeted NPs in combination with VEGF siRNA significantly prevented the progression of liver fibrosis in CCl4-treated mice. In conclusion, the multifunctional CXCR4-targeted NPs delivering VEGF siRNAs provide an effective antifibrotic therapeutic strategy.

  16. Taurine drinking ameliorates hepatic granuloma and fibrosis in mice infected with Schistosoma japonicum.

    Science.gov (United States)

    Yu, Yan-Rong; Ni, Xian-Qiang; Huang, Jie; Zhu, Yong-Hong; Qi, Yong-Fen

    2016-04-01

    In schistosomiasis, egg-induced hepatic granuloma formation is a cytokine-mediated, predominantly CD4(+) Th2 immune response that can give rise to hepatic fibrosis. Hepatic fibrosis is the main cause of increased morbidity and mortality in humans with schistosome infection. Taurine has various physiological functions and hepatoprotective properties as well as anti-inflammatory and immunomodulatory activity. However, little is known about the role of taurine in schistosome egg-induced granuloma formation and fibrosis. We aimed to evaluate the therapeutic potential of taurine as preventative treatment for Schistosoma japonicum infection. Mice infected with S. japonicum cercariae were supplied with taurine drinking water (1% w/v) for 4 weeks starting at 4 weeks post-infection. Taurine supplementation significantly improved the liver pathologic findings, reduced the serum levels of aminotransferases and area of hepatic granuloma, and prevented fibrosis progression. In addition, taurine decreased the expression of the granulomatous and fibrogenic mediators transforming growth factor β1, tumor necrosis factor α, monocyte chemotactic protein 1α and macrophage inflammatory protein 1α as well as the endoplasmic reticulum stress marker glucose-regulated protein 78. Thus, taurine can significantly attenuate S. japonicum egg-induced hepatic granuloma and fibrosis, which may depend in part on the downregulation of some relevant cytokine/chemokines and reducing the endoplasmic reticulum stress response.

  17. Role of Epigenetic Histone Modifications in Diabetic Kidney Disease Involving Renal Fibrosis

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    Jing Sun

    2017-01-01

    Full Text Available One of the commonest causes of end-stage renal disease is diabetic kidney disease (DKD. Renal fibrosis, characterized by the accumulation of extracellular matrix (ECM proteins in glomerular basement membranes and the tubulointerstitium, is the final manifestation of DKD. The TGF-β pathway triggers epithelial-to-mesenchymal transition (EMT, which plays a key role in the accumulation of ECM proteins in DKD. DCCT/EDIC studies have shown that DKD often persists and progresses despite glycemic control in diabetes once DKD sets in due to prior exposure to hyperglycemia called “metabolic memory.” These imply that epigenetic factors modulate kidney gene expression. There is evidence to suggest that in diabetes and hyperglycemia, epigenetic histone modifications have a significant effect in modulating renal fibrotic and ECM gene expression induced by TGF-β1, as well as its downstream profibrotic genes. Histone modifications are also implicated in renal fibrosis through its ability to regulate the EMT process triggered by TGF-β signaling. In view of this, efforts are being made to develop HAT, HDAC, and HMT inhibitors to delay, stop, or even reverse DKD. In this review, we outline the latest advances that are being made to regulate histone modifications involved in DKD.

  18. Celecoxib ameliorates portal hypertension of the cirrhotic rats through the dual inhibitory effects on the intrahepatic fibrosis and angiogenesis.

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    Gao, Jin-Hang; Wen, Shi-Lei; Yang, Wen-Juan; Lu, Yao-Yao; Tong, Huan; Huang, Zhi-Yin; Liu, Zhang-Xu; Tang, Cheng-Wei

    2013-01-01

    Increased intra-hepatic resistance to portal blood flow is the primary factor leading to portal hypertension in cirrhosis. Up-regulated expression of cyclooxygenase-2 (COX-2) in the cirrhotic liver might be a potential target to ameliorate portal hypertension. To verify the effect of celecoxib, a selective inhibitor of COX-2, on portal hypertension and the mechanisms behind it. Cirrhotic liver model of rat was established by peritoneal injection of thiacetamide (TAA). 36 rats were randomly assigned to control, TAA and TAA+celecoxib groups. Portal pressures were measured by introduction of catheters into portal vein. Hepatic fibrosis was assessed by the visible hepatic fibrotic areas and mRNAs for collagen III and α-SMA. The neovasculature was determined by hepatic vascular areas, vascular casts and CD31 expression. Expressions of COX-2, vascular endothelial growth factor (VEGF), VEGF receptor-2 (VEGFR-2) and related signal molecules were quantitated. Compared with TAA group, the portal pressure in TAA+celecoxib group was significantly decreased by 17.8%, pportal venules. The data of fibrotic areas, CD31expression, mRNA levels of α-SMA and collagen III in TAA+celecoxib group were much lower than those in TAA group, pprotein levels of VEGF, VEGFR-2 and COX-2 induced by TAA was significantly inhibited after celecoxib treatment. The expressions of prostaglandin E2 (PGE2), phosphorylated extracellular signal-regulated kinase (p-ERK), hypoxia-inducible factor-1α (HIF-1α), and c-fos were also down-regulated after celecoxib treatment. Long term administration of celecoxib can efficiently ameliorate portal hypertension in TAA rat model by its dual inhibitory effects on the intrahepatic fibrosis and angiogenesis. The anti-angiogenesis effect afforded by celecoxib may attribute to its modulation on VEGF/VEGFR-2 through the down-regulation of integrated signal pathways involving PGE2- HIF-1α- VEGF and p-ERK- c-fos- VEGFR-2.

  19. Involvement of NF-κBIZ and related cytokines in age-associated renal fibrosis.

    Science.gov (United States)

    Chung, Ki Wung; Jeong, Hyeong Oh; Lee, Bonggi; Park, Daeui; Kim, Dae Hyun; Choi, Yeun Ja; Lee, Eun Kyeong; Kim, Kyung Mok; Park, June Whoun; Yu, Byung Pal; Chung, Hae Young

    2017-01-31

    Chronic inflammation is a major contributor to age-related nephropathic changes, including renal fibrosis. In this study, various experimental paradigms were designed to delineate the role played by NF-κBIZ (also known as IκBζ) in age-associated renal fibrosis. Analyses based on RNA-sequencing findings obtained by next generation sequencing (NGS) revealed the upregulations of NF-κBIZ and of IL-6 and MCP-1 (both known to be regulated by NF-κBIZ) during aging. The up-regulation of NF-κBIZ in aged rat kidneys coincided with increased macrophage infiltration. In LPS-treated macrophages, oxidative stress was found to play a pivotal role in NF-κBIZ expression, suggesting age-related oxidative stress is associated with NF-κBIZ activation. Furthermore, these in vitro findings were confirmed in LPS-treated old rats, which showed higher levels of oxidative stress and NF-κBIZ in kidneys than LPS-treated young rats. Additional in vitro experiments using macrophages and kidney fibroblasts demonstrated NF-κBIZ and related cytokines participate in fibrosis. In particular, increased levels of NF-κBIZ-associated cytokines in macrophages significantly up-regulated TGF-β induced kidney fibroblast activation. Moreover, experiments with NF-κBIZ knocked down macrophages showed reduced TGF-β-induced kidney fibroblast activation. The findings of the present study provide evidence regarding an involvement of NF-κBIZ in age-associated progressive renal fibrosis and provides potential targets for its prevention.

  20. Decay-accelerating factor 1 deficiency exacerbates leptospiral-induced murine chronic nephritis and renal fibrosis.

    Directory of Open Access Journals (Sweden)

    María F Ferrer

    Full Text Available Leptospirosis is a global zoonosis caused by pathogenic Leptospira, which can colonize the proximal renal tubules and persist for long periods in the kidneys of infected hosts. Here, we characterized the infection of C57BL/6J wild-type and Daf1-/- mice, which have an enhanced host response, with a virulent Leptospira interrogans strain at 14 days post-infection, its persistence in the kidney, and its link to kidney fibrosis at 90 days post-infection. We found that Leptospira interrogans can induce acute moderate nephritis in wild-type mice and is able to persist in some animals, inducing fibrosis in the absence of mortality. In contrast, Daf1-/- mice showed acute mortality, with a higher bacterial burden. At the chronic stage, Daf1-/- mice showed greater inflammation and fibrosis than at 14 days post-infection and higher levels at all times than the wild-type counterpart. Compared with uninfected mice, infected wild-type mice showed higher levels of IL-4, IL-10 and IL-13, with similar levels of α-smooth muscle actin, galectin-3, TGF-β1, IL-17, IFN-γ, and lower IL-12 levels at 90 days post-infection. In contrast, fibrosis in Daf1-/- mice was accompanied by high expression of α-smooth muscle actin, galectin-3, IL-10, IL-13, and IFN-γ, similar levels of TGF-β1, IL-12, and IL-17 and lower IL-4 levels. This study demonstrates the link between Leptospira-induced murine chronic nephritis with renal fibrosis and shows a protective role of Daf1.

  1. Edaravone attenuates lipopolysaccharide-induced acute respiratory distress syndrome associated early pulmonary fibrosis via amelioration of oxidative stress and transforming growth factor-β1/Smad3 signaling.

    Science.gov (United States)

    Wang, Xida; Lai, Rongde; Su, Xiangfen; Chen, Guibin; Liang, Zijing

    2018-01-01

    Pulmonary fibrosis is responsible for the both short-term and long-term outcomes in patients with acute respiratory distress syndrome (ARDS). There is still no effective cure to improve prognosis. The purpose of this study was to investigate whether edaravone, a free radical scavenger, have anti-fibrosis effects in the rat model of ARDS associated early pulmonary fibrosis by lipopolysaccharide (LPS) administration. Rats were subjected to intravenous injection of LPS, and edaravone was given intraperitoneally after LPS administration daily for 7 consecutive days. LPS treatment rapidly increased lung histopathology abnormalities, coefficient of lung, hydroxyproline and collagen I levels, stimulated myofibroblast differentiation and induced expression of TGF-β1 and activation of TGF-β1/Smad3 signaling as early as day 7 after LPS injection. Moreover, LPS intoxication significantly increased the contents of malondialdehyde (MDA), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), whereas it dramatically decreased superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) activities from day 1 after LPS treatment. On the contrary, edaravone treatment ameliorated LPS-induced myofibroblast differentiation and pulmonary fibrosis, simultaneously, and attenuated LPS-stimulated oxidative stress and activation of TGF-β1/Smad3 signaling. Collectively, edaravone may attenuate ARDS associated early pulmonary fibrosis through amelioration of oxidative stress and TGF-β1/Smad3 signaling pathway. Edaravone may be a promising drug candidate for the treatment of ARDS-related pulmonary fibrosis in early period. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. The Flavonoid Quercetin Ameliorates Liver Inflammation and Fibrosis by Regulating Hepatic Macrophages Activation and Polarization in Mice

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    Xi Li

    2018-02-01

    Full Text Available At present, there are no effective antifibrotic drugs for patients with chronic liver disease; hence, the development of antifibrotic therapies is urgently needed. Here, we performed an experimental and translational study to investigate the potential and underlying mechanism of quercetin treatment in liver fibrosis, mainly focusing on the impact of quercetin on macrophages activation and polarization. BALB/c mice were induced liver fibrosis by carbon tetrachloride (CCl4 for 8 weeks and concomitantly treated with quercetin (50 mg/kg or vehicle by daily gavage. Liver inflammation, fibrosis, and hepatic stellate cells (HSCs activation were examined. Moreover, massive macrophages accumulation, M1 macrophages and their related markers, such as tumor necrosis factor (TNF-α, interleukin (IL-1β, IL-6, and monocyte chemotactic protein-1 (MCP-1 in livers were analyzed. In vitro, we used Raw 264.7 cells to examine the effect of quercetin on M1-polarized macrophages activation. Our results showed that quercetin dramatically ameliorated liver inflammation, fibrosis, and inhibited HSCs activation. These results were attributed to the reductive recruitment of macrophages (F4/80+ and CD68+ into the liver in quercetin-treated fibrotic mice confirmed by immunostaining and expression levels of marker molecules. Importantly, quercetin strongly inhibited M1 polarization and M1-related inflammatory cytokines in fibrotic livers when compared with vehicle-treated mice. In vitro, studies further revealed that quercetin efficiently inhibited macrophages activation and M1 polarization, as well as decreased the mRNA expression of M1 macrophage markers such as TNF-α, IL-1β, IL-6, and nitric oxide synthase 2. Mechanistically, the inhibition of M1 macrophages by quercetin was associated with the decreased levels of Notch1 expression on macrophages both in vivo and in vitro. Taken together, our data indicated that quercetin attenuated CCl4-induced liver inflammation and

  3. Ameliorative effects of Moringa oleifera Lam seed extract on liver fibrosis in rats.

    Science.gov (United States)

    Hamza, Alaaeldin A

    2010-01-01

    This study was carried out to evaluate the effect of Moringa oleifera Lam (Moringa) seed extract on liver fibrosis. Liver fibrosis was induced by the oral administration of 20% carbon tetrachloride (CCl(4)), twice weekly and for 8 weeks. Simultaneously, M.oleifera Lam seed extract (1g/kg) was orally administered daily. The biochemical and histological results showed that Moringa reduced liver damage as well as symptoms of liver fibrosis. The administration of Moringa seed extract decreased the CCl(4)-induced elevation of serum aminotransferase activities and globulin level. The elevations of hepatic hydroxyproline content and myeloperoxidase activity were also reduced by Moringa treatment. Furthermore, the immunohistochemical study showed that Moringa markedly reduced the numbers of smooth muscle alpha-actin-positive cells and the accumulation of collagens I and III in liver. Moringa seed extract showed significant inhibitory effect on 1,1-diphenyl-2-picrylhydrazyl free radical, as well as strong reducing antioxidant power. The activity of superoxide dismutase as well as the content of both malondialdehyde and protein carbonyl, which are oxidative stress markers, were reversed after treatment with Moringa. Finally, these results suggested that Moringa seed extract can act against CCl(4)-induced liver injury and fibrosis in rats by a mechanism related to its antioxidant properties, anti-inflammatory effect and its ability to attenuate the hepatic stellate cells activation. Copyright 2009 Elsevier Ltd. All rights reserved.

  4. Interferon gamma peptidomimetic targeted to hepatic stellate cells ameliorates acute and chronic liver fibrosis in vivo

    NARCIS (Netherlands)

    Bansal, Ruchi; Prakash, Jai; De Ruiter, Marieke; Poelstra, Klaas

    2014-01-01

    Hepatic stellate cells play a crucial role in the pathogenesis of hepatic fibrosis. Thus, pharmacological inhibition of pro-fibrotic activities of these cells might lead to an effective therapy for this disease. Among the potent antifibrotics, interferon gamma (IFN gamma), a proinflammatory

  5. Interferon gamma peptidomimetic targeted to hepatic stellate cells ameliorates acute and chronic liver fibrosis in vivo

    NARCIS (Netherlands)

    Bansal, Ruchi; Prakash, Jai; de Ruiter, Marieke; Poelstra, Klaas

    2014-01-01

    Hepatic stellate cells play a crucial role in the pathogenesis of hepatic fibrosis. Thus, pharmacological inhibition of pro-fibrotic activities of these cells might lead to an effective therapy for this disease. Among the potent anti-fibrotics, interferon gamma (IFNγ), a proinflammatory cytokine, is

  6. Targeting of TAM Receptors Ameliorates Fibrotic Mechanisms in Idiopathic Pulmonary Fibrosis.

    Science.gov (United States)

    Espindola, Milena S; Habiel, David M; Narayanan, Rohan; Jones, Isabelle; Coelho, Ana L; Murray, Lynne A; Jiang, Dianhua; Noble, Paul W; Hogaboam, Cory M

    2018-06-01

    Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant lung remodeling, which progressively abolishes lung function in an RTK (receptor tyrosine kinase)-dependent manner. Gas6 (growth arrest-specific 6) ligand, Tyro3 (TYRO3 protein tyrosine kinase 3), and Axl (anexelekto) RTK expression and activity are increased in IPF. To determine if targeting these RTK pathways would inhibit fibroblast activation and the development of pulmonary fibrosis. Quantitative genomic, proteomic, and functional analyses were used to determine Gas6/TAM (Tyro3, Axl, and Mertk [MER proto-oncogene, tyrosine kinase]) RTK expression and activation in tissues and fibroblasts from normal and IPF lungs. The profibrotic impact of these RTK pathways were also examined in bleomycin-induced pulmonary fibrosis and in SCID/Bg mice that developed pulmonary fibrosis after the intravenous administration of primary IPF fibroblasts. Gas6, Axl, and Tyro3 were increased in both rapidly and slowly progressive IPF compared with normal lung samples and fibroblasts. Targeting these pathways with either specific antibodies directed at Gas6 or Axl, or with small-molecule TAM inhibitors indicated that the small molecule-mediated targeting approach was more efficacious in both in vitro and in vivo studies. Specifically, the TAM receptor inhibitor R428 (also known as BGB324) significantly inhibited the synthetic, migratory, and proliferative properties of IPF fibroblasts compared with the other Gas6/TAM receptor targeting agents. Finally, loss of Gas6 expression decreased lung fibrotic responses to bleomycin and treatment with R428 inhibited pulmonary fibrosis in humanized SCID/Bg mice. Gas6/TAM receptor activity contributes to the activation of pulmonary fibroblasts in IPF, suggesting that targeting this RTK pathway might be an effective antifibrotic strategy in this disease.

  7. Tranilast prevents renal interstitial fibrosis by blocking mast cell infiltration in a rat model of diabetic kidney disease.

    Science.gov (United States)

    Yin, Dan-Dan; Luo, Jun-Hui; Zhao, Zhu-Ye; Liao, Ying-Jun; Li, Ying

    2018-05-01

    Renal interstitial fibrosis is a final pathway that is observed in various types of kidney diseases, including diabetic kidney disease (DKD). The present study investigated the effect of tranilast on renal interstitial fibrosis and the association between its role and mast cell infiltration in a rat model of DKD. A total of 30 healthy 6‑week‑old male Sprague‑Dawley rats were randomly divided into the following four groups: Normal control group; DKD model group; low‑dose tranilast group (200 mg/kg/day); and high‑dose tranilast group (400 mg/kg/day). The morphological alterations of tubulointerstitial fibrosis were evaluated by Masson's trichrome staining, while mast cell infiltration into the renal tubular interstitium was measured by toluidine blue staining and complement C3a receptor 1 (C3aR) immunohistochemical staining (IHC). The expression of fibronectin (FN), collagen I (Col‑I), stem cell factor (SCF) and proto‑oncogene c‑kit (c‑kit) was detected by IHC, western blotting and reverse transcription‑quantitative‑polymerase chain reaction. The results demonstrated that tubulointerstitial fibrosis and mast cell infiltration were observed in DKD model rats, and this was improved dose‑dependently in the tranilast treatment groups. The expression of FN, Col‑I, SCF and c‑kit mRNA and protein was upregulated in the tubulointerstitium of DKD model rats compared with the normal control rats, and tranilast inhibited the upregulated expression of these markers. Furthermore, the degree of SCF and c‑kit expression demonstrated a significant positive correlation with C3aR‑positive mast cells and the markers of renal interstitial fibrosis. The results of the present study indicate that mast cell infiltration may promote renal interstitial fibrosis via the SCF/c‑kit signaling pathway. Tranilast may prevent renal interstitial fibrosis through inhibition of mast cell infiltration mediated through the SCF/c-kit signaling pathway.

  8. Blockade of lysophosphatidic acid receptors LPAR1/3 ameliorates lung fibrosis induced by irradiation

    International Nuclear Information System (INIS)

    Gan, Lu; Xue, Jian-Xin; Li, Xin; Liu, De-Song; Ge, Yan; Ni, Pei-Yan; Deng, Lin; Lu, You; Jiang, Wei

    2011-01-01

    Highlights: → Lysophosphatidic acid (LPA) levels and its receptors LPAR1/3 transcripts were elevated during the development of radiation-induced lung fibrosis. → Lung fibrosis was obviously alleviated in mice treated with the dual LPAR1/3 antagonist, VPC12249. → VPC12249 administration effectively inhibited radiation-induced fibroblast accumulation in vivo, and suppressed LPA-induced fibroblast proliferation in vitro. → LPA-LPAR1/3 signaling regulated TGFβ1 and CTGF expressions in radiation-challenged lungs, but only influenced CTGF expression in cultured fibroblasts. → LPA-LPAR1/3 signaling induced fibroblast proliferation through a CTGF-dependent pathway, rather than through TGFβ1 activation. -- Abstract: Lung fibrosis is a common and serious complication of radiation therapy for lung cancer, for which there are no efficient treatments. Emerging evidence indicates that lysophosphatidic acid (LPA) and its receptors (LPARs) are involved in the pathogenesis of fibrosis. Here, we reported that thoracic radiation with 16 Gy in mice induced development of radiation lung fibrosis (RLF) accompanied by obvious increases in LPA release and LPAR1 and LPAR3 (LPAR1/3) transcripts. RLF was significantly alleviated in mice treated with the dual LPAR1/3 antagonist, VPC12249. VPC12249 administration effectively prolonged animal survival, restored lung structure, inhibited fibroblast accumulation and reduced collagen deposition. Moreover, profibrotic cytokines in radiation-challenged lungs obviously decreased following administration of VPC12249, including transforming growth factor β1 (TGFβ1) and connective tissue growth factor (CTGF). In vitro, LPA induced both fibroblast proliferation and CTGF expression in a dose-dependent manner, and both were suppressed by blockade of LPAR1/3. The pro-proliferative activity of LPA on fibroblasts was inhibited by siRNA directed against CTGF. Together, our data suggest that the LPA-LPAR1/3 signaling system is involved in the

  9. Blockade of lysophosphatidic acid receptors LPAR1/3 ameliorates lung fibrosis induced by irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Gan, Lu [State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu (China); Xue, Jian-Xin [Department of Thoracic Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu (China); Laboratory of Stem Cell Biology, West China Hospital, Sichuan University, Chengdu (China); Li, Xin [Department of Thoracic Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu (China); Liu, De-Song [Department of Pediatrics, Sichuan Provincial Hospital of Women and Children, Chengdu (China); Ge, Yan; Ni, Pei-Yan; Deng, Lin [State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu (China); Lu, You, E-mail: radyoulu@hotmail.com [State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu (China); Department of Thoracic Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu (China); Jiang, Wei, E-mail: wcumsjw72@hotmail.com [State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu (China); Molecular Medicine Research Center, West China Hospital, Sichuan University, Chengdu (China)

    2011-05-27

    Highlights: {yields} Lysophosphatidic acid (LPA) levels and its receptors LPAR1/3 transcripts were elevated during the development of radiation-induced lung fibrosis. {yields} Lung fibrosis was obviously alleviated in mice treated with the dual LPAR1/3 antagonist, VPC12249. {yields} VPC12249 administration effectively inhibited radiation-induced fibroblast accumulation in vivo, and suppressed LPA-induced fibroblast proliferation in vitro. {yields} LPA-LPAR1/3 signaling regulated TGF{beta}1 and CTGF expressions in radiation-challenged lungs, but only influenced CTGF expression in cultured fibroblasts. {yields} LPA-LPAR1/3 signaling induced fibroblast proliferation through a CTGF-dependent pathway, rather than through TGF{beta}1 activation. -- Abstract: Lung fibrosis is a common and serious complication of radiation therapy for lung cancer, for which there are no efficient treatments. Emerging evidence indicates that lysophosphatidic acid (LPA) and its receptors (LPARs) are involved in the pathogenesis of fibrosis. Here, we reported that thoracic radiation with 16 Gy in mice induced development of radiation lung fibrosis (RLF) accompanied by obvious increases in LPA release and LPAR1 and LPAR3 (LPAR1/3) transcripts. RLF was significantly alleviated in mice treated with the dual LPAR1/3 antagonist, VPC12249. VPC12249 administration effectively prolonged animal survival, restored lung structure, inhibited fibroblast accumulation and reduced collagen deposition. Moreover, profibrotic cytokines in radiation-challenged lungs obviously decreased following administration of VPC12249, including transforming growth factor {beta}1 (TGF{beta}1) and connective tissue growth factor (CTGF). In vitro, LPA induced both fibroblast proliferation and CTGF expression in a dose-dependent manner, and both were suppressed by blockade of LPAR1/3. The pro-proliferative activity of LPA on fibroblasts was inhibited by siRNA directed against CTGF. Together, our data suggest that the LPA-LPAR1

  10. Targeted Sterically Stabilized Phospholipid siRNA Nanomedicine for Hepatic and Renal Fibrosis

    Directory of Open Access Journals (Sweden)

    Fatima Khaja

    2016-01-01

    Full Text Available Since its discovery, small interfering RNA (siRNA has been considered a potent tool for modulating gene expression. It has the ability to specifically target proteins via selective degradation of messenger RNA (mRNA not easily accessed by conventional drugs. Hence, RNA interference (RNAi therapeutics have great potential in the treatment of many diseases caused by faulty protein expression such as fibrosis and cancer. However, for clinical application siRNA faces a number of obstacles, such as poor in vivo stability, and off-target effects. Here we developed a unique targeted nanomedicine to tackle current siRNA delivery issues by formulating a biocompatible, biodegradable and relatively inexpensive nanocarrier of sterically stabilized phospholipid nanoparticles (SSLNPs. This nanocarrier is capable of incorporating siRNA in its core through self-association with a novel cationic lipid composed of naturally occuring phospholipids and amino acids. This overall assembly protects and delivers sufficient amounts of siRNA to knockdown over-expressed protein in target cells. The siRNA used in this study, targets connective tissue growth factor (CTGF, an important regulator of fibrosis in both hepatic and renal cells. Furthermore, asialoglycoprotein receptors are targeted by attaching the galactosamine ligand to the nanocarries which enhances the uptake of nanoparticles by hepatocytes and renal tubular epithelial cells, the major producers of CTGF in fibrosis. On animals this innovative nanoconstruct, small interfering RNA in sterically stabilized phospholipid nanoparticles (siRNA-SSLNP, showed favorable pharmacokinetic properties and accumulated mostly in hepatic and renal tissues making siRNA-SSLNP a suitable system for targeting liver and kidney fibrotic diseases.

  11. Renal function, nephrogenic systemic fibrosis and other adverse reactions associated with gadolinium-based contrast media.

    Science.gov (United States)

    Canga, Ana; Kislikova, Maria; Martínez-Gálvez, María; Arias, Mercedes; Fraga-Rivas, Patricia; Poyatos, Cecilio; de Francisco, Angel L M

    2014-01-01

    Nephrogenic systemic fibrosis is a fibrosing disorder that affects patients with impaired renal function and is associated with the administration of gadolinium-based contrast media used in MRI. Despite being in a group of drugs that were considered safe, report about this potentially serious adverse reaction was a turning point in the administration guidelines of these contrast media. There has been an attempt to establish safety parameters to identify patients with risk factors of renal failure. The close pharmacovigilance and strict observation of current regulations, with special attention being paid to the value of glomerular filtration, have reduced the published cases involving the use of gadolinium-based contrast media. In a meeting between radiologists and nephrologists we reviewed the most relevant aspects currently and recommendations for its prevention.

  12. Fanconi's syndrome, interstitial fibrosis and renal failure by aristolochic acid in Chinese herbs.

    Science.gov (United States)

    Hong, Yin-Tai; Fu, Lin-Shien; Chung, Lin-Huei; Hung, Shien-Chung; Huang, Yi-Ting; Chi, Chin-Shiang

    2006-04-01

    Aristolochic acid-associated nephropathy (AAN) has been identified as a separate entity of progressive tubulo-interstitial nephropathy. Its characteristic pathological findings, including hypocellular interstitial fibrosis, intimal thickening of interlobular and afferent arterioles with glomeruli sparing or mild sclerosis, have been identified. Many cases of AAN in adults have been reported in Taiwan as well as throughout the world, but it has seldom been described in children. We report on a 10-year-old boy who presented with severe anemia, Fanconi's syndrome, and progressive renal failure. Renal biopsy revealed typical findings of AAN. Aristolochic acids I and II were identified from a Chinese herb mixture ingested by the boy. AAN was diagnosed after other etiologies had been excluded. The case demonstrates the hazards of Chinese herbs with regard to children's health in Taiwan and suggests that more attention should be paid to this issue.

  13. Interferon gamma peptidomimetic targeted to hepatic stellate cells ameliorates acute and chronic liver fibrosis in vivo.

    Science.gov (United States)

    Bansal, Ruchi; Prakash, Jai; De Ruiter, Marieke; Poelstra, Klaas

    2014-04-10

    Hepatic stellate cells play a crucial role in the pathogenesis of hepatic fibrosis. Thus, pharmacological inhibition of pro-fibrotic activities of these cells might lead to an effective therapy for this disease. Among the potent anti-fibrotics, interferon gamma (IFNγ), a proinflammatory cytokine, is highly efficacious but it failed in clinical trials due to the poor efficacy and multiple adverse effects attributed to the ubiquitous IFNγ receptor (IFNγR) expression. To resolve these drawbacks, we chemically synthesized a chimeric molecule containing (a) IFNγ signaling peptide (IFNγ peptidomimetic, mimγ) that retains the agonistic activities of IFNγ but lacks an extracellular receptor recognition sequence for IFNγR; coupled via heterobifunctional PEG linker to (b) bicyclic platelet derived growth factor beta receptor (PDGFβR)-binding peptide (BiPPB) to induce internalization into the stellate cells that express PDGFβR. The synthesized targeted IFNγ peptidomimetic (mimγ-BiPPB) was extensively investigated for its anti-fibrotic and adverse effects in acute and chronic CCl4-induced liver fibrosis models in mice. Treatment with mimγ-BiPPB, after the onset of disease, markedly inhibited both early and established hepatic fibrosis as reflected by a reduced intrahepatic α-SMA, desmin and collagen-I mRNA expression and protein levels. While untargeted mimγ and BiPPB had no effect, and native IFNγ only induced a moderate reduction. Additionally, no off-target effects, e.g. systemic inflammation, were found with mimγ-BiPPB, which were substantially observed in mice treated with native IFNγ. The present study highlights the beneficial effects of a novel BiPPB mediated cell-specific targeting of IFNγ peptidomimetic to the disease-inducing cells and therefore represents a highly potential therapeutic approach to treat fibrotic diseases. Copyright © 2014 Elsevier B.V. All rights reserved.

  14. Identification of Tisp40 as an Essential Regulator of Renal Tubulointerstitial Fibrosis via TGF-β/Smads Pathway

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    Cheng-cheng Xiao

    2017-06-01

    Full Text Available Background: Tisp40, a transcription factor of the CREB/CREM family, is involved in cell proliferation, differentiation and other biological functions, but its role in renal tubulointerstitial fibrosis is unknown. Methods: In our study, we investigated the effects of Tisp40 on extracellular matrix (ECM accumulation, epithelial-mesenchymal transition (EMT and the underlying molecular mechanisms in transforming growth factor-β (TGF-β-stimulated TCMK-1 cells by quantitative real-time polymerase chain reaction (qPCR, Western blot analysis and immunofluorescence in vitro, and further explored the role of Tisp40 on renal fibrosis induced by ischemia-reperfusion (I/R by qPCR, Western blot analysis, hydroxyproline analysis, Masson trichrome staining and immunohistochemistry staining in vivo. Results: The data showed that Tisp40 was upregulated in a model of renal fibrosis induced by I/R injury (IRI. Upon IRI, Tisp40-deficient mice showed attenuated renal fibrosis compared with wild-type mice. Furthermore, the expression of α-smooth muscle actin, E-cadherin, fibronectin, and collagen I was suppressed. Tisp40 overexpression aggravated ECM accumulation and EMT in the TGF-β-stimulated TCMK-1 cell line, whereas the opposite occurred in cells treated with small interfering RNA (siRNA targeting Tisp40. Importantly, it is changes in the Smad pathway that attenuate renal fibrosis. Conclusion: These findings suggest that Tisp40 plays a critical role in the TGF-β/ Smads pathway involved in this process. Hence, Tisp40 could be a useful therapeutic target in the fight against renal tubulointerstitial fibrosis.

  15. Arctigenin suppresses renal interstitial fibrosis in a rat model of obstructive nephropathy.

    Science.gov (United States)

    Li, Ao; Zhang, Xiaoxun; Shu, Mao; Wu, Mingjun; Wang, Jun; Zhang, Jingyao; Wang, Rui; Li, Peng; Wang, Yitao

    2017-07-01

    Renal tubulointerstitial fibrosis (TIF) is commonly the final result of a variety of progressive injuries and leads to end-stage renal disease. There are few therapeutic agents currently available for retarding the development of renal TIF. The aim of the present study is to evaluate the role of arctigenin (ATG), a lignan component derived from dried burdock (Arctium lappa L.) fruits, in protecting the kidney against injury by unilateral ureteral obstruction (UUO) in rats. Rats were subjected to UUO and then administered with vehicle, ATG (1 and 3mg/kg/d), or losartan (20mg/kg/d) for 11 consecutive days. The renoprotective effects of ATG were evaluated by histological examination and multiple biochemical assays. Our results suggest that ATG significantly protected the kidney from injury by reducing tubular dilatation, epithelial atrophy, collagen deposition, and tubulointerstitial compartment expansion. ATG administration dramatically decreased macrophage (CD68-positive cell) infiltration. Meanwhile, ATG down-regulated the mRNA levels of pro-inflammatory chemokine monocyte chemoattractant protein-1 (MCP-1) and cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interferon-γ (IFN-γ), in the obstructed kidneys. This was associated with decreased activation of nuclear factor κB (NF-κB). ATG attenuated UUO-induced oxidative stress by increasing the activity of renal manganese superoxide dismutase (SOD2), leading to reduced levels of lipid peroxidation. Furthermore, ATG inhibited the epithelial-mesenchymal transition (EMT) of renal tubules by reducing the abundance of transforming growth factor-β1 (TGF-β1) and its type I receptor, suppressing Smad2/3 phosphorylation and nuclear translocation, and up-regulating Smad7 expression. Notably, the efficacy of ATG in renal protection was comparable or even superior to losartan. ATG could protect the kidney from UUO-induced injury and fibrogenesis by suppressing inflammation, oxidative

  16. Celecoxib ameliorates portal hypertension of the cirrhotic rats through the dual inhibitory effects on the intrahepatic fibrosis and angiogenesis.

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    Jin-Hang Gao

    Full Text Available BACKGROUND: Increased intra-hepatic resistance to portal blood flow is the primary factor leading to portal hypertension in cirrhosis. Up-regulated expression of cyclooxygenase-2 (COX-2 in the cirrhotic liver might be a potential target to ameliorate portal hypertension. OBJECTIVE: To verify the effect of celecoxib, a selective inhibitor of COX-2, on portal hypertension and the mechanisms behind it. METHODS: Cirrhotic liver model of rat was established by peritoneal injection of thiacetamide (TAA. 36 rats were randomly assigned to control, TAA and TAA+celecoxib groups. Portal pressures were measured by introduction of catheters into portal vein. Hepatic fibrosis was assessed by the visible hepatic fibrotic areas and mRNAs for collagen III and α-SMA. The neovasculature was determined by hepatic vascular areas, vascular casts and CD31 expression. Expressions of COX-2, vascular endothelial growth factor (VEGF, VEGF receptor-2 (VEGFR-2 and related signal molecules were quantitated. RESULTS: Compared with TAA group, the portal pressure in TAA+celecoxib group was significantly decreased by 17.8%, p<0.01. Celecoxib treatment greatly reduced the tortuous hepatic portal venules. The data of fibrotic areas, CD31expression, mRNA levels of α-SMA and collagen III in TAA+celecoxib group were much lower than those in TAA group, p<0.01. Furthermore, the up-regulation of hepatic mRNA and protein levels of VEGF, VEGFR-2 and COX-2 induced by TAA was significantly inhibited after celecoxib treatment. The expressions of prostaglandin E2 (PGE2, phosphorylated extracellular signal-regulated kinase (p-ERK, hypoxia-inducible factor-1α (HIF-1α, and c-fos were also down-regulated after celecoxib treatment. CONCLUSIONS: Long term administration of celecoxib can efficiently ameliorate portal hypertension in TAA rat model by its dual inhibitory effects on the intrahepatic fibrosis and angiogenesis. The anti-angiogenesis effect afforded by celecoxib may attribute to its

  17. Ameliorative Effect of Curcumin-Encapsulated Hyaluronic Acid–PLA Nanoparticles on Thioacetamide-Induced Murine Hepatic Fibrosis

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    Yu-Nong Chen

    2016-12-01

    Full Text Available In this study, we developed curcumin-encapsulated hyaluronic acid–polylactide nanoparticles (CEHPNPs to be used for liver fibrosis amelioration. CD44, the hyaluronic acid (HA receptor, is upregulated on the surface of cancer cells and on activated hepatic stellate cells (aHSCs rather than normal cells. CEHPNPs could bind to CD44 and be internalized effectively through endocytosis to release curcumin, a poor water-soluble liver protective agent. Thus, CEHPNPs were potentially not only improving drug efficiency, but also targeting aHSCs. HA and polylactide (PLA were crosslinked by adipic acid dihydrazide (ADH. The synthesis of HA–PLA was monitored by Fourier-transform infrared (FTIR and Nuclear Magnetic Resonance (NMR. The average particle size was approximately 60–70 nm as determined by dynamic light scattering (DLS and scanning electron microscope (SEM. Zeta potential was around −30 mV, which suggested a good stability of the particles. This drug delivery system induced significant aHSC cell death without affecting quiescent HSCs, hepatic epithelial, and parenchymal cells. This system reduced drug dosage without sacrificing therapeutic efficacy. The cytotoxicity IC50 (inhibitory concentration at 50% value of CEHPNPs was approximately 1/30 to that of the free drug treated group in vitro. Additionally, the therapeutic effects of CEHPNPs were as effective as the group treated with the same curcumin dose intensity in vivo. CEHPNPs significantly reduced serum aspartate transaminase/alanine transaminase (ALT/AST significantly, and attenuated tissue collagen production and cell proliferation as revealed by liver biopsy. Conclusively, the advantages of superior biosafety and satisfactory therapeutic effect mean that CEHPNPs hold great potential for treating hepatic fibrosis.

  18. Glycogen synthase kinase-3 inhibition attenuates fibroblast activation and development of fibrosis following renal ischemia-reperfusion in mice

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    Shailendra P. Singh

    2015-08-01

    Full Text Available Glycogen synthase kinase-3β (GSK3β is a serine/threonine protein kinase that plays an important role in renal tubular injury and regeneration in acute kidney injury. However, its role in the development of renal fibrosis, often a long-term consequence of acute kidney injury, is unknown. Using a mouse model of renal fibrosis induced by ischemia-reperfusion injury, we demonstrate increased GSK3β expression and activity in fibrotic kidneys, and its presence in myofibroblasts in addition to tubular epithelial cells. Pharmacological inhibition of GSK3 using TDZD-8 starting before or after ischemia-reperfusion significantly suppressed renal fibrosis by reducing the myofibroblast population, collagen-1 and fibronectin deposition, inflammatory cytokines, and macrophage infiltration. GSK3 inhibition in vivo reduced TGF-β1, SMAD3 activation and plasminogen activator inhibitor-1 levels. Consistently in vitro, TGF-β1 treatment increased GSK3β expression and GSK3 inhibition abolished TGF-β1-induced SMAD3 activation and α-smooth muscle actin (α-SMA expression in cultured renal fibroblasts. Importantly, overexpression of constitutively active GSK3β stimulated α-SMA expression even in the absence of TGF-β1 treatment. These results suggest that TGF-β regulates GSK3β, which in turn is important for TGF-β–SMAD3 signaling and fibroblast-to-myofibroblast differentiation. Overall, these studies demonstrate that GSK3 could promote renal fibrosis by activation of TGF-β signaling and the use of GSK3 inhibitors might represent a novel therapeutic approach for progressive renal fibrosis that develops as a consequence of acute kidney injury.

  19. Inhibition of Extracellular Signal-Regulated Kinases Ameliorates Hypertension-Induced Renal Vascular Remodeling in Rat Models

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    Li Jing

    2011-11-01

    Full Text Available The aim of this study is to investigate the effect of the extracellular signal-regulated kinases 1/2 (ERK1/2 inhibitor, PD98059, on high blood pressure and related vascular changes. Blood pressure was recorded, thicknesses of renal small artery walls were measured and ERK1/2 immunoreactivity and erk2 mRNA in renal vascular smooth muscle cells (VSMCs and endothelial cells were detected by immunohistochemistry and in situ hybridization in normotensive wistar kyoto (WKY rats, spontaneously hypertensive rats (SHR and PD98059-treated SHR. Compared with normo-tensive WKY rats, SHR developed hypertension at 8 weeks of age, thickened renal small artery wall and asymmetric arrangement of VSMCs at 16 and 24 weeks of age. Phospho-ERK1/2 immunoreactivity and erk2 mRNA expression levels were increased in VSMCs and endothelial cells of the renal small arteries in the SHR. Treating SHR with PD98059 reduced the spontaneous hypertension-induced vascular wall thickening. This effect was associated with suppressions of erk2 mRNA expression and ERK1/2 phosphorylation in VSMCs and endothelial cells of the renal small arteries. It is concluded that inhibition of ERK1/2 ameliorates hypertension induced vascular remodeling in renal small arteries.

  20. Heterogenic transplantation of bone marrow-derived rhesus macaque mesenchymal stem cells ameliorates liver fibrosis induced by carbon tetrachloride in mouse

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    Xufeng Fu

    2018-02-01

    Full Text Available Liver fibrosis is a disease that causes high morbidity and has become a major health problem. Liver fibrosis can lead to the end stage of liver diseases (livercirrhosisand hepatocellularcarcinoma. Currently, liver transplantation is the only effective treatment for end-stage liver disease. However, the shortage of organ donors, high cost of medical surgery, immunological rejection and transplantation complications severely hamper liver transplantation therapy. Mesenchymal stem cells (MSCs have been regarded as promising cells for clinical applications in stem cell therapy in the treatment of liver diseases due to their unique multipotent differentiation capacity, immunoregulation and paracrine effects. Although liver fibrosis improvements by MSC transplantation in preclinical experiments as well as clinical trials have been reported, the in vivo fate of MSCs after transportation and their therapeutic mechanisms remain unclear. In this present study, we isolated MSCs from the bone marrow of rhesus macaques. The cells exhibited typical MSC markers and could differentiate into chondrocytes, osteocytes, and adipocytes, which were not affected by labeling with enhanced green fluorescent protein (EGFP. The harvested MSCs respond to interferon-γ stimulation and have the ability to inhibit lymphocyte proliferation in vitro. EGFP-labeled MSCs (1 × 106 cells were transplanted into mice with carbon tetrachloride-induced liver fibrosis via tail vein injection. The ability of the heterogenic MSC infusion to ameliorate liver fibrosis in mice was evaluated by a blood plasma chemistry index, pathological examination and liver fibrosis-associated gene expression. Additionally, a small number of MSCs that homed and engrafted in the mouse liver tissues were evaluated by immunofluorescence analysis. Our results showed that the transplantation of heterogenic MSCs derived from monkey bone marrow can be used to treat liver fibrosis in the mouse model and that the

  1. Tubulointerstitial fibrosis in patients with IgG4-related kidney disease: pathological findings on repeat renal biopsy

    NARCIS (Netherlands)

    Arai, Haruna; Hayashi, Hiroki; Takahashi, Kazuo; Koide, Shigehisa; Sato, Waichi; Hasegawa, Midori; Yamaguchi, Yutaka; Aten, Jan; Ito, Yasuhiko; Yuzawa, Yukio

    2015-01-01

    Renal parenchymal lesions in patients with IgG4-related kidney disease (IgG4-RKD) are characterized by tubulointerstitial nephritis with storiform fibrosis and infiltration by high numbers of IgG4-positive plasma cells. The aim of this study was to evaluate the clinical and pathological effects of

  2. Immunomodulatory Molecule IRAK-M Balances Macrophage Polarization and Determines Macrophage Responses during Renal Fibrosis.

    Science.gov (United States)

    Steiger, Stefanie; Kumar, Santhosh V; Honarpisheh, Mohsen; Lorenz, Georg; Günthner, Roman; Romoli, Simone; Gröbmayr, Regina; Susanti, Heni-Eka; Potempa, Jan; Koziel, Joanna; Lech, Maciej

    2017-08-15

    Activation of various innate immune receptors results in IL-1 receptor-associated kinase (IRAK)-1/IRAK-4-mediated signaling and secretion of proinflammatory cytokines such as IL-12, IL-6, or TNF-α, all of which are implicated in tissue injury and elevated during tissue remodeling processes. IRAK-M, also known as IRAK-3, is an inhibitor of proinflammatory cytokine and chemokine expression in intrarenal macrophages. Innate immune activation contributes to both acute kidney injury and tissue remodeling that is associated with chronic kidney disease (CKD). Our study assessed the contribution of macrophages in CKD and the role of IRAK-M in modulating disease progression. To evaluate the effect of IRAK-M in chronic renal injury in vivo, a mouse model of unilateral ureteral obstruction (UUO) was employed. The expression of IRAK-M increased within 2 d after UUO in obstructed compared with unobstructed kidneys. Mice deficient in IRAK-M were protected from fibrosis and displayed a diminished number of alternatively activated macrophages. Compared to wild-type mice, IRAK-M-deficient mice showed reduced tubular injury, leukocyte infiltration, and inflammation following renal injury as determined by light microscopy, immunohistochemistry, and intrarenal mRNA expression of proinflammatory and profibrotic mediators. Taken together, these results strongly support a role for IRAK-M in renal injury and identify IRAK-M as a possible modulator in driving an alternatively activated profibrotic macrophage phenotype in UUO-induced CKD. Copyright © 2017 by The American Association of Immunologists, Inc.

  3. Reactive Oxygen Species Modulation of Na/K-ATPase Regulates Fibrosis and Renal Proximal Tubular Sodium Handling

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    Jiang Liu

    2012-01-01

    Full Text Available The Na/K-ATPase is the primary force regulating renal sodium handling and plays a key role in both ion homeostasis and blood pressure regulation. Recently, cardiotonic steroids (CTS-mediated Na/K-ATPase signaling has been shown to regulate fibrosis, renal proximal tubule (RPT sodium reabsorption, and experimental Dahl salt-sensitive hypertension in response to a high-salt diet. Reactive oxygen species (ROS are an important modulator of nephron ion transport. As there is limited knowledge regarding the role of ROS-mediated fibrosis and RPT sodium reabsorption through the Na/K-ATPase, the focus of this review is to examine the possible role of ROS in the regulation of Na/K-ATPase activity, its signaling, fibrosis, and RPT sodium reabsorption.

  4. Vitamin D Can Ameliorate Chlorhexidine Gluconate-Induced Peritoneal Fibrosis and Functional Deterioration through the Inhibition of Epithelial-to-Mesenchymal Transition of Mesothelial Cells

    Directory of Open Access Journals (Sweden)

    Yi-Che Lee

    2015-01-01

    Full Text Available Background. Peritoneal dialysis (PD can induce fibrosis and functional alterations in PD patients’ peritoneal membranes, due to long-term unphysiological dialysate exposure, partially occurring via triggering of epithelial-to-mesenchymal transition (EMT in peritoneal mesothelial cells (MCs. Vitamin D can ameliorate these negative effects; however, the mechanism remains unexplored. Therefore, we investigated its possible links to MCs EMT inhibition. Methods. Peritoneal fibrosis was established in Sprague-Dawley rats by chlorhexidine gluconate (CG intraperitoneal injection for 21 days, with and without 1α,25(OH2D3 treatment. Morphological and functional evaluation and western blot analysis of EMT marker were performed upon peritoneum tissue. In vitro study was also performed in a primary human peritoneal MC culture system; MCs were incubated with transforming growth factor-β1 (TGF-β1 in the absence or presence of 1α,25(OH2D3. EMT marker expression, migration activities, and cytoskeleton redistribution of MCs were determined. Results. 1α,25(OH2D3 ameliorated CG-induced morphological and functional deterioration in animal model, along with CG-induced upregulation of α-SMA and downregulation of E-cadherin expression. Meanwhile, 1α,25(OH2D3 also ameliorated TGF-β1-induced decrease in E-cadherin expression, increase in Snai1 and α-SMA expression, intracellular F-actin redistribution, and migration activity in vitro. Conclusion. 1α,25(OH2D3 can ameliorate CG-induced peritoneal fibrosis and attenuate functional deterioration through inhibiting MC EMT.

  5. Local delivery of biodegradable pirfenidone nanoparticles ameliorates bleomycin-induced pulmonary fibrosis in mice

    Science.gov (United States)

    Trivedi, Ruchit; Redente, Elizabeth F.; Thakur, Ashish; Riches, David W. H.; Kompella, Uday B.

    2012-12-01

    Our purpose was to assess sustained delivery and enhanced efficacy of pirfenidone-loaded nanoparticles after intratracheal instillation. Poly(lactide-co-glycolide) nanoparticles containing pirfenidone (NPs) were prepared and characterized. Biodistribution of NPs and solution was assessed using LC-MS after intratracheal administration in C57Bl/6 mice at 3 and 24 h and 1 week post-administration. Efficacy was tested in C57Bl/6 mice in a bleomycin-induced pulmonary fibrosis model. Mice received 10 μg pirfenidone intratracheally in solution or NPs, once a week, for 3 weeks after bleomycin administration. Drug effects were monitored on day 28. Lung hydroxyproline content, total number of cells, and numbers of macrophages, lymphocytes, and neutrophils in bronchoalveolar lavage (BAL) were assessed. Numbers of macrophages, lymphocytes, and neutrophils were assessed in the lung as well. NPs sustained significantly higher levels of pirfenidone in the lungs and BAL at 24 h and 1 week, compared to the solution group. Pirfenidone solution and NPs significantly reduced hydroxyproline levels by 57 and 81%, respectively, compared to bleomycin alone. At the end of 4 weeks, BAL cellularity was reduced by 25.4% and 56% with solution and NP treatment, respectively. The numbers of lymphocytes and neutrophils in the BAL were also reduced by 58.9 and 82.4% for solution and 74.5% and 89.7% for NPs, respectively. The number of inflammatory macrophages in the lung was reduced by 62.8% and the number of neutrophils was reduced by 59.1% in the NP group and by 37.7% and 44.5%, respectively, in the solution group, compared to bleomycin alone. In conclusion, nanoparticles sustain lung pirfenidone delivery and enhance its anti-fibrotic efficacy.

  6. Chemical Composition of Golden Berry Leaves Against Hepato-renal Fibrosis.

    Science.gov (United States)

    Khalaf-Allah, Abd El-Rahman M; El-Gengaihi, Souad E; Hamed, Manal A; Zahran, Hanan G; Mohammed, Mona A

    2016-01-01

    The role of Physalis peruviana (golden berry) as functional food against hepato-renal fibrosis induced by carbon tetrachloride (CCl4) was evaluated. The chemical composition of leaves referred the presence of withanolides and flavonoids. Two compounds, ursolic acid and lupeol, were isolated and their structures were elucidated by different spectral analysis techniques. The biological evaluation was conducted on different animal groups; control rats, control orally treated with plant extract (500 mg/kg body weight twice a week for six consecutive weeks), CCl4 (0.5 ml/kg body weight diluted to 1:9 (v/v) in olive oil and injected intraperitoneally) group, CCl4 treated with plant extract and CCl4 treated with silymarin as a reference herbal drug. The evaluation was done through measuring oxidative stress markers; malondialdehyde (MDA), superoxide dismutase (SOD) and nitric oxide (NO). Liver function indices; aspartate and alanine aminotransferases (AST & ALT), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), bilirubin and total hepatic protein were also estimated. Kidney disorder biomarkers; creatinine, urea and serum protein were also evaluated. The results revealed plant safety and decrease in NO, MDA, IgG, ALP, tissue protein, bilirubin, creatinine and urea levels. Increase in SOD, AST, ALT, GGT and serum protein levels were observed. Improvement in liver and kidney histopathological architectures were also seen. In conclusion, Physalis peruviana recorded a significant protective role in liver and kidney against fibrosis. Further studies are needed to evaluate its isolated compounds and its use in pharmacological applications and clinical uses.

  7. The Soluble Epoxide Hydrolase Inhibitor AR9281 Decreases Blood Pressure, Ameliorates Renal Injury and Improves Vascular Function in Hypertension

    Directory of Open Access Journals (Sweden)

    Sean Shaw

    2009-12-01

    Full Text Available Soluble epoxide hydrolase inhibitors (sEHIs are demonstrating promise as potential pharmaceutical agents for the treatment of cardiovascular disease, diabetes, inflammation, and kidney disease. The present study determined the ability of a first-inclass sEHI, AR9281, to decrease blood pressure, improve vascular function, and decrease renal inflammation and injury in angiotensin hypertension. Rats were infused with angiotensin and AR9281 was given orally during the 14-day infusion period. Systolic blood pressure averaged 180 ± 5 mmHg in vehicle treated and AR9281 treatment significantly lowered blood pressure to 142 ± 7 mmHg in angiotensin hypertension. Histological analysis demonstrated decreased injury to the juxtamedullary glomeruli. Renal expression of inflammatory genes was increased in angiotensin hypertension and two weeks of AR9281 treatment decreased this index of renal inflammation. Vascular function in angiotensin hypertension was also improved by AR9281 treatment. Decreased afferent arteriolar and mesenteric resistance endothelial dependent dilator responses were ameliorated by AR9281 treatment of angiotensin hypertensive rats. These data demonstrate that the first-in-class sEHI, AR9281, lowers blood pressure, improves vascular function and reduces renal damage in angiotensin hypertension.

  8. Altered renal expression of angiotensin II receptors, renin receptor, and ACE-2 precede the development of renal fibrosis in aging rats.

    Science.gov (United States)

    Schulman, Ivonne Hernandez; Zhou, Ming-Sheng; Treuer, Adriana V; Chadipiralla, Kiranmai; Hare, Joshua M; Raij, Leopoldo

    2010-01-01

    The susceptibility to fibrosis and progression of renal disease is mitigated by inhibition of the renin-angiotensin system (RAS). We hypothesized that activation of the intrarenal RAS predisposes to renal fibrosis in aging. Intrarenal expression of angiotensin II type 1 (AT(1)R), type 2 (AT(2)R), and (pro)renin receptors, ACE and ACE-2, as well as pro- and antioxidant enzymes were measured in 3-month-old (young), 14-month-old (middle-aged), and 24-month-old (old) male Sprague-Dawley rats. Old rats manifested glomerulosclerosis and severe tubulointerstitial fibrosis with increased fibronectin and TGF-β expression (7-fold). AT(1)R /AT(2)R ratios were increased in middle-aged (cortical 1.6-fold, medullary 5-fold) and old rats (cortical 2-fold, medullary 4-fold). Similarly, (pro)renin receptor expression was increased in middle-aged (cortical 2-fold, medullary 3-fold) and old (cortical 5-fold, medullary 3-fold) rats. Cortical ACE was increased (+35%) in old rats, whereas ACE-2 was decreased (-50%) in middle-aged and old rats. NADPH oxidase activity was increased (2-fold), whereas antioxidant capacity and expression of the mitochondrial enzyme manganese superoxide dismutase (cortical -40%, medullary -53%) and medullary endothelial nitric oxide synthase (-48%) were decreased in old rats. Age-related intrarenal activation of the RAS preceded the development of severe renal fibrosis, suggesting that it contributes to the increased susceptibility to renal injury observed in the elderly. Copyright © 2010 S. Karger AG, Basel.

  9. Automated quantification of renal interstitial fibrosis for computer-aided diagnosis: A comprehensive tissue structure segmentation method.

    Science.gov (United States)

    Tey, Wei Keat; Kuang, Ye Chow; Ooi, Melanie Po-Leen; Khoo, Joon Joon

    2018-03-01

    Interstitial fibrosis in renal biopsy samples is a scarring tissue structure that may be visually quantified by pathologists as an indicator to the presence and extent of chronic kidney disease. The standard method of quantification by visual evaluation presents reproducibility issues in the diagnoses. This study proposes an automated quantification system for measuring the amount of interstitial fibrosis in renal biopsy images as a consistent basis of comparison among pathologists. The system extracts and segments the renal tissue structures based on colour information and structural assumptions of the tissue structures. The regions in the biopsy representing the interstitial fibrosis are deduced through the elimination of non-interstitial fibrosis structures from the biopsy area and quantified as a percentage of the total area of the biopsy sample. A ground truth image dataset has been manually prepared by consulting an experienced pathologist for the validation of the segmentation algorithms. The results from experiments involving experienced pathologists have demonstrated a good correlation in quantification result between the automated system and the pathologists' visual evaluation. Experiments investigating the variability in pathologists also proved the automated quantification error rate to be on par with the average intra-observer variability in pathologists' quantification. Interstitial fibrosis in renal biopsy samples is a scarring tissue structure that may be visually quantified by pathologists as an indicator to the presence and extent of chronic kidney disease. The standard method of quantification by visual evaluation presents reproducibility issues in the diagnoses due to the uncertainties in human judgement. An automated quantification system for accurately measuring the amount of interstitial fibrosis in renal biopsy images is presented as a consistent basis of comparison among pathologists. The system identifies the renal tissue structures

  10. Morin ameliorates chemically induced liver fibrosis in vivo and inhibits stellate cell proliferation in vitro by suppressing Wnt/β-catenin signaling

    Energy Technology Data Exchange (ETDEWEB)

    MadanKumar, Perumal; NaveenKumar, Perumal; Manikandan, Samidurai [Department of Biochemistry, University of Madras, Guindy Campus, Chennai 600 025, Tamil Nadu (India); Devaraj, Halagowder [Department of Zoology, University of Madras, Guindy Campus, Chennai 600 025, Tamil Nadu (India); NiranjaliDevaraj, Sivasithamparam, E-mail: niranjali@yahoo.com [Department of Biochemistry, University of Madras, Guindy Campus, Chennai 600 025, Tamil Nadu (India)

    2014-06-01

    The anti-fibrotic effect of morin was examined in LX-2 cells (culture-activated human hepatic stellate cells) and in diethylnitrosamine induced rat model of liver fibrosis. The in vitro study was designed to determine whether morin affects the survival of cultured LX-2 cells, while the in vivo study was designed to evaluate the antioxidant and anti-fibrotic efficacy of morin on diethylnitrosamine induced liver fibrosis in male albino Wistar rat. The activities of liver function enzymes in serum, liver lipid peroxide levels, activities of serum antioxidant enzymes and liver architecture were monitored to cast light on the antioxidant and hepatoprotective nature of morin. To establish the anti-fibrotic effects of morin, the levels of key Wnt signaling molecules which are strongly associated with the signal transduction pathway of HSC activation were measured. Overall, from the in vitro results, it was observed that morin at 50 μM concentration inhibited the proliferation of cultured LX-2 cells, inhibited Wnt signaling and induced G1 cell cycle arrest. The in vivo results further confirmed that morin by downregulating the expressions of GSK-3β, β-catenin and cyclin D1 ameliorated DEN-induced liver fibrosis. Hence morin could be employed as a promising chemopreventive natural supplement for liver fibrosis. - Highlights: • In vivo and in vitro results revealed the active participation of Wnt signaling. • Morin at 50 μM inhibited LX-2 cell proliferation by suppressing Wnt signaling. • Morin exhibited hepatoprotective effects against DEN induced liver fibrosis. • Morin inhibited HSC activation in vivo by downregulating Wnt/β-catenin signaling.

  11. Bromide supplementation exacerbated the renal dysfunction, injury and fibrosis in a mouse model of Alport syndrome.

    Science.gov (United States)

    Yokota, Tsubasa; Omachi, Kohei; Suico, Mary Ann; Kojima, Haruka; Kamura, Misato; Teramoto, Keisuke; Kaseda, Shota; Kuwazuru, Jun; Shuto, Tsuyoshi; Kai, Hirofumi

    2017-01-01

    A seminal study recently demonstrated that bromide (Br-) has a critical function in the assembly of type IV collagen in basement membrane (BM), and suggested that Br- supplementation has therapeutic potential for BM diseases. Because salts of bromide (KBr and NaBr) have been used as antiepileptic drugs for several decades, repositioning of Br- for BM diseases is probable. However, the effects of Br- on glomerular basement membrane (GBM) disease such as Alport syndrome (AS) and its impact on the kidney are still unknown. In this study, we administered daily for 16 weeks 75 mg/kg or 250 mg/kg (within clinical dosage) NaBr or NaCl (control) via drinking water to 6-week-old AS mice (mouse model of X-linked AS). Treatment with 75 mg/kg NaBr had no effect on AS progression. Surprisingly, compared with 250 mg/kg NaCl, 250 mg/kg NaBr exacerbated the progressive proteinuria and increased the serum creatinine and blood urea nitrogen in AS mice. Histological analysis revealed that glomerular injury, renal inflammation and fibrosis were exacerbated in mice treated with 250 mg/kg NaBr compared with NaCl. The expressions of renal injury markers (Lcn2, Lysozyme), matrix metalloproteinase (Mmp-12), pro-inflammatory cytokines (Il-6, Il-8, Tnf-α, Il-1β) and pro-fibrotic genes (Tgf-β, Col1a1, α-Sma) were also exacerbated by 250 mg/kg NaBr treatment. Notably, the exacerbating effects of Br- were not observed in wild-type mice. These findings suggest that Br- supplementation needs to be carefully evaluated for real positive health benefits and for the absence of adverse side effects especially in GBM diseases such as AS.

  12. Aminoglycoside exposure and renal function before lung transplantation in adult cystic fibrosis patients.

    Science.gov (United States)

    Novel-Catin, Etienne; Pelletier, Solenne; Reynaud, Quitterie; Nove-Josserand, Raphaele; Durupt, Stephane; Dubourg, Laurence; Durieu, Isabelle; Fouque, Denis

    2018-04-18

    Patients with cystic fibrosis (CF) are at risk of kidney injury even before undergoing lung transplantation, because of prolonged exposure to aminoglycosides (AGs), chronic dehydration and complications of diabetes mellitus. The usual equations estimating the glomerular filtration rate (GFR), such as Cockcroft-Gault and Modification of Diet in Renal Disease, are not adapted to the CF population due to patients' low body weight and reduced muscle mass. The aim of this study was to precisely measure GFR in adult CF patients and to see whether repeated AG treatment would impair renal function before lung transplantation. Inulin or iohexol clearances were performed in 25 adult CF patients when they entered the lung transplant waiting list. No patient was treated with AGs at the time of GFR measurement. Body mass index (BMI), history of diabetes mellitus and blood pressure were recorded. Exposure to intravenous (IV) AGs within 5 years prior to the GFR measurement was obtained from the patient's medical files. Urine samples were collected to check for albuminuria and proteinuria. The population was predominantly female (67%). The mean age was 32 years, the mean BMI was 19 kg/m2 and 28% had CF-related diabetes. Median exposure to IV AG within 5 years before GFR measurement was 155 days with a mean dosage of 7.7mg/kg/day. The mean measured GFR was 106 mL/min/1.73 m2 and the mean estimated GFR according to the Chronic Kidney Disease Epidemiology Collaboration formula was 124 mL/min/1.73 m2. Despite prolonged exposure to high-dose IV AG, no decline in GFR was observed in these patients.

  13. Heat-processed ginseng saponin ameliorates the adenine-induced renal failure in rats

    OpenAIRE

    Kim, Eun Jin; Oh, Hyun-A; Choi, Hyuck Jai; Park, Jeong Hill; Kim, Dong-Hyun; Kim, Nam Jae

    2013-01-01

    To evaluate the effect of the saponin of heat-processed ginseng (Sun ginseng, SG), we investigated the protective effect of SG total saponin fraction against adenine-induced chronic renal failure in rats. SG saponin significantly decreased the levels of urea nitrogen and creatinine in the serum, but increased the urinary excretion of urea nitrogen and creatinine, indicating an improvement of renal function. SG saponin also inhibited adenine-induced kidney hypertrophy and edema. SG saponin red...

  14. Reducing VEGF-B Signaling Ameliorates Renal Lipotoxicity and Protects against Diabetic Kidney Disease.

    Science.gov (United States)

    Falkevall, Annelie; Mehlem, Annika; Palombo, Isolde; Heller Sahlgren, Benjamin; Ebarasi, Lwaki; He, Liqun; Ytterberg, A Jimmy; Olauson, Hannes; Axelsson, Jonas; Sundelin, Birgitta; Patrakka, Jaakko; Scotney, Pierre; Nash, Andrew; Eriksson, Ulf

    2017-03-07

    Diabetic kidney disease (DKD) is the most common cause of severe renal disease, and few treatment options are available today that prevent the progressive loss of renal function. DKD is characterized by altered glomerular filtration and proteinuria. A common observation in DKD is the presence of renal steatosis, but the mechanism(s) underlying this observation and to what extent they contribute to disease progression are unknown. Vascular endothelial growth factor B (VEGF-B) controls muscle lipid accumulation through regulation of endothelial fatty acid transport. Here, we demonstrate in experimental mouse models of DKD that renal VEGF-B expression correlates with the severity of disease. Inhibiting VEGF-B signaling in DKD mouse models reduces renal lipotoxicity, re-sensitizes podocytes to insulin signaling, inhibits the development of DKD-associated pathologies, and prevents renal dysfunction. Further, we show that elevated VEGF-B levels are found in patients with DKD, suggesting that VEGF-B antagonism represents a novel approach to treat DKD. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Sodium Tanshinone IIA Sulfonate Ameliorates Bladder Fibrosis in a Rat Model of Partial Bladder Outlet Obstruction by Inhibiting the TGF-β/Smad Pathway Activation.

    Directory of Open Access Journals (Sweden)

    Xiaoxiao Jiang

    Full Text Available Transforming growth factor (TGF-β1 is known to play a pivotal role in a diverse range of biological systems including modulation of fibrosis in several organs. The precise role of TGF-β/Smad signaling in the progression of bladder fibrosis secondary to partial bladder outlet obstruction (PBOO is yet to be conclusively. Using a rat PBOO model, we investigated TGF-β1 expression and exaimined whether sodium tanshinone IIA sulfonate (STS could inhibit TGF-β/Smad signaling pathway activation and ameliorate bladder fibrosis. Forty-eight female Sprague-Dawley rats were randomly divided into three groups: sham operation group (n = 16, PBOO operation without STS treatment group (n = 16 and PBOO operation with STS treatment group (n = 16. Thirty-two rats underwent the operative procedure to create PBOO and subsequently received intraperitoneal injections of STS (10 mg/kg/d; n = 16 or vehicle (n = 16 two days after the surgery. Sham surgery was conducted on 16 rats, which received intraperitoneal vehicle injection two days later. In each of the three groups, an equal number of rats were sacrificed at weeks 4 and 8 after the PBOO or sham operation. The TGF-β/Smad signaling pathway was analyzed using western blotting, immunohistochemical staining and reverse transcriptase polymerase chain reaction (RT-PCR. One-way analysis of variance was conducted to draw statistical inferences. At 4 and 8 weeks, the expression of TGF-β1 and phosphorylated Smad2 and Smad3 in STS-treated PBOO rats was significantly lower than in the PBOO rats not treated with STS. Alpha smooth muscle actin (α-SMA, collagen I and collagen III expression at 4 and 8 weeks post PBOO was lower in STS-treated PBOO rats when compared to that in PBOO rats not treated with STS. Our findings indicate that STS ameliorates bladder fibrosis by inhibiting TGF-β/Smad signaling pathway activation, and may prove to be a potential therapeutic measure for preventing bladder fibrosis secondary to PBOO

  16. Ginsenoside 25-OCH3-PPD promotes activity of LXRs to ameliorate P2X7R-mediated NLRP3 inflammasome in the development of hepatic fibrosis.

    Science.gov (United States)

    Han, Xin; Song, Jian; Lian, Li-Hua; Yao, You-Li; Shao, Dan-Yang; Fan, Ying; Hou, Li-Shuang; Wang, Ge; Zheng, Shuang; Wu, Yan-Ling; Nan, Ji-Xing

    2018-06-22

    Ginseng is widely used in energy drinks, dietary supplements and herbal medicines, and its pharmacological actions are related with energy metabolism. As an important modulating energy metabolism pathway, liver X receptors (LXRs) can promote the resolving of hepatic fibrosis and inflammation. The present study aims to evaluate the regulation of 25-OCH3-PPD, a ginsenoside isolated from Panax ginseng, against hepatic fibrosis and inflammation in thioacetamide (TAA)-stimulated mice by activating LXRs pathway. 25-OCH3-PPD decreases serum ALT/AST levels and improves the histological pathology of liver in TAA-induced mice; attenuates transcripts of pro-fibrogenic markers associated with hepatic stellate cell activation; attenuates the levels of pro-Inflammatory cytokines and blocks apoptosis happened in liver; inhibits NLRP3 inflammasome by affecting P2X7R activation; regulates PI3K/Akt and LKB1/AMPK-SIRT1. 25-OCH3-PPD also facilitates LX25Rs and FXR activities decreased by TAA stimulation. 25-OCH3-PPD also decreases α-SMA via regulation of LXRs and P2X7R-NLRP3 in vitro. Our data suggest the possibility that 25-OCH3-PPD promotes activity of LXRs to ameliorate P2X7R-mediated NLRP3 inflammasome in the development of hepatic fibrosis.

  17. Nephrogenic Systemic Fibrosis Risk After Liver Magnetic Resonance Imaging With Gadoxetate Disodium in Patients With Moderate to Severe Renal Impairment

    Science.gov (United States)

    Lauenstein, Thomas; Ramirez-Garrido, Francisco; Kim, Young Hoon; Rha, Sung Eun; Ricke, Jens; Phongkitkarun, Sith; Boettcher, Joachim; Gupta, Rajan T.; Korpraphong, Pornpim; Tanomkiat, Wiwatana; Furtner, Julia; Liu, Peter S.; Henry, Maren; Endrikat, Jan

    2015-01-01

    Objective The objective of this study was to assess the risk of gadoxetate disodium in liver imaging for the development of nephrogenic systemic fibrosis (NSF) in patients with moderate to severe renal impairment. Materials and Methods We performed a prospective, multicenter, nonrandomized, open-label phase 4 study in 35 centers from May 2009 to July 2013. The study population consisted of patients with moderate to severe renal impairment scheduled for liver imaging with gadoxetate disodium. All patients received a single intravenous bolus injection of 0.025-mmol/kg body weight of liver-specific gadoxetate disodium. The primary target variable was the number of patients who develop NSF within a 2-year follow-up period. Results A total of 357 patients were included, with 85 patients with severe and 193 patients with moderate renal impairment, which were the clinically most relevant groups. The mean time period from diagnosis of renal disease to liver magnetic resonance imaging (MRI) was 1.53 and 5.46 years in the moderate and severe renal impairment cohort, respectively. Overall, 101 patients (28%) underwent additional contrast-enhanced MRI with other gadolinium-based MRI contrast agents within 12 months before the start of the study or in the follow-up. No patient developed symptoms conclusive of NSF within the 2-year follow-up. Conclusions Gadoxetate disodium in patients with moderate to severe renal impairment did not raise any clinically significant safety concern. No NSF cases were observed. PMID:25756684

  18. Amelioration of pancreatic and renal derangements in streptozotocin-induced diabetic rats by polyphenol extracts of Ginger (Zingiber officinale) rhizome.

    Science.gov (United States)

    Kazeem, Mutiu Idowu; Akanji, Musbau Adewunmi; Yakubu, Musa Toyin

    2015-12-01

    Free and bound polyphenol extracts of Zingiber officinale rhizome were investigated for their antidiabetic potential in the pancreatic and renal tissues of diabetic rats at a dose of 500mg/kg body weight. Forty Wistar rats were completely randomized into five groups: A-E consisting of eight animals each. Group A (control) comprises normal healthy animals and were orally administered 1.0mL distilled water on a daily basis for 42 days while group B-E were made up of 50mg/kg streptozotocin (STZ)-induced diabetic rats. Group C and D received 1.0mL 500mg/kg body weight free and bound polyphenol extracts respectively while group E received 1.0mL 0.6mg/kg of glibenclamide. Administration of the extracts to the diabetic rats significantly reduced (pZingiber officinale could ameliorate diabetes-induced pancreatic and renal derangements in rats. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  19. Precision-cut kidney slices (PCKS to study development of renal fibrosis and efficacy of drug targeting ex vivo

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    Fariba Poosti

    2015-10-01

    Full Text Available Renal fibrosis is a serious clinical problem resulting in the greatest need for renal replacement therapy. No adequate preventive or curative therapy is available that could be clinically used to target renal fibrosis specifically. The search for new efficacious treatment strategies is therefore warranted. Although in vitro models using homogeneous cell populations have contributed to the understanding of the pathogenetic mechanisms involved in renal fibrosis, these models poorly mimic the complex in vivo milieu. Therefore, we here evaluated a precision-cut kidney slice (PCKS model as a new, multicellular ex vivo model to study the development of fibrosis and its prevention using anti-fibrotic compounds. Precision-cut slices (200-300 μm thickness were prepared from healthy C57BL/6 mouse kidneys using a Krumdieck tissue slicer. To induce changes mimicking the fibrotic process, slices were incubated with TGFβ1 (5 ng/ml for 48 h in the presence or absence of the anti-fibrotic cytokine IFNγ (1 µg/ml or an IFNγ conjugate targeted to PDGFRβ (PPB-PEG-IFNγ. Following culture, tissue viability (ATP-content and expression of α-SMA, fibronectin, collagen I and collagen III were determined using real-time PCR and immunohistochemistry. Slices remained viable up to 72 h of incubation, and no significant effects of TGFβ1 and IFNγ on viability were observed. TGFβ1 markedly increased α-SMA, fibronectin and collagen I mRNA and protein expression levels. IFNγ and PPB-PEG-IFNγ significantly reduced TGFβ1-induced fibronectin, collagen I and collagen III mRNA expression, which was confirmed by immunohistochemistry. The PKCS model is a novel tool to test the pathophysiology of fibrosis and to screen the efficacy of anti-fibrotic drugs ex vivo in a multicellular and pro-fibrotic milieu. A major advantage of the slice model is that it can be used not only for animal but also for (fibrotic human kidney tissue.

  20. 14S,21R-dihydroxy-docosahexaenoic acid treatment enhances mesenchymal stem cell amelioration of renal ischemia/reperfusion injury.

    Science.gov (United States)

    Tian, Haibin; Lu, Yan; Shah, Shraddha P; Wang, Quansheng; Hong, Song

    2012-05-01

    Bone marrow mesenchymal stem cells (MSCs) have shown potential to improve treatment of renal failure. The prohealing functions of MSCs have been found to be enhanced by treatment with the lipid mediator, 14S,21R-dihydroxy-docosa4Z,7Z,10Z,12E,16Z,19Z-hexaenoic acid (14S,21R-diHDHA). In this article, using a murine model of renal ischemia/reperfusion (I/R) injury, we found that treatment with 14S,21R-diHDHA enhanced MSC amelioration of renal I/R injury. Treated MSCs more efficiently inhibited I/R-induced elevation of serum creatinine levels, reduced renal tubular cell death, and inhibited infiltration of neutrophils, macrophages, and dendritic cells in kidneys. Conditioned medium from treated MSCs reduced the generation of tumor necrosis factor-α and reactive oxygen species by macrophages under I/R conditions. Infusion of treated MSCs more efficiently reduced I/R-damage to renal histological structures compared with untreated MSCs (injury score: 7.9±0.4 vs. 10.5±0.5). Treated MSCs were resistant to apoptosis in vivo when transplanted under capsules of I/R-injured kidneys (active caspase-3+ MSCs: 4.2%±2.8% vs. 11.7%±2.4% of control) and in vitro when cultured under I/R conditions. Treatment with 14S,21R-diHDHA promoted viability of MSCs through a mechanism involving activation of the phosphoinositide 3-kinase -Akt signaling pathway. Additionally, treatment of MSCs with 14S,21R-diHDHA promoted secretion of renotrophic hepatocyte growth factor and insulin growth factor-1. Similar results were obtained when 14S,21RdiHDHA was used to inhibit apoptosis of human MSCs (hMSCs) and to increase the generation of renotrophic cytokines from hMSCs. These findings provide a lead for new strategies in the treatment of acute kidney injury with MSCs.

  1. Imaging of Myocardial Fibrosis in Patients with End-Stage Renal Disease: Current Limitations and Future Possibilities

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    M. P. M. Graham-Brown

    2017-01-01

    Full Text Available Cardiovascular disease in patients with end-stage renal disease (ESRD is driven by a different set of processes than in the general population. These processes lead to pathological changes in cardiac structure and function that include the development of left ventricular hypertrophy and left ventricular dilatation and the development of myocardial fibrosis. Reduction in left ventricular hypertrophy has been the established goal of many interventional trials in patients with chronic kidney disease, but a recent systematic review has questioned whether reduction of left ventricular hypertrophy improves cardiovascular mortality as previously thought. The development of novel imaging biomarkers that link to cardiovascular outcomes and that are specific to the disease processes in ESRD is therefore required. Postmortem studies of patients with ESRD on hemodialysis have shown that the extent of myocardial fibrosis is strongly linked to cardiovascular death and accurate imaging of myocardial fibrosis would be an attractive target as an imaging biomarker. In this article we will discuss the current imaging methods available to measure myocardial fibrosis in patients with ESRD, the reliability of the techniques, specific challenges and important limitations in patients with ESRD, and how to further develop the techniques we have so they are sufficiently robust for use in future clinical trials.

  2. Ameliorating activity of ginger (Zingiber officinale) extract against lead induced renal toxicity in male rats.

    Science.gov (United States)

    Reddy, Y Amarnath; Chalamaiah, M; Ramesh, B; Balaji, G; Indira, P

    2014-05-01

    Lead poisoning has been known to be associated with structural and functional abnormalities of multiple organ systems of human body. The aim of this investigation was to study the renal protective effects of ginger (Zingiber officinale) extract in lead induced toxicity rats. In this study renal glutathione (GSH) level, glutathione peroxidase (GPX), glutathione-s-transferase (GST), and catalase enzymes were measured in lead nitrate (300 mg/kg BW), and lead nitrate plus ginger extract (150 mg/kg BW) treated rat groups for 1 week and 3 weeks respectively. The glutathione level and GSH dependent antioxidant enzymes such as glutathione peroxidase, glutathione-s-transferase, and catalase significantly (P < 0.05) increased in ginger extract treated rat groups. In addition, histological studies showed lesser renal changes in lead plus ginger extract treated rat groups than that of lead alone treated rat groups. These results indicate that ginger extract alleviated lead toxic effects by enhancing the levels of glutathione, glutathione peroxidase, glutathione-s-transferase and catalase.

  3. Ameliorative effects of tannic acid on carbon tetrachloride-induced liver fibrosis in vivo and in vitro

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    Xi Chu

    2016-01-01

    Full Text Available We investigated the ameliorative effects and potential mechanisms of tannic acid (TA in carbon tetrachloride (CCl4-intoxicated mice and hepatic stellate cells (HSCs. Liver fibrosis was observed in CCl4 (800 ml/kg-induced mice, and high viability was observed in CCl4 (10 mM-intoxicated HSCs. Pre-treatment of mice with TA (25 or 50 g/kg/day significantly ameliorated hepatic morphology and coefficient values and reduced the activities of aspartate aminotransferase (AST and alanine aminotransferase (ALT, the concentrations of malondialdehyde (MDA and serum levels of endothelin-1 (ET-1. In addition, TA increased the activities of superoxide dismutase (SOD, catalase (CAT, glutathione peroxidase (GSH-Px, and endothelial nitric oxide synthase (eNOS and the serum level of NO. Moreover, TA reduced the expression of angiotensin II receptor-1 (ATR-1, interleukin-1β (IL-1β, tumor necrosis factor-α (TNF-α, transforming growth factor-β (TGF-β, caspase-3, c-fos, c-jun, the ratio of Bax/bcl-2, tissue inhibitor of metalloproteinase-1 (TIMP-1 and TA increased matrix metal proteinase-9 (MMP-9, matrix metalloproteinase-1 (MMP-1. Furthermore, TA (0.01 μM, 0.1 μM or 1 μM decreased the TIMP-1/MMP-1 ratio and reduced the viability of HSCs. These results indicated that TA exerts significant liver-protective effects in mice with CCl4-induced liver fibrosis. The potential mechanism may rely on the inhibition of collagen accumulation, oxidative stress, inflammation and apoptosis.

  4. Renal Medullary and Cortical Correlates in Fibrosis, Epithelial Mass, Microvascularity, and Microanatomy Using Whole Slide Image Analysis Morphometry.

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    Alton B Farris

    Full Text Available Renal tubulointerstitial injury often leads to interstitial fibrosis and tubular atrophy (IF/TA. IF/TA is typically assessed in the renal cortex and can be objectively quantitated with computerized image analysis (IA. However, the human medulla accounts for a substantial proportion of the nephron; therefore, medullary scarring will have important cortical consequences and may parallel overall chronic renal injury. Trichrome, periodic acid-Schiff (PAS, and collagen III immunohistochemistry (IHC were visually examined and quantitated on scanned whole slide images (WSIs (N = 67 cases. When tuned to measure fibrosis, IA of trichrome and Trichrome-PAS (T-P WSIs correlated for all anatomic compartments (among cortex, medulla, and entire tissue, r = 0.84 to 0.89, P all <0.0001; and collagen III deposition correlated between compartments (r = 0.69 to 0.89, P <0.0001 to 0.0002; however, trichrome and T-P measures did not correlate with collagen deposition, suggesting heterogeneous contributions to extracellular matrix deposition. Epithelial cell mass (EPCM correlated between cortex and medulla when measured with cytokeratin IHC and with the trichrome red portion (r = 0.85 and 0.66, respectively, all P < 0.0001. Visual assessment also correlated between compartments for fibrosis and EPCM. Correlations were found between increasing medullary inner stripe (IS width and fibrosis in all of the tissue and the medulla by trichrome morphometry (r = 0.56, P < 0.0001, and r = 0.48, P = 0.00008, respectively. Weak correlations were found between increasing IS width and decreasing visual assessment of all tissue EPCM. Microvessel density (MVD and microvessel area (MVA measured using a MVD algorithm applied to CD34 IHC correlated significantly between all compartments (r = 0.76 to 0.87 for MVD and 0.71 to 0.87 for MVA, P all < 0.0001. Overall, these findings demonstrate the interrelatedness of the cortex and medulla and the importance of considering the renal

  5. Tyrosine kinase inhibitor BIBF1120 ameliorates inflammation, angiogenesis and fibrosis in CCl4-induced liver fibrogenesis mouse model

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    Öztürk Akcora, Büsra; Storm, Gerrit; Prakash, Jai; Bansal, Ruchi

    2017-01-01

    Hepatic fibrosis, a progressive chronic disease mainly caused by hepatitis viral infections, alcohol abuse or metabolic syndrome leading to liver dysfunction and is the growing cause of mortality worldwide. Tyrosine kinase inhibitor BIBF1120 (Nintedanib) has been evaluated in clinical trials for

  6. Silent information regulator 1 (SIRT1) ameliorates liver fibrosis via promoting activated stellate cell apoptosis and reversion

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    Wu, Yuting, E-mail: wuyuting1302@sina.com; Liu, Xuejiao; Zhou, Qun; Huang, Cheng; Meng, Xiaoming; Xu, Fengyun; Li, Jun, E-mail: lj@ahmu.edu.cn

    2015-12-01

    SIRT1 (silent information regulator 1), a conserved NAD +-dependent histone deacetylase, is closely related with various biological processes. Moreover, the important role of SIRT1 in alcoholic liver disease, nonalcoholic fatty liver and HCC had been widely reported. Recently, a novel role of SIRT1 was uncovered in organ fibrosis diseases. Here, we investigated the inhibitory effect of SIRT1 in liver fibrogenesis. SIRT1 protein was dramatically decreased in CCl4-treated mice livers. Stimulation of LX-2 cells with TGF-β1 also resulted in a significant suppression of SIRT1 protein. Nevertheless, TGF-β1-induced LX-2 cell activation was inhibited by SIRT1 plasmid, and this was accompanied by up-regulation of cell apoptosis-related proteins. Overexpression of SIRT1 also attenuated TGF-β1-induced expression of myofibroblast markers α-SMA and COL1a. However, the important characteristic of the recovery of liver fibrosis is not only the apoptosis of activated stellate cells but also the reversal of the myofibroblast-like phenotype to a quiescent-like phenotype. Restoration of SIRT1 protein was observed in the in vivo spontaneously liver fibrosis reversion model and in vitro MDI (isobutylmethylxanthine, dexamethasone, and insulin)-induced reversed stellate cells, and forced expression of SIRT1 also promoted the reversal of activated stellate cells. Furthermore, lncRNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) was increased in liver fibrosis. RNAi-mediated suppression of MALAT1 resulted in a decrease of myofibroblast markers and restoration of SIRT1 protein. These observations suggested that SIRT1 contributed to apoptosis and reversion of activated LX-2 cells and SIRT1 might be regulated by MALAT1 in liver fibrosis. Therefore, SIRT1 could be considered as a valuable therapeutic target for translational studies of liver fibrosis. - Highlights: • This is the first report of SIRT1 expression and function in liver fibrogenesis and reversion.

  7. Branched-Chain Amino Acids Ameliorate Fibrosis and Suppress Tumor Growth in a Rat Model of Hepatocellular Carcinoma with Liver Cirrhosis

    Science.gov (United States)

    Cha, Jung Hoon; Bae, Si Hyun; Kim, Hye Lim; Park, Na Ri; Choi, Eun Suk; Jung, Eun Sun; Choi, Jong Young; Yoon, Seung Kew

    2013-01-01

    Purpose Recent studies have revealed that branched-chain amino acids (BCAA) reduce the development of hepatocellular carcinoma (HCC) in patients with obesity and hepatitis C virus infection by improving insulin resistance (IR). The aim of this study was to examine the anti-cancer and anti-fibrotic effects of BCAA on the development of diethylnitrosamine (DEN)-induced HCC and liver cirrhosis in a rat model. Methods Male SD rats received weekly intraperitoneal injections of DEN (50 mg/kg of body weight) for 16 weeks to induce HCC. They were fed a diet containing 3% casein, 3% or 6% BCAA for 13 weeks beginning 6 weeks after DEN administration. DEN was used to induce HCC through stepwise development from cirrhosis to HCC. The effect of BCAA was evaluated in tumor tissues by histopathologic analyses, reverse transcription-polymerase chain reaction, and Western blotting. Results The mean area and number of dysplastic nodules (DNs) and tumors in the casein group tended to be larger than those in the BCAA group 16 weeks after DEN administration. The mean fibrotic area in the BCAA group was smaller than that in the casein group. The BCAA group showed decreased mRNA levels for markers of fibrosis, angiogenesis, and apoptosis inhibition. Compared with the casein group, the BCAA group had lower levels of α-smooth muscle actin, vascular endothelial growth factor, p-β-catenin, p-p38 mitogen-activated protein kinase, proliferating cell nuclear antigen, and caspase-3 protein expression, as well as a higher level of cleaved caspase-3 protein expression. Conclusions BCAA supplementation of the diet ameliorated liver fibrosis and HCC development in a DEN-induced rat model of HCC with liver cirrhosis, but not in the IR model. These results provide a rationale for anti-fibrosis and chemoprevention using BCAA treatment for HCC with liver cirrhosis, as well as decreasing the ammonia level. PMID:24223741

  8. Branched-chain amino acids ameliorate fibrosis and suppress tumor growth in a rat model of hepatocellular carcinoma with liver cirrhosis.

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    Jung Hoon Cha

    Full Text Available PURPOSE: Recent studies have revealed that branched-chain amino acids (BCAA reduce the development of hepatocellular carcinoma (HCC in patients with obesity and hepatitis C virus infection by improving insulin resistance (IR. The aim of this study was to examine the anti-cancer and anti-fibrotic effects of BCAA on the development of diethylnitrosamine (DEN-induced HCC and liver cirrhosis in a rat model. METHODS: Male SD rats received weekly intraperitoneal injections of DEN (50 mg/kg of body weight for 16 weeks to induce HCC. They were fed a diet containing 3% casein, 3% or 6% BCAA for 13 weeks beginning 6 weeks after DEN administration. DEN was used to induce HCC through stepwise development from cirrhosis to HCC. The effect of BCAA was evaluated in tumor tissues by histopathologic analyses, reverse transcription-polymerase chain reaction, and Western blotting. RESULTS: The mean area and number of dysplastic nodules (DNs and tumors in the casein group tended to be larger than those in the BCAA group 16 weeks after DEN administration. The mean fibrotic area in the BCAA group was smaller than that in the casein group. The BCAA group showed decreased mRNA levels for markers of fibrosis, angiogenesis, and apoptosis inhibition. Compared with the casein group, the BCAA group had lower levels of α-smooth muscle actin, vascular endothelial growth factor, p-β-catenin, p-p38 mitogen-activated protein kinase, proliferating cell nuclear antigen, and caspase-3 protein expression, as well as a higher level of cleaved caspase-3 protein expression. CONCLUSIONS: BCAA supplementation of the diet ameliorated liver fibrosis and HCC development in a DEN-induced rat model of HCC with liver cirrhosis, but not in the IR model. These results provide a rationale for anti-fibrosis and chemoprevention using BCAA treatment for HCC with liver cirrhosis, as well as decreasing the ammonia level.

  9. 24-nor-ursodeoxycholic acid ameliorates inflammatory response and liver fibrosis in a murine model of hepatic schistosomiasis.

    Science.gov (United States)

    Sombetzki, Martina; Fuchs, Claudia D; Fickert, Peter; Österreicher, Christoph H; Mueller, Michaela; Claudel, Thierry; Loebermann, Micha; Engelmann, Robby; Langner, Cord; Sahin, Emine; Schwinge, Dorothee; Guenther, Nina D; Schramm, Christoph; Mueller-Hilke, Brigitte; Reisinger, Emil C; Trauner, Michael

    2015-04-01

    Intrahepatic granuloma formation and fibrosis characterize the pathological features of Schistosoma mansoni infection. Based on previously observed substantial anti-fibrotic effects of 24-nor-ursodeoxycholic acid (norUDCA) in Abcb4/Mdr2(-/-) mice with cholestatic liver injury and biliary fibrosis, we hypothesized that norUDCA improves inflammation-driven liver fibrosis in S. mansoni infection. Adult NMRI mice were infected with 50 S. mansoni cercariae and after 12 weeks received either norUDCA- or ursodeoxycholic acid (UDCA)-enriched diet (0.5% wt/wt) for 4 weeks. Bile acid effects on liver histology, serum biochemistry, key regulatory cytokines, hepatic hydroxyproline content as well as granuloma formation were compared to naive mice and infected controls. In addition, effects of norUDCA on primary T-cell activation/proliferation and maturation of the antigen-presenting-cells (dendritic cells, macrophages) were determined in vitro. UDCA as well as norUDCA attenuated the inflammatory response in livers of S. mansoni infected mice, but exclusively norUDCA changed cellular composition and reduced size of hepatic granulomas as well as TH2-mediated hepatic fibrosis in vivo. Moreover, norUDCA affected surface expression level of major histocompatibility complex (MHC) class II of macrophages and dendritic cells as well as activation/proliferation of T-lymphocytes in vitro, whereas UDCA had no effect. This study demonstrates pronounced anti-inflammatory and anti-fibrotic effects of norUDCA compared to UDCA in S. mansoni induced liver injury, and indicates that norUDCA directly represses antigen presentation of antigen presenting cells and subsequent T-cell activation in vitro. Therefore, norUDCA represents a promising drug for the treatment of this important cause of liver fibrosis. Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  10. Silymarin and caffeine combination ameliorates experimentally-induced hepatic fibrosis through down-regulation of LPAR1 expression.

    Science.gov (United States)

    Eraky, Salma M; El-Mesery, Mohamed; El-Karef, Amro; Eissa, Laila A; El-Gayar, Amal M

    2018-05-01

    Lysophosphatidic acid is a lipid mediator that is supposed to be implicated in hepatic fibrosis. Silymarin and caffeine are natural compounds known for their anti-inflammatory and antioxidant effects. Our study aimed to explore the effect of silymarin, caffeine, and their combination on lysophosphatidic acid receptor 1 (LPAR1) pathway in thioacetamide (TAA)-induced hepatic fibrosis. Hepatic fibrosis was induced in male Sprague-Dawley rats by intraperitoneal injection of 200 mg/kg of TAA twice a week for 8 weeks. Silymarin (50 mg/kg), caffeine (50 mg/kg), and their combination (50 mg/kg silymarin + 50 mg/kg caffeine) were orally given to rats every day for 8 weeks along with TAA injection. Liver functions were measured. Histopathological examination of liver tissues was performed using hematoxylin and eosin and Masson's trichrome staining. mRNA expressions of LPAR1, transforming growth factor beta 1 (TGF-β1), connective tissue growth factor (CTGF), and alpha smooth muscle actin (α-SMA) were measured using RT-PCR. LPAR1 tissue expression was scored using immunohistochemistry. Silymarin, caffeine, and their combination significantly improved liver function. They caused significant decrease in fibrosis and necro-inflammatory scores. Combination of silymain and caffeine caused a significant decrease in the necro-inflammatory score than the single treatment with silymarin or caffeine. In addition, silymarin, caffeine, and their combination significantly decreased hepatic LPAR1, TGF-β1, CTGF, and α-SMA gene expressions and LPAR1 tissue expression. Silymarin, caffeine, and their combination protect against liver fibrosis through down-regulation of LPAR1, TGF-β1, and CTGF. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  11. Human pluripotent stem cell-derived erythropoietin-producing cells ameliorate renal anemia in mice.

    Science.gov (United States)

    Hitomi, Hirofumi; Kasahara, Tomoko; Katagiri, Naoko; Hoshina, Azusa; Mae, Shin-Ichi; Kotaka, Maki; Toyohara, Takafumi; Rahman, Asadur; Nakano, Daisuke; Niwa, Akira; Saito, Megumu K; Nakahata, Tatsutoshi; Nishiyama, Akira; Osafune, Kenji

    2017-09-27

    The production of erythropoietin (EPO) by the kidneys, a principal hormone for the hematopoietic system, is reduced in patients with chronic kidney disease (CKD), eventually resulting in severe anemia. Although recombinant human EPO treatment improves anemia in patients with CKD, returning to full red blood cell production without fluctuations does not always occur. We established a method to generate EPO-producing cells from human induced pluripotent stem cells (hiPSCs) by modifying previously reported hepatic differentiation protocols. These cells showed increased EPO expression and secretion in response to low oxygen conditions, prolyl hydroxylase domain-containing enzyme inhibitors, and insulin-like growth factor 1. The EPO protein secreted from hiPSC-derived EPO-producing (hiPSC-EPO) cells induced the erythropoietic differentiation of human umbilical cord blood progenitor cells in vitro. Furthermore, transplantation of hiPSC-EPO cells into mice with CKD induced by adenine treatment improved renal anemia. Thus, hiPSC-EPO cells may be a useful tool for clarifying the mechanisms of EPO production and may be useful as a therapeutic strategy for treating renal anemia. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

  12. Gold nanoparticles ameliorate acetaminophen induced hepato-renal injury in rats.

    Science.gov (United States)

    Reshi, Mohd Salim; Shrivastava, Sadhana; Jaswal, Amita; Sinha, Neelu; Uthra, Chhavi; Shukla, Sangeeta

    2017-04-04

    Valuable effects of gold particles have been reported and used in complementary medicine for decades. The aim of this study was to evaluate the therapeutic efficacy of gold nanoparticles (AuNPs) against acetaminophen (APAP) induced toxicity. Albino rats were administered APAP at a dose of 2g/kg p.o. once only. After 24h of APAP intoxication, animals were treated with three different doses of AuNPs (50μg/kg, 100μg/kg, 150μg/kg) orally or silymarin at a dose of 50mg/kg p.o., once only. Animals of all the groups were sacrificed after 24h of last treatment. APAP administered group showed a significant rise in the AST, ALT, SALP, LDH, cholesterol, bilirubin, albumin, urea and creatinine in serum which indicated the hepato-renal damage. A significantly enhanced LPO and a depleted level of GSH were observed in APAP intoxicated rats. Declined activities of SOD and Catalase, after acetaminophen exposure indicated oxidative stress in liver and kidney. The activities of ATPase and glucose-6-Phosphatase were significantly inhibited after APAP administration. AuNPs treatment reversed all variables significantly towards normal level and was found nontoxic. Thus it is concluded that gold nanoparticles played a beneficial role in reducing acetaminophen induced toxicity and can be used in the development of drug against hepatic as well as renal diseases, after further preclinical and clinical studies. Copyright © 2017 Elsevier GmbH. All rights reserved.

  13. An Aqueous-Ethanol Extract of Liriope spicata var. prolifera Ameliorates Diabetic Nephropathy through Suppression of Renal Inflammation

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    Hung-Jen Lu

    2013-01-01

    Full Text Available The tuberous root of Liriope spicata var. prolifera (TRLS; Liliaceae family is valued for the ability to promote glucose homeostasis, and it may therefore be utilized as an adjuvant therapy in the control of diabetic complications. The aim of the present study was to examine the effects of an aqueous ethanol extract from TRLS (TRLS-ext (100 or 200 mg kg−1 per day for eight weeks on rats with streptozotocin-induced diabetic nephropathy (DN. Renal dysfunction in diabetic rats was ameliorated by TRLS-ext as evidenced by reduced creatinine clearance, as well as increased blood urea nitrogen and proteinuria. Treatment with TRLS-ext was found to markedly improve histological architecture in the diabetic kidney. Hyperglycemia induced degradation of inhibitory kappa B and reduced nuclear factor kappa B activation, leading to increased infiltration of macrophages and increased levels of proinflammatory cytokines, including interleukin-1 and tumor necrosis factor-α. All of the above abnormalities were reversed by TRLS-ext treatment, which also decreased the expression of intercellular adhesion molecule-1, monocyte chemoattractant protein-1, and fibronectin in the diabetic kidneys. These findings provide a perspective on the renoprotective effects of TRLS-ext in DN.

  14. Calcium, zinc and vitamin E ameliorate cadmium-induced renal oxidative damage in albino Wistar rats

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    Pradeepkiran Jangampalli Adi

    Full Text Available This study was aimed to examine the protective effects of supplementation with calcium + zinc (Ca + Zn or vitamin E (Vit-E on Cd-induced renal oxidative damage. Young albino Wistar rats (180 ± 10 g (n = 6 control rats, Cd, Cd + Ca + Zn, and Cd + Vit-E experimental groups and the experimental period was 30 days. Rats were exposed to Cd (20 mg/kg body weight alone treated as Cd treated group and the absence or presence of Ca + Zn (2 mg/kg each or Vit-E (20 mg/kg body weight supplementation treated as two separate groups. The activities of the stress marker enzymes superoxide dismutase (SOD, catalase (CAT, glutathione reductase (GR, glutathione peroxidase (GPx, glutathione-S-transferase (GST and lipid peroxidase (LPx were determined in renal mitochondrial fractions of experimental rats. We observed quantitative changes in SOD isoenzymatic patterns by non-denaturing PAGE analysis, and quantified band densities. These results showed that Cd exposure leads to decreases in SOD, CAT, GR, and GPx activities and a concomitant increase in LPx and GST activities. Ca + Zn and Vit-E administration with Cd significantly reversed Cd-induced perturbations in oxidative stress marker enzymes. However, Vit-E showed more inhibitory activity against Cd than did Ca + Zn, and it protected against Cd-induced nephrotoxicity. Keywords: Cadmium (Cd, Oxidative stress, Lipid peroxidation, Nephrotoxicity, PAGE analysis

  15. Renal-protective and ameliorating impacts of omega-3 fatty acids against aspartame damaged MDCK cells.

    Science.gov (United States)

    Pandurangan, Muthuraman; Enkhtaivan, Gansukh; Veerappan, Muthuviveganandavel; Mistry, Bhupendra; Patel, Rahul; Moon, So Hyun; Nagajyothi, Patnamsetty Chidanandha; Kim, Doo Hwan

    2017-11-01

    Aspartame is widely used artificial sweeteners as food additives. Several researchers have pointed that the controversial report on the use of aspartame over more than decades. Omega-3 fatty acids are essential and unsaturated fatty acids, and it plays a remarkable role in vision, intelligence, neural development, and metabolism of neurotransmitters. Therefore, the present study was aimed to investigate the effect of omega-3 fatty acids on aspartame treated renal cells. Experimental groups were divided into three such as sham control, aspartame treated, and aspartame with omega-3 fatty acids. Cell viability was determined by sulforhodamine-b assay and flow cytometric analysis. The experimental results showed that the aspartame induced altered cell viability were reduced following treatment of aspartame with omega-3 fatty acids. Altered cell morphology was recovered by omega-3 fatty acids. DNA damage appeared in the highest concentration of aspartame used in this study. DNA damage characteristics such as comet tail and tiny head sections did not appear in the omega-3 fatty acids treated cells. Several microvilli and vesicular structures were found in aspartame treated cells. Altered morphology such as rounding, microvilli, and formation of dome-like structures did not appear in the omega-3 fatty acids with aspartame treated cells. Caspase-3 mRNA and protein expression were increased in aspartame treated cells, and these levels were reduced following omega-3 fatty acids treatment. Taking all these data together, it is suggested that the omega-3 fatty acids may be a therapeutic agent to reduce the aspartame induced biochemical and morphological alterations in normal renal cells. © 2017 BioFactors, 43(6):847-857, 2017. © 2017 International Union of Biochemistry and Molecular Biology.

  16. The effects of dietary fish oil on inflammation, fibrosis and oxidative stress associated with obstructive renal injury in rats.

    Science.gov (United States)

    Peake, Jonathan M; Gobe, Glenda C; Fassett, Robert G; Coombes, Jeff S

    2011-03-01

    We examined whether dietary supplementation with fish oil modulates inflammation, fibrosis and oxidative stress following obstructive renal injury. Three groups of Sprague-Dawley rats (n=16 per group) were fed for 4 wk on normal rat chow (oleic acid), chow containing fish oil (33 g eicosapentaenoic acid and 26 g docosahexaenoic acid per kg diet), or chow containing safflower oil (60 g linoleic acid per kg diet). All diets contained 7% fat. After 4 wk, the rats were further subdivided into four smaller groups (n=4 per group). Unilateral ureteral obstruction was induced in three groups (for 4, 7 and 14 days). The fourth group for each diet did not undergo surgery, and was sacrificed as controls at 14 days. When rats were sacrificed, plasma and portions of the kidneys were removed and frozen; other portions of kidney tissue were fixed and prepared for histology. Compared with normal chow and safflower oil, fish oil attenuated collagen deposition, macrophage infiltration, TGF-β expression, apoptosis, and tissue levels of arachidonic acid, MIP-1α, IL-1β, MCP-1 and leukotriene B(4). Compared with normal chow, fish oil increased the expression of HO-1 protein in kidney tissue. Fish oil intake reduced inflammation, fibrosis and oxidative stress following obstructive renal injury. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  17. Astragaloside IV suppresses transforming growth factor-β1 induced fibrosis of cultured mouse renal fibroblasts via inhibition of the MAPK and NF-κB signaling pathways

    Energy Technology Data Exchange (ETDEWEB)

    Che, Xiajing; Wang, Qin; Xie, Yuanyuan; Xu, Weijia; Shao, Xinghua; Mou, Shan, E-mail: shan_mou@126.com; Ni, Zhaohui, E-mail: doctor_nzh@126.com

    2015-09-04

    Renal fibrosis, a progressive process characterized by the accumulation of extracellular matrix (ECM) leading to organ dysfunction, is a characteristic of chronic kidney diseases. Among fibrogenic factors known to regulate the renal fibrotic process, transforming growth factor-β (TGF-β) plays a central role. In the present study, we examined the effect of Astragaloside IV (AS-IV), a component of the traditional Chinese medicinal plant Astragalus membranaceus, on the processes associated with renal fibrosis in cultured mouse renal fibroblasts treated with TGF-β1. RT-PCR, western blotting, immunofluorescence staining and collagen assays showed that AS-IV suppressed TGF-β1 induced fibroblast proliferation, transdifferentiation, and ECM production in a dose-dependent manner. Examination of the underlying mechanisms showed that the effect of AS-IV on the inhibition of fibroblast differentiation and ECM formation were mediated by its modulation of the activity of the MAPK and NF-κB signaling pathways. Taken together, our results indicate that AS-IV alleviates renal interstitial fibrosis via a mechanism involving the MAPK and NF-κB signaling pathways and demonstrate the therapeutic potential of AS-IV for the treatment of chronic kidney diseases. - Highlights: • AS-IV suppressed TGF-β1 induced renal fibroblast proliferation. • AS-IV suppressed TGF-β1 induced renal fibroblast transdifferentiation. • AS-IV suppressed TGF-β1 induced ECM production. • AS-IV alleviates renal fibrosis via the MAPK and NF-κB signaling pathways.

  18. Kidney stone matrix proteins ameliorate calcium oxalate monohydrate induced apoptotic injury to renal epithelial cells.

    Science.gov (United States)

    Narula, Shifa; Tandon, Simran; Singh, Shrawan Kumar; Tandon, Chanderdeep

    2016-11-01

    Kidney stone formation is a highly prevalent disease, affecting 8-10% of the human population worldwide. Proteins are the major constituents of human kidney stone's organic matrix and considered to play critical role in the pathogenesis of disease but their mechanism of modulation still needs to be explicated. Therefore, in this study we investigated the effect of human kidney stone matrix proteins on the calcium oxalate monohydrate (COM) mediated cellular injury. The renal epithelial cells (MDCK) were exposed to 200μg/ml COM crystals to induce injury. The effect of proteins isolated from human kidney stone was studied on COM injured cells. The alterations in cell-crystal interactions were examined by phase contrast, polarizing, fluorescence and scanning electron microscopy. Moreover, its effect on the extent of COM induced cell injury, was quantified by flow cytometric analysis. Our study indicated the antilithiatic potential of human kidney stone proteins on COM injured MDCK cells. Flow cytometric analysis and fluorescence imaging ascertained that matrix proteins decreased the extent of apoptotic injury caused by COM crystals on MDCK cells. Moreover, the electron microscopic studies of MDCK cells revealed that matrix proteins caused significant dissolution of COM crystals, indicating cytoprotection against the impact of calcium oxalate injury. The present study gives insights into the mechanism implied by urinary proteins to restrain the pathogenesis of kidney stone disease. This will provide a better understanding of the formation of kidney stones which can be useful for the proper management of the disease. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. Soluble Receptor for Advanced Glycation End Product Ameliorates Chronic Intermittent Hypoxia Induced Renal Injury, Inflammation, and Apoptosis via P38/JNK Signaling Pathways

    Directory of Open Access Journals (Sweden)

    Xu Wu

    2016-01-01

    Full Text Available Obstructive sleep apnea (OSA associated chronic kidney disease is mainly caused by chronic intermittent hypoxia (CIH triggered tissue damage. Receptor for advanced glycation end product (RAGE and its ligand high mobility group box 1 (HMGB1 are expressed on renal cells and mediate inflammatory responses in OSA-related diseases. To determine their roles in CIH-induced renal injury, soluble RAGE (sRAGE, the RAGE neutralizing antibody, was intravenously administered in a CIH model. We also evaluated the effect of sRAGE on inflammation and apoptosis. Rats were divided into four groups: (1 normal air (NA, (2 CIH, (3 CIH+sRAGE, and (4 NA+sRAGE. Our results showed that CIH accelerated renal histological injury and upregulated RAGE-HMGB1 levels involving inflammatory (NF-κB, TNF-α, and IL-6, apoptotic (Bcl-2/Bax, and mitogen-activated protein kinases (phosphorylation of P38, ERK, and JNK signal transduction pathways, which were abolished by sRAGE but p-ERK. Furthermore, sRAGE ameliorated renal dysfunction by attenuating tubular endothelial apoptosis determined by immunofluorescence staining of CD31 and TUNEL. These findings suggested that RAGE-HMGB1 activated chronic inflammatory transduction cascades that contributed to the pathogenesis of the CIH-induced renal injury. Inhibition of RAGE ligand interaction by sRAGE provided a therapeutic potential for CIH-induced renal injury, inflammation, and apoptosis through P38 and JNK pathways.

  20. Green Tea Polyphenols Ameliorate the Early Renal Damage Induced by a High-Fat Diet via Ketogenesis/SIRT3 Pathway

    Directory of Open Access Journals (Sweden)

    Weijie Yi

    2017-01-01

    Full Text Available Scope. Several reports in the literature have suggested the renoprotective effects of ketone bodies and green tea polyphenols (GTPs. Our previous study found that GTP consumption could elevate the renal expression of the ketogenic rate-limiting enzyme, which was decreased by a high-fat diet (HFD in rats. Here, we investigated whether ketogenesis can mediate renoprotection by GTPs against an HFD. Methods and Results. Wistar rats were fed a standard or HFD with or without GTPs for 18 weeks. The renal oxidative stress level, kidney function, renal expression, and activity levels of mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA synthase 2 (HMGCS2 and sirtuin 3(SIRT3 were detected. The increased renal oxidative stress and the loss of renal function induced by the HFD were ameliorated by GTPs. Renal ketogenesis and SIRT3 expression and activity levels, which were reduced by the HFD, were restored by GTPs. In vitro, HEK293 cells were transfected with the eukaryotic expression plasmid pcDNA HMGCS2. GTP treatment could upregulate HMGCS2 and SIRT3 expression. Although SIRT3 expression was not affected by HMGCS2 transfection, the 4-hydroxy-2-nonenal (4-HNE level and the acetyl-MnSOD (K122/MnSOD ratio were reduced in HMGCS2-transfected cells in the context of H2O2. Conclusion. The ketogenesis/SIRT3 pathway mediates the renoprotection of GTPs against the oxidative stress induced by an HFD.

  1. High prevalence of nephrogenic systemic fibrosis in chronic renal failure patients exposed to gadodiamide, a gadolinium-containing magnetic resonance contrast agent

    DEFF Research Database (Denmark)

    Rydahl, Casper; Thomsen, Henrik S; Marckmann, Peter

    2008-01-01

    OBJECTIVE: Nephrogenic systemic fibrosis (NSF) is a serious disease affecting renal failure patients. It may be caused by some gadolinium (Gd)-containing contrast agents, including gadodiamide. The study aimed at estimating the prevalence of NSF after gadodiamide exposure for patients with chronic...

  2. Tacrolimus increases Nox4 expression in human renal fibroblasts and induces fibrosis-related genes by aberrant TGF-beta receptor signalling

    NARCIS (Netherlands)

    Kern, Georg; Mair, Sabine M; Noppert, Susie-Jane; Jennings, Paul; Schramek, Herbert; Rudnicki, Michael; Mueller, Gerhard A; Mayer, Gert; Koppelstaetter, Christian

    2014-01-01

    Chronic nephrotoxicity of immunosuppressives is one of the main limiting factors in the long-term outcome of kidney transplants, leading to tissue fibrosis and ultimate organ failure. The cytokine TGF-β is considered a key factor in this process. In the human renal fibroblast cell line TK-173, the

  3. Taurine Supplementation Improves Erectile Function in Rats with Streptozotocin-induced Type 1 Diabetes via Amelioration of Penile Fibrosis and Endothelial Dysfunction.

    Science.gov (United States)

    Ruan, Yajun; Li, Mingchao; Wang, Tao; Yang, Jun; Rao, Ke; Wang, Shaogang; Yang, Weiming; Liu, Jihong; Ye, Zhangqun

    2016-05-01

    For patients with diabetes, erectile dysfunction (ED) is common and greatly affects quality of life. However, these patients often exhibit a poor response to first-line oral phosphodiesterase type 5 inhibitors. To investigate whether taurine, a sulfur-containing amino acid, affects diabetic ED (DED). Type 1 diabetes mellitus was induced in male rats by using streptozotocin. After 12 weeks, an apomorphine test was conducted to confirm DED. Only rats with DED were administered taurine or vehicle for 4 weeks. Age-matched nondiabetic rats were administered saline intraperitoneally for 4 weeks. Erectile function was evaluated by electrical stimulation of the cavernous nerve. Histologic and molecular alterations of the corpus cavernosum also were analyzed. Erectile function was significantly reduced in the diabetic rats compared with in the nondiabetic rats, and was improved in the diabetic rats treated with taurine. The corpus cavernosum of the rats with DED exhibited severe fibrosis and decreased smooth muscle content. Deposition of extracellular matrix proteins was increased in the diabetic rats, while expression of endothelial nitric oxide synthase/cyclic guanosine monophosphate/nitric oxide pathway-related proteins was reduced. Taurine supplementation ameliorated erectile response as well as histologic and molecular alterations. Taurine supplementation improves erectile function in rats with DED probably by potential antifibrotic activity. This finding provides evidence for a potential new therapy for DED. Copyright © 2016 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.

  4. Acoustic radiation force impulse elastography of the kidneys: is shear wave velocity affected by tissue fibrosis or renal blood flow?

    Science.gov (United States)

    Asano, Kenichiro; Ogata, Ai; Tanaka, Keiko; Ide, Yoko; Sankoda, Akiko; Kawakita, Chieko; Nishikawa, Mana; Ohmori, Kazuyoshi; Kinomura, Masaru; Shimada, Noriaki; Fukushima, Masaki

    2014-05-01

    The aim of this study was to identify the main influencing factor of the shear wave velocity (SWV) of the kidneys measured by acoustic radiation force impulse elastography. The SWV was measured in the kidneys of 14 healthy volunteers and 319 patients with chronic kidney disease. The estimated glomerular filtration rate was calculated by the serum creatinine concentration and age. As an indicator of arteriosclerosis of large vessels, the brachial-ankle pulse wave velocity was measured in 183 patients. Compared to the degree of interobserver and intraobserver deviation, a large variance of SWV values was observed in the kidneys of the patients with chronic kidney disease. Shear wave velocity values in the right and left kidneys of each patient correlated well, with high correlation coefficients (r = 0.580-0.732). The SWV decreased concurrently with a decline in the estimated glomerular filtration rate. A low SWV was obtained in patients with a high brachial-ankle pulse wave velocity. Despite progression of renal fibrosis in the advanced stages of chronic kidney disease, these results were in contrast to findings for chronic liver disease, in which progression of hepatic fibrosis results in an increase in the SWV. Considering that a high brachial-ankle pulse wave velocity represents the progression of arteriosclerosis in the large vessels, the reduction of elasticity succeeding diminution of blood flow was suspected to be the main influencing factor of the SWV in the kidneys. This study indicates that diminution of blood flow may affect SWV values in the kidneys more than the progression of tissue fibrosis. Future studies for reducing data variance are needed for effective use of acoustic radiation force impulse elastography in patients with chronic kidney disease.

  5. Amelioration of radiation-induced pulmonary fibrosis by a water-soluble bifunctional sulfoxide radiation mitigator (MMS350).

    Science.gov (United States)

    Kalash, Ronny; Epperly, Michael W; Goff, Julie; Dixon, Tracy; Sprachman, Melissa M; Zhang, Xichen; Shields, Donna; Cao, Shaonan; Franicola, Darcy; Wipf, Peter; Berhane, Hebist; Wang, Hong; Au, Jeremiah; Greenberger, Joel S

    2013-11-01

    A water-soluble ionizing radiation mitigator would have considerable advantages for the management of acute and chronic effects of ionizing radiation. We report that a novel oxetanyl sulfoxide (MMS350) is effective both as a protector and a mitigator of clonal mouse bone marrow stromal cell lines in vitro, and is an effective in vivo mitigator when administered 24 h after 9.5 Gy (LD100/30) total-body irradiation of C57BL/6NHsd mice, significantly improving survival (P = 0.0097). Furthermore, MMS350 (400 μM) added weekly to drinking water after 20 Gy thoracic irradiation significantly decreased: expression of pulmonary inflammatory and profibrotic gene transcripts and proteins; migration into the lungs of bone marrow origin luciferase+/GFP+ (luc+/GFP+) fibroblast progenitors (in both luc+ marrow chimeric and luc+ stromal cell line injected mouse models) and decreased radiation-induced pulmonary fibrosis (P < 0.0001). This nontoxic and orally administered small molecule may be an effective therapeutic in clinical radiotherapy and as a counter measure against the acute and chronic effects of ionizing radiation.

  6. Magnesium Lithospermate B from Salvia miltiorrhiza Bunge Ameliorates Aging-Induced Renal Inflammation and Senescence via NADPH Oxidase-Mediated Reactive Oxygen Generation.

    Science.gov (United States)

    Park, Chan Hum; Shin, Sung Ho; Lee, Eun Kyeong; Kim, Dae Hyun; Kim, Min-Jo; Roh, Seong-Soo; Yokozawa, Takako; Chung, Hae Young

    2017-05-01

    The present study was conducted to examine whether magnesium lithospermate B (MLB) extracted from Salviae miltiorrhizae radix was renoprotective in pathways related to age-related oxidative stress in aged rats. Magnesium lithospermate B was orally administered at a dose of 2- or 8-mg/kg body weight for 16 consecutive days, and the effects were compared with those of vehicle in old and young rats. Magnesium lithospermate B administration to old rats ameliorated renal oxidative stress through reduction of reactive oxygen species. The old rats exhibited a dysregulation of the expression of proteins related to oxidative stress and inflammation in the kidneys, and MLB administration significantly reduced the protein expression of major subunits of nicotinamide adenine dinucleotide phosphate oxidase (Nox4 and p22 phox ), phospho-p38, nuclear factor-kappa B p65, cyclooxygenase-2, and inducible nitric oxide synthase. In addition, MLB-treated old rats showed lower levels of senescence-related proteins such as p16, ADP-ribosylation factor 6, p53, and p21 through effects on the mitogen-activated protein kinase pathway. Magnesium lithospermate B administration also significantly attenuated the age-related increase in serum urea nitrogen, reflecting renal dysfunction, up-regulated podocyte structural proteins, and reduced renal structural injury. Our results provide important evidence that MLB reduces the renal damage of oxidative stress in old rats. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

  7. Urinary collagen degradation products as early markers of progressive renal fibrosis

    DEFF Research Database (Denmark)

    Hijmans, Ryanne S.; Rasmussen, Daniel Guldager Kring; Yazdani, Saleh

    2017-01-01

    -fibrotic S1P-receptor modulator FTY720 treatment. Methods: Proteinuria was induced in male Wistar rats by Adriamycin (ADR) injection (n = 16). Healthy rats served as controls (n = 12). Six weeks post-injection, all underwent renal biopsy, and FTY720-treatment started in ADR-rats (n = 8) and controls (n = 6...... controls, P ADR-rats versus controls...

  8. Fimasartan, a Novel Angiotensin-Receptor Blocker, Protects against Renal Inflammation and Fibrosis in Mice with Unilateral Ureteral Obstruction: the Possible Role of Nrf2

    Science.gov (United States)

    Kim, Soojeong; Kim, Sung Jun; Yoon, Hye Eun; Chung, Sungjin; Choi, Bum Soon; Park, Cheol Whee; Shin, Seok Joon

    2015-01-01

    Objectives: A newly developed angiotensin II receptor blocker, fimasartan, is effective in lowering blood pressure through its action on the renin-angiotensin system. Renal interstitial fibrosis, believed to be due to oxidative injury, is an end-stage process in the progression of chronic kidney disease. Nuclear factor erythroid 2-related factor 2 (Nrf2) is known to regulate cellular oxidative stress and induce expression of antioxidant genes. In this study we investigated the role of Nrf2 in fimasartan-mediated antioxidant effects in mice with renal fibrosis induced by unilateral ureteral obstruction (UUO). Materials and Methods: UUO was induced surgically in mice, followed by either no treatment with fimasartan or the intraperitoneal administration of fimasartan (3 mg/kg/day). On day 7, we evaluated the changes in the renin-angiotensin system (RAS) and the expression of Nrf2 and its downstream antioxidant genes, as well as renal inflammation, apoptosis, and fibrosis in the obstructed kidneys. The effect of fimasartan on the Nrf2 pathway was also investigated in HK-2 cells stimulated by tumor necrosis factor-α. Results: The mice with surgically induced UUO showed increased renal inflammation and fibrosis as evidenced by histopathologic findings and total collagen content in the kidney. These effects were attenuated in the obstructed kidneys of the fimasartan-treated mice. Fimasartan treatment inhibited RAS activation and the expression of Nox1, Nox2, and Nox4. In contrast, fimasartan upregulated the renal expression of Nrf2 and its downstream signaling molecules (such as NQO1; HO-1; GSTa2 and GSTm3). Furthermore, it increased the expression of antioxidant enzymes, including CuSOD, MnSOD, and catalase. The fimasartan-treated mice had significantly less apoptosis on TUNEL staining, with decreased levels of pro-apoptotic protein and increased levels of anti-apoptotic protein. In the HK-2 cells, fimasartan treatment inhibited RAS activation, decreased expression of

  9. Inhibition of IκB Kinase at 24 Hours After Acute Kidney Injury Improves Recovery of Renal Function and Attenuates Fibrosis.

    Science.gov (United States)

    Johnson, Florence L; Patel, Nimesh S A; Purvis, Gareth S D; Chiazza, Fausto; Chen, Jianmin; Sordi, Regina; Hache, Guillaume; Merezhko, Viktoria V; Collino, Massimo; Yaqoob, Muhammed M; Thiemermann, Christoph

    2017-07-03

    Acute kidney injury (AKI) is a major risk factor for the development of chronic kidney disease. Nuclear factor-κB is a nuclear transcription factor activated post-ischemia, responsible for the transcription of proinflammatory proteins. The role of nuclear factor-κB in the renal fibrosis post-AKI is unknown. We used a rat model of AKI caused by unilateral nephrectomy plus contralateral ischemia (30 minutes) and reperfusion injury (up to 28 days) to show impairment of renal function (peak: 24 hours), activation of nuclear factor-κB (peak: 48 hours), and fibrosis (28 days). In humans, AKI is diagnosed by a rise in serum creatinine. We have discovered that the IκB kinase inhibitor IKK16 (even when given at peak serum creatinine) still improved functional and structural recovery and reduced myofibroblast formation, macrophage infiltration, transforming growth factor-β expression, and Smad2/3 phosphorylation. AKI resulted in fibrosis within 28 days (Sirius red staining, expression of fibronectin), which was abolished by IKK16. To confirm the efficacy of IKK16 in a more severe model of fibrosis, animals were subject to 14 days of unilateral ureteral obstruction, resulting in tubulointerstitial fibrosis, myofibroblast formation, and macrophage infiltration, all of which were attenuated by IKK16. Inhibition of IκB kinase at peak creatinine improves functional recovery, reduces further injury, and prevents fibrosis. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

  10. Nephrogenic systemic fibrosis: A brief review

    Directory of Open Access Journals (Sweden)

    Rajesh Waikhom

    2011-01-01

    Full Text Available Nephrogenic systemic fibrosis is a fibrosing disorder of the skin that develops in patients with advanced renal failure. It mostly presents with progressive hardening or induration of the skin of the extremities. Systemic involvement is also known to occur in this entity. Exposure to gadolinium contrast for radiological evaluation has been identified as the offending agent. The condition is progressive and can be seriously disabling. Therapeutic options are limited and not rewarding in majority of the cases. Awareness of this entity is important so that proper precautionary measures can be taken at the earliest to ameliorate the condition.

  11. Amelioration of renal ischaemia-reperfusion injury by liposomal delivery of curcumin to renal tubular epithelial and antigen-presenting cells.

    Science.gov (United States)

    Rogers, N M; Stephenson, M D; Kitching, A R; Horowitz, J D; Coates, P T H

    2012-05-01

    Renal ischaemia-reperfusion (IR) injury is an inevitable consequence of renal transplantation, causing significant graft injury, increasing the risk of rejection and contributing to poor long-term graft outcome. Renal injury is mediated by cytokine and chemokine synthesis, inflammation and oxidative stress resulting from activation of the NF-κB pathway. We utilized liposomal incorporation of a potent inhibitor of the NF-κB pathway, curcumin, to target delivery to renal tubular epithelial and antigen-presenting cells. Liposomes containing curcumin were administered before bilateral renal ischaemia in C57/B6 mice, with subsequent reperfusion. Renal function was assessed from plasma levels of urea and creatinine, 4 and 24 h after reperfusion. Renal tissue was examined for NF-κB activity and oxidative stress (histology, immunostaining) and for apoptosis (TUNEL). Cytokines and chemokines were measured by RT-PCR and Western blotting. Liposomal curcumin significantly improved serum creatinine, reduced histological injury and cellular apoptosis and lowered Toll-like receptor-4, heat shock protein-70 and TNF-α mRNA expression. Liposomal curcumin also reduced neutrophil infiltration and diminished inflammatory chemokine expression. Curcumin liposomes reduced intracellular superoxide generation and increased superoxide dismutase levels, decreased inducible NOS mRNA expression and 3-nitrotyrosine staining consistent with limitations in nitrosative stress and inhibited renal tubular mRNA and protein expression of thioredoxin-interacting protein. These actions of curcumin were mediated by inhibition of NF-κB, MAPK and phospho-S6 ribosomal protein. Liposomal delivery of curcumin promoted effective, targeted delivery of this non-toxic compound that provided cytoprotection via anti-inflammatory and multiple antioxidant mechanisms following renal IR injury. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

  12. Breast Regression Protein-39/Chitinase 3-Like 1 Promotes Renal Fibrosis after Kidney Injury via Activation of Myofibroblasts.

    Science.gov (United States)

    Montgomery, Tinika A; Xu, Leyuan; Mason, Sherene; Chinnadurai, Amirtha; Lee, Chun Geun; Elias, Jack A; Cantley, Lloyd G

    2017-11-01

    The normal response to kidney injury includes a robust inflammatory infiltrate of PMNs and macrophages. We previously showed that the small secreted protein breast regression protein-39 (BRP-39), also known as chitinase 3-like 1 (CHI3L1) and encoded by the Chi3l1 gene, is expressed at high levels by macrophages during the early stages of kidney repair and promotes tubular cell survival via IL-13 receptor α 2 (IL13R α 2)-mediated signaling. Here, we investigated the role of BRP-39 in profibrotic responses after AKI. In wild-type mice, failure to resolve tubular injury after unilateral ischemia-reperfusion injury (U-IRI) led to sustained low-level Chi3l1 mRNA expression by renal cells and promoted macrophage persistence and severe interstitial fibrosis. Analysis of macrophages isolated from wild-type kidneys 14 days after U-IRI revealed high-level expression of the profibrotic BRP-39 receptor Ptgdr2 / Crth2 and expression of the profibrotic markers Lgals3 , Pdgfb , Egf , and Tgfb In comparison, injured kidneys from mice lacking BRP-39 had significantly fewer macrophages, reduced expression of profibrotic growth factors, and decreased accumulation of extracellular matrix. BRP-39 depletion did not affect myofibroblast accumulation but did attenuate myofibroblast expression of Col1a1 , Col3a1 , and Fn1 Together, these results identify BRP-39 as an important activator of macrophage-myofibroblast crosstalk and profibrotic signaling in the setting of maladaptive kidney repair. Copyright © 2017 by the American Society of Nephrology.

  13. Andrographolide ameliorates diabetic nephropathy by attenuating hyperglycemia-mediated renal oxidative stress and inflammation via Akt/NF-κB pathway.

    Science.gov (United States)

    Ji, Xiaoqian; Li, Changzheng; Ou, Yitao; Li, Ning; Yuan, Kai; Yang, Guizhi; Chen, Xiaoyan; Yang, Zhicheng; Liu, Bing; Cheung, Wai W; Wang, Lijing; Huang, Ren; Lan, Tian

    2016-12-05

    Diabetic nephropathy (DN) is characterized by proliferation of mesangial cells, mesangial hypertrophy and extracellular matrix (ECM) accumulation. Our recent study found that andrographolide inhibited high glucose-induced mesangial cell proliferation and fibronectin expression through inhibition of AP-1 pathway. However, whether andrographolide has reno-protective roles in DN has not been fully elucidated. Here, we studied the pharmacological effects of andrographolide against the progression of DN and high glucose-induced mesangial dysfunction. Diabetes was induced in C57BL/6 mice by intraperitoneal injection of streptozotocin (STZ). After 1 weeks after STZ injection, normal diet was substituted with a high-fat diet (HFD). Diabetic mice were intraperitoneal injected with andrographolide (2 mg/kg, twice a week). After 8 weeks, functional and histological analyses were carried out. Parallel experiments uncovering the molecular mechanism by which andrographolide prevents from DN was performed in mesangial cells. Andrographolide inhibited the increases in fasting blood glucose, triglyceride, kidney/body weight ratio, blood urea nitrogen, serum creatinine and 24-h albuminuria in diabetic mice. Andrographolide also prevented renal hypertrophy and ECM accumulation. Furthermore, andrographolide markedly attenuated NOX1 expression, ROS production and pro-inflammatory cytokines as well. Additionally, andrographolide inhibited Akt/NF-κB signaling pathway. These results demonstrate that andrographolide is protective against the progression of experimental DN by inhibiting renal oxidative stress, inflammation and fibrosis. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  14. Small Molecule Inhibiting Nuclear Factor-kB Ameliorates Oxidative Stress and Suppresses Renal Inflammation in Early Stage of Alloxan-Induced Diabetic Nephropathy in Rat.

    Science.gov (United States)

    Borgohain, Manash P; Lahkar, Mangala; Ahmed, Sahabuddin; Chowdhury, Liakat; Kumar, Saurabh; Pant, Rajat; Choubey, Abhinav

    2017-05-01

    Diabetic nephropathy is one of the major microvascular complications of diabetes mellitus which ultimately gives rise to cardiovascular diseases. Prolonged hyperglycaemia and chronic renal inflammation are the two key players in the development and progression of diabetic nephropathy. Nuclear factor kB (NF-kB)-mediated inflammatory cascade is a strong contributor to the renovascular inflammation in diabetic nephropathy. Here, we studied the effects of piceatannol, a potent NF-kB inhibitor, on various oxidative stress markers and NF-kB dependent diabetic renoinflammatory cascades in rat induced by alloxan (ALX). Experimental diabetes was induced in male Wistar rats by a single intraperitoneal dose, 150 mg/kg body-weight (b.w.) of ALX. Diabetic rats were treated with Piceatannol (PCTNL) at a dose of 30 and 50 mg/kg b.w. After 14 days of oral treatment, PCTNL significantly restored blood sugar level, glomerular filtration rate, serum markers and plasma lipids. PCTNL administration also reversed the declined activity of cellular antioxidant machineries namely superoxide dismutase and glutathione and the elevated levels of malondialdehyde and nitric oxide. Moreover, piceatannol-treated groups showed marked inhibition of renal pro-inflammatory cytokines and NF-kB p65/p50 binding to DNA. Renal histopathological investigations also supported its ameliorative effects against diabetic kidney damage. Importantly, effects were more prominent at a dose of 50 mg/kg, and in terms of body-weight gain, PCTNL failed to effect significantly. However, overall findings clearly demonstrated that PCTNL provides remarkable renoprotection in diabetes by abrogating oxidative stress and NF-kB activation - and might be helpful in early stage of diabetic nephropathy. © 2016 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

  15. Nephrogenic systemic fibrosis versus contrast-induced nephropathy: risks and benefits of contrast-enhanced MR and CT in renally impaired patients

    DEFF Research Database (Denmark)

    Martin, Diego R; Semelka, Richard C; Chapman, Arlene

    2009-01-01

    -sectional imaging modality. Factors to consider include the relative risks of the contrast agent. Other factors include the relative procedural risks, including radiation risks and the relative expected diagnostic yield of the examination technique (12). In this review we describe both nephrogenic systemic fibrosis...... and contrast-induced nephropathy to compare the implications with regard to relative risks and benefits of contrast-enhanced MRI or CT in patients with impaired renal function. J. Magn. Reson. Imaging 2009;30:1350-1356. (c) 2009 Wiley-Liss, Inc....

  16. Transforming growth factor-β-sphingosine kinase 1/S1P signaling upregulates microRNA-21 to promote fibrosis in renal tubular epithelial cells.

    Science.gov (United States)

    Liu, Xiujuan; Hong, Quan; Wang, Zhen; Yu, Yanyan; Zou, Xin; Xu, Lihong

    2016-02-01

    Renal fibrosis is a progressive pathological change characterized by tubular cell apoptosis, tubulointerstitial fibroblast proliferation, and excessive deposition of extracellular matrix (ECM). miR-21 has been implicated in transforming growth factor-β (TGF-β)-stimulated tissue fibrosis. Recent studies showed that sphingosine kinase/sphingosine-1-phosphate (SphK/S1P) are also critical for TGF-β-stimulated tissue fibrosis; however, it is not clear whether SphK/S1P interacts with miR-21 or not. In this study, we hypothesized that SphK/S1P signaling is linked to upregulation of miR-21 by TGF-β. To verify this hypothesis, we first determined that miR-21 was highly expressed in renal tubular epithelial cells (TECs) stimulated with TGF-β by using qRT-PCR and Northern blotting. Simultaneously, inhibition of miR-21, mediated by the corresponding antimir, markedly decreased the expression and deposition of type I collagen, fibronectin (Fn), cysteine-rich protein 61 (CCN1), α-smooth muscle actin, and fibroblast-specific protein1 in TGF-β-treated TECs. ELISA and qRT-PCR were used to measure the S1P and SphK1 levels in TECs. S1P production was induced by TGF-β through activation of SphK1. Furthermore, it was observed that TGF-β-stimulated upregulation of miR-21 was abolished by SphK1 siRNA and was restored by the addition of exogenous S1P. Blocking S1PR2 also inhibited upregulation of miR-21. Additionally, miR-21 overexpression attenuated the repression of TGF-β-stimulated ECM deposition and epithelial-mesenchymal transition by SphK1 and S1PR2 siRNA. In summary, our study demonstrates a link between SphK1/S1P and TGF-β-induced miR-21 in renal TECs and may represent a novel therapeutic target in renal fibrosis. © 2015 by the Society for Experimental Biology and Medicine.

  17. Assessment of Liver Fibrosis by Transient Elastography Should Be Done After Hemodialysis in End Stage Renal Disease Patients with Liver Disease.

    Science.gov (United States)

    Taneja, Sunil; Borkakoty, Amritangsu; Rathi, Sahaj; Kumar, Vivek; Duseja, Ajay; Dhiman, Radha K; Gupta, Krishan L; Chawla, Yogesh

    2017-11-01

    The patients with end stage renal disease (ESRD) are at greater risk of acquiring chronic hepatitis B or C and subsequently development of liver disease. The aim of the study was to assess liver fibrosis by transient elastography (TE) and look for factors associated with change in liver stiffness measurement (LSM) with one session of hemodialysis (HD). Consecutive ESRD patients on maintenance hemodialysis (MHD) with suspected liver disease were enrolled. They underwent LSM by TE before and after one session of HD. Bioelectric impedance analysis was done to evaluate the volume status at the time of TE. Sixty-eight patients with mean age of 40 ± 14 years were included. There was a significant reduction in LSM after HD (18.5 [95% CI 14.8-23.1] vs. 11.2 [95% CI 8.8-13.7] kPa, p  or  2.5 L (8.6 [95% CI 5.7-11.5] vs. 5.1 [95% CI 2.9-7.5], p = 0.05). In 18 patients who underwent liver biopsy, LSM after HD performed better at detecting significant fibrosis, with area under receiver operating characteristics curve 0.71 [95% CI 0.46-0.97], versus 0.64 [95% CI 0.38-0.90], respectively. An LSM value of 12.2 kPa after HD was 71% sensitive and 74% specific for detection of significant fibrosis (≥ F2), while values less than 9 kPa ruled out significant fibrosis with a sensitivity and specificity of 37 and 100%, respectively. LSM by TE decreases significantly after HD in patients with ESRD on long-term MHD. Hence, TE should be done after HD for accurate assessment of liver fibrosis.

  18. Andrographolide Ameliorates Liver Fibrosis in Mice: Involvement of TLR4/NF-κB and TGF-β1/Smad2 Signaling Pathways

    Directory of Open Access Journals (Sweden)

    Liteng Lin

    2018-01-01

    Full Text Available Liver fibrosis is characterized by activated hepatic stellate cells (HSC and extracellular matrix accumulation. Blocking the activation of HSC and the inflammation response are two major effective therapeutic strategies for liver fibrosis. In addition to the long history of using andrographolide (Andro for inflammatory disorders, we aimed at elucidating the pharmacological effects and potential mechanism of Andro on liver fibrosis. In this study, liver fibrosis was induced by carbon tetrachloride (CCl4 and the mice were intraperitoneally injected with Andro for 6 weeks. HSC cell line (LX-2 and primary HSC were also treated with Andro in vitro. Treatment of CCl4-induced mice with Andro decreased the levels of alanine aminotransferase (ALT and aspartate aminotransferase (AST, Sirius red staining as well as the expression of α smooth muscle actin (α-SMA and transforming growth factor- (TGF- β1. Furthermore, the expression of Toll-like receptor (TLR4 and NF-κB p50 was also inhibited by Andro. Additionally, in vitro data confirmed that Andro treatment not only attenuated the expression of profibrotic and proinflammatory factors but also blocked the TGF-β1/Smad2 and TLR4/NF-κB p50 pathways. These results demonstrate that Andro prevents liver inflammation and fibrosis, which is in correlation with the inhibition of the TGF-β1/Smad2 and TLR4/NF-κB p50 pathways, highlighting Andro as a potential therapeutic strategy for liver fibrosis.

  19. The study on serum and urine of renal interstitial fibrosis rats induced by unilateral ureteral obstruction based on metabonomics and network analysis methods.

    Science.gov (United States)

    Xiang, Zheng; Sun, Hao; Cai, Xiaojun; Chen, Dahui

    2016-04-01

    Transmission of biological information is a biochemical process of multistep cascade from genes/proteins to metabolites. However, because most metabolites reflect the terminal information of the biochemical process, it is difficult to describe the transmission process of disease information in terms of the metabolomics strategy. In this paper, by incorporating network and metabolomics methods, an integrated approach was proposed to systematically investigate and explain the molecular mechanism of renal interstitial fibrosis. Through analysis of the network, the cascade transmission process of disease information starting from genes/proteins to metabolites was putatively identified and uncovered. The results indicated that renal fibrosis was involved in metabolic pathways of glycerophospholipid metabolism, biosynthesis of unsaturated fatty acids and arachidonic acid metabolism, riboflavin metabolism, tyrosine metabolism, and sphingolipid metabolism. These pathways involve kidney disease genes such as TGF-β1 and P2RX7. Our results showed that combining metabolomics and network analysis can provide new strategies and ideas for the interpretation of pathogenesis of disease with full consideration of "gene-protein-metabolite."

  20. Phytochemical screening, and assessment of ameliorating effect of aqueous and ethanolic extracts of Gmelina arborea on drug induced hepatic and renal insufficiency in rats.

    Science.gov (United States)

    Anthony, Ogbonnaya Enyinnaya; Mbuh, Awah Francis; Emmanuel, Mounmbegna Philippe

    2012-04-01

    Phytochemical screening of stem bark and leaves of Gmelina arborea; and effect of aqueous and ethanolic extracts of Gmelina arborea stembark on hepatic and renal insufficiency in rats was assessed in this study. Phytochemical screening was carried out on the air-dried leaf, oven-dried leaf, air-dried stembark and oven-dried stembark samples. Sixty five (65) wister albino rats, (50.7-117.5 g) were divided into thirteen groups of five animals each. Three groups serve as Controls and were administered Cisplatin (5mg/kg b.w; i.p), Paracetamol (200mg/kg b.w; i.p) and Normal saline (0.002 ml/kg b.w; oral). Other groups were administered, either, cisplatin and extracts (1g/kg b.w; oral); Paracetamol and extracts (1g/kg b.w; oral); extracts alone; or drugs and combination of extracts. Animals were starved, 24 hours prior to sacrifice and sacrificed on the 9th day after commencement of treatment. Phytochemical screening results show the presence of alkaloid, flavonoid, tannin, saponin, cyanogenic glycoside, phytate, and carbohydrate. Saponin and carbohydrate were shown to be much higher in concentration than other phytochemicals. The percentage composition of cyanogenic glycoside and phytate were highest in air-dried stembark and oven-dried leaf samples, respectively. All the Gmelina arborea extracts and extract mixture administered to both paracetamol and cisplatin treated animals, significantly, lowers both the activities of the SGOT and SGPT, and the levels of serum creatinine and urea. When administered alone, the aqueous and ethanolic extracts show little or no sign of toxicity. Thus Gmelina arborea extracts may have ameliorating effect on hepatic and renal insufficiency caused by paracetamol and cisplatin respectively, and any inherent toxicity may be reduced or eliminated through adequate heat treatment.

  1. Electroacupuncture Ameliorates Acute Renal Injury in Lipopolysaccharide-Stimulated Rabbits via Induction of HO-1 through the PI3K/Akt/Nrf2 Pathways.

    Science.gov (United States)

    Yu, Jian-Bo; Shi, Jia; Zhang, Yuan; Gong, Li-Rong; Dong, Shu-An; Cao, Xin-Shun; Wu, Li-Li; Wu, Li-Na

    2015-01-01

    Electroacupuncture at select acupoints have been verified to protect against organ dysfunctions during endotoxic shock. And, heme oxygenase (HO)-1 as a phase II enzyme and antioxidant contributed to the protection of kidney in septic shock rats. The phosphatidylinositol 3-kinase (PI3K)-Akt pathway mediated the activation of NF-E2 related factor-2 (Nrf2), which was involved in HO-1 induction. To understand the efficacy of electroacupuncture stimulation in ameliorating acute kidney injury (AKI) through the PI3K/Akt/Nrf2 pathway and subsequent HO-1 upregulation, a dose of LPS 5mg/kg was administered intravenously to replicate the rabbit model of AKI induced by endotoxic shock. Electroacupuncture pretreatment was handled bilaterally at Zusanli and Neiguan acupoints for five consecutive days while sham electroacupuncture at non-acupoints as control. Results displayed that electroacupuncture stimulation significantly alleviated the morphologic renal damage, attenuated renal tubular apoptosis, suppressed the elevated biochemical indicators of AKI caused by LPS, enhanced the expressions of phospho-Akt, HO-1protein, Nrf2 total and nucleoprotein, and highlighted the proportions of Nrf2 nucleoprotein as a parallel. Furthermore, partial protective effects of elecroacupuncture were counteracted by preconditioning with wortmannin (the selective PI3K inhibitor), indicating a direct involvement of PI3K/Akt pathway. Inconsistently, wortmannin pretreatment made little difference to the expressions of HO-1, Nrf2 nucleoprotein and total protein, which indicated that PI3K/Akt may be not the only pathway responsible for electroacupuncture-afforded protection against LPS-induced AKI. These findings provide new insights into the potential future clinical applications of electroacupuncture for AKI induced by endotoxic shock instead of traditional remedies.

  2. Semen Brassicae ameliorates hepatic fibrosis by regulating transforming growth factor-β1/Smad, nuclear factor-κB, and AKT signaling pathways in rats.

    Science.gov (United States)

    Cao, Si; Zheng, Baoping; Chen, Tao; Chang, Xinfeng; Yin, Bao; Huang, Zhihua; Shuai, Ping; Han, Limin

    2018-01-01

    There is no effective treatment for liver fibrosis, which is a common phase during the progression of many chronic liver diseases to cirrhosis. Previous studies found that Semen Brassicae therapy can effectively improve the clinical symptoms of patients with asthma, allergic rhinitis, and chronic lung diseases; however, its effects on liver fibrosis in rats and its possible mechanisms of action remain unclear. Rats were injected intraperitoneally with 4% thioacetamide aqueous solution (5 mL·kg -1 ) at a dose of 200 mg·kg -1 twice a week for 8 consecutive weeks to establish the liver fibrosis model and were then treated with different concentrations of Semen Brassicae extract. After Semen Brassicae treatment, the morphology of the liver tissue was analyzed using hematoxylin and eosin and Masson's trichrome staining, and liver index and liver fibrosis grade were calculated. Thereafter, the levels of collagen-I, collagen-III, α-SMA, transforming growth factor (TGF)-β1, p-Smad 2/3, Smad 2/3, Smad4, NF-κB-p65, p-NF-κB-p65, IL-1β, IL-6, AKT, and p-AKT were determined using Western blotting. Compared with the untreated model group, the Semen Brassicae-treated group showed significantly decreased liver function indices; expression levels of collagen-I, collagen-III, and α-SMA; and hepatic fibrosis. Further studies also showed that the expression of TGF-β1, Smad4, p-Smad 2/3/Smad 2/3, p-NF-κB-p65/NF-κB-p65, IL-1β, IL-6, and p-AKT/AKT significantly decreased after the treatment. These results indicate that Semen Brassicae exhibits an anti-hepatic fibrosis effect, and the underlying mechanism of action may be related to the regulation of TGF-β1/Smad, NF-κB, and AKT signaling pathways and the reduction of extracellular matrix deposition.

  3. Role of Magnetic Resonance Elastography as a Noninvasive Measurement Tool of Fibrosis in a Renal Allograft: A Case Report.

    Science.gov (United States)

    Kim, J K; Yuen, D A; Leung, G; Jothy, S; Zaltzman, J; Ramesh Prasad, G V; Prabhudesai, V; Mnatzakanian, G; Kirpalani, A

    2017-09-01

    A major reason for poor long-term kidney transplant outcomes is the development of chronic allograft injury, characterized by interstitial fibrosis and tubular atrophy. Currently, an invasive biopsy that samples only tool of allograft fibrosis in a kidney transplant patient at 2 time points. The MRE whole-kidney stiffness values reflected the changes in fibrosis of the kidney allograft as assessed by histologic examination. To our knowledge, this technique is the first observation of change over time in MRE-derived whole-kidney stiffness in an allograft that is consistent with changes in histology-derived fibrosis scores in a single patient. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Fuzheng Huayu Recipe Ameliorates Liver Fibrosis by Restoring Balance between Epithelial-to-Mesenchymal Transition and Mesenchymal-to-Epithelial Transition in Hepatic Stellate Cells

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    Qin Pan

    2015-01-01

    Full Text Available Activation of hepatic stellate cells (HSCs depending on epithelial-to-mesenchymal transition (EMT reflects the key event of liver fibrosis. Contrastively, mesenchymal-to-epithelial transition (MET of HSCs facilitates the fibrosis resolution. Here we investigated the effect of Fuzheng Huayu (FZHY recipe, a Chinese herbal decoction made of Radix Salviae Miltiorrhizae, Semen Persicae, Cordyceps sinensis, Pollen Pini, and Gynostemma pentaphyllum, on liver fibrosis concerning the balance of EMT and MET in HSCs. In contrast to the increased TGF-β1/BMP-7 ratio in activated HSCs, FZHY administration induced significant upregulation of BMP-7 and downregulation of TGF-β1 at both transcription and translation levels. Restoration of TGF-β1/BMP-7 ratio inhibited the expression of p38 MAPK and phosphorylated p38 MAPK, resulting in the reversal of epithelial-to-mesenchymal transition (EMT to mesenchymal-to-epithelial transition (MET as characterized by the abolishment of EMT markers (α-SMA and desmin and reoccurrence of MET marker (E-cadherin. In vivo treatment of FZHY recipe also demonstrated the statistical reduction of activated HSCs with EMT phenotype, which attenuated the carbon tetrachloride- (CCl4- induced liver fibrosis in a dose-dependent manner. These findings may highlight a novel antifibrotic role of FZHY recipe on the basis of rebalancing EMT and MET in HSCs.

  5. Renin-angiotensin system inhibition ameliorates CCl4-induced liver fibrosis in mice through the inactivation of nuclear transcription factor kappa B.

    Science.gov (United States)

    Saber, Sameh; Mahmoud, Amr A A; Helal, Noha S; El-Ahwany, Eman; Abdelghany, Rasha H

    2018-06-01

    Therapeutic interventions for liver fibrosis are still limited due to the complicated molecular pathogenesis. Renin-angiotensin system (RAS) seems to contribute to the development of hepatic fibrosis. Therefore, we aimed to examine the effect of RAS inhibition on CCl 4 -induced liver fibrosis. Mice were treated with silymarin (30 mg·kg -1 ), perindopril (1 mg·kg -1 ), fosinopril (2 mg·kg -1 ), or losartan (10 mg·kg -1 ). The administration of RAS inhibitors improved liver histology and decreased protein expression of alpha smooth muscle actin (α-SMA) and hepatic content of hydroxyproline. These effects found to be mediated via inactivation of nuclear transcription factor kappa B (NFκB) pathway by the inhibition of NFκB p65 phosphorylation at the Ser536 residue and phosphorylation-induced degradation of nuclear factor kappa-B inhibitor alpha (NFκBia) subsequently inhibited NFκB-induced TNF-α and TGF-β1, leading to lower levels of tissue inhibitor of metalloproteinase-1 (TIMP-1) and vascular endothelial growth factor (VEGF). We concluded that the tissue affinity of the angiotensin converting enzyme inhibitors (ACEIs) has no impact on its antifibrotic activity and that interfering the RAS either through the inhibition of ACE or the blockade of AT1R has the same therapeutic benefit. These results suggest RAS inhibitors as promising candidates for further clinical trials in the management of hepatic fibrosis.

  6. Experimental Nonalcoholic Steatohepatitis and Liver Fibrosis Are Ameliorated by Pharmacologic Activation of Nrf2 (NF-E2 p45-Related Factor 2

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    Ritu S. Sharma

    2018-01-01

    Conclusions: Pharmacologic activation of Nrf2 in mice that had already been rendered obese and insulin resistant reversed insulin resistance, suppressed hepatic steatosis, and mitigated against NASH and liver fibrosis, effects that we principally attribute to inhibition of ER, inflammatory, and oxidative stress.

  7. Semen Brassicae ameliorates hepatic fibrosis by regulating transforming growth factor-β1/Smad, nuclear factor-κB, and AKT signaling pathways in rats

    Directory of Open Access Journals (Sweden)

    Cao S

    2018-05-01

    Full Text Available Si Cao,1,2,* Baoping Zheng,3,* Tao Chen,4 Xinfeng Chang,4 Bao Yin,1 Zhihua Huang,4 Ping Shuai,4 Limin Han2 1School of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China; 2Gannan Medical University, Ganzhou, Jiangxi, China; 3Department of Chinese Medicine, The First Affiliated Hospital, Gannan Medical University, Ganzhou, Jiangxi, China; 4School of Basic Medical Sciences, Gannan Medical University, Ganzhou, Jiangxi, China *These authors contributed equally to this work Purpose: There is no effective treatment for liver fibrosis, which is a common phase during the progression of many chronic liver diseases to cirrhosis. Previous studies found that Semen Brassicae therapy can effectively improve the clinical symptoms of patients with asthma, allergic rhinitis, and chronic lung diseases; however, its effects on liver fibrosis in rats and its possible mechanisms of action remain unclear. Methods: Rats were injected intraperitoneally with 4% thioacetamide aqueous solution (5 mL·kg-1 at a dose of 200 mg·kg-1 twice a week for 8 consecutive weeks to establish the liver fibrosis model and were then treated with different concentrations of Semen Brassicae extract. After Semen Brassicae treatment, the morphology of the liver tissue was analyzed using hematoxylin and eosin and Masson’s trichrome staining, and liver index and liver fibrosis grade were calculated. Thereafter, the levels of collagen-I, collagen-III, α-SMA, transforming growth factor (TGF-β1, p-Smad 2/3, Smad 2/3, Smad4, NF-κB-p65, p-NF-κB-p65, IL-1β, IL-6, AKT, and p-AKT were determined using Western blotting. Results: Compared with the untreated model group, the Semen Brassicae-treated group showed significantly decreased liver function indices; expression levels of collagen-I, collagen-III, and α-SMA; and hepatic fibrosis. Further studies also showed that the expression of TGF-β1, Smad4, p-Smad 2/3/Smad 2/3, p

  8. Vitamin A-coupled liposomes containing siRNA against HSP47 ameliorate skin fibrosis in chronic graft-versus-host disease.

    Science.gov (United States)

    Yamakawa, Tomohiro; Ohigashi, Hiroyuki; Hashimoto, Daigo; Hayase, Eiko; Takahashi, Shuichiro; Miyazaki, Miyono; Minomi, Kenjiro; Onozawa, Masahiro; Niitsu, Yoshiro; Teshima, Takanori

    2018-03-29

    Chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (SCT) is characterized by multiorgan fibrosis and profoundly affects the quality of life of transplant survivors. Heat shock protein 47 (HSP47), a collagen-specific molecular chaperone, plays a critical role in collagen synthesis in myofibroblasts. We explored the role of HSP47 in the fibrotic process of cutaneous chronic GVHD in mice. Immunohistochemical analysis showed massive fibrosis with elevated amounts of collagen deposits and accumulation of F4/80 + macrophages, as well as myofibroblasts expressing HSP47 and retinol-binding protein 1 in the skin after allogeneic SCT. Repeated injection of anti-colony-stimulating factor (CSF-1) receptor-blocking antibodies significantly reduced HSP47 + myofibroblasts in the skin, indicating a macrophage-dependent accumulation of myofibroblasts. Vitamin A-coupled liposomes carrying HSP47 small interfering RNA (siRNA) (VA-lip HSP47) delivered HSP47 siRNA to cells expressing vitamin A receptors and knocked down their HSP47 in vitro. Intravenously injected VA-lip HSP47 were specifically distributed to skin fibrotic lesions and did not affect collagen synthesis in healthy skin. VA-lip HSP47 knocked down HSP47 expression in myofibroblasts and significantly reduced collagen deposition without inducing systemic immunosuppression. It also abrogated fibrosis in the salivary glands. These results highlight a cascade of fibrosis in chronic GVHD; macrophage production of transforming growth factor β mediates fibroblast differentiation to HSP47 + myofibroblasts that produce collagen. VA-lip HSP47 represent a novel strategy to modulate fibrosis in chronic GVHD by targeting HSP47 + myofibroblasts without inducing immunosuppression. © 2018 by The American Society of Hematology.

  9. Adipose derived mesenchymal stem cells transplantation via portal vein improves microcirculation and ameliorates liver fibrosis induced by CCl4 in rats

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    Wang Yu

    2012-06-01

    Full Text Available Abstract Introduction Adipose derived mesenchymal stem cells (ADMSCs, carrying the similar characteristics to bone marrow mesenchymal stem cells, only much more abundant and easier to obtain, may be a promising treatment for liver fibrosis. We aim to investigate the therapeutic potential of ADMSCs transplantation in liver fibrosis caused by carbon tetrachloride (CCl4 in rats as well as its underlying mechanism, and to further explore the appropriate infusion pathway. Methods ADMSCs were isolated, cultured and identified. Placebo and ADMSCs were transplanted via portal vein and tail vein respectively into carbon tetrachloride (CCl4-induced liver fibrosis rats. Computed tomography (CT perfusion scan and microvessel counts were performed to measure the alteration of liver microcirculation after therapy. Liver function tests and histological findings were estimated. Results CT perfusion scan shown significant decrease of hepatic arterial perfusion index, significant increased portal vein perfusion, total liver perfusion in rats receiving ADMSCs from portal vein, and Factor VIII (FVIII immunohistochemical staining shown significant decrease of microvessels in rats receiving ADMSCs from portal vein, indicating microcirculation improvement in portal vein group. Vascular endothelial growth Factor (VEGF was significantly up-regulated in fibrosis models, and decreased after ADMSCs intraportal transplantation. A significant improvement of liver functional test and histological findings in portal vein group were observed. No significance was found in rats receiving ADMSCs from tail vein. Conclusions ADMSCs have a therapeutic effect against CCl4-mediated liver fibrosis. ADMSCs may benefit the fibrotic liver through alteration of microcirculation, evidenced by CT perfusion scan and down-regulation of VEGF. Intraportal transplantation is a better pathway than tail vein transplantation.

  10. 1,25-(OH)2-vitamin D3 prevents activation of hepatic stellate cells in vitro and ameliorates inflammatory liver damage but not fibrosis in the Abcb4−/− model

    International Nuclear Information System (INIS)

    Reiter, Florian P.; Hohenester, Simon; Nagel, Jutta M.; Wimmer, Ralf; Artmann, Renate; Wottke, Lena; Makeschin, Marie-Christine; Mayr, Doris; Rust, Christian; Trauner, Michael; Denk, Gerald U.

    2015-01-01

    Background/Purpose of the study: Vitamin D 3 -deficiency is common in patients with chronic liver-disease and may promote disease progression. Vitamin D 3 -administration has thus been proposed as a therapeutic approach. Vitamin D 3 has immunomodulatory effects and may modulate autoimmune liver-disease such as primary sclerosing cholangitis. Although various mechanisms of action have been proposed, experimental evidence is limited. Here we test the hypothesis that active 1,25-(OH) 2 -vitamin D 3 inhibits activation of hepatic stellate cells (HSC) in vitro and modulates liver-injury in vivo. Methods: Proliferation and activation of primary murine HSC were assessed by BrdU- and PicoGreen ® -assays, immunoblotting, immunofluorescence-microscopy, quantitative-PCR, and zymography following calcitriol-treatment. Wild-type and ATP-binding cassette transporter b4 −/− (Abcb4 −/− )-mice received calcitriol for 4 weeks. Liver-damage, inflammation, and fibrosis were assessed by serum liver-tests, Sirius-red staining, quantitative-PCR, immunoblotting, immunohistochemistry and hydroxyproline quantification. Results: In vitro, calcitriol inhibited activation and proliferation of murine HSC as shown by reduced α-smooth muscle actin and platelet-derived growth factor-receptor-β-protein-levels, BrdU and PicoGreen®-assays. Furthermore, mRNA-levels and activity of matrix metalloproteinase 13 were profoundly increased. In vivo, calcitriol ameliorated inflammatory liver-injury reflected by reduced levels of alanine aminotransferase in Abcb4 −/− -mice. In accordance, their livers had lower mRNA-levels of F4/80, tumor necrosis factor-receptor 1 and a lower count of portal CD11b positive cells. In contrast, no effect on overall fibrosis was observed. Conclusion: Calcitriol inhibits activation and proliferation of HSCs in vitro. In Abcb4 −/− -mice, administration of calcitriol ameliorates inflammatory liver-damage but has no effect on biliary fibrosis after 4 weeks

  11. 1,25-(OH){sub 2}-vitamin D{sub 3} prevents activation of hepatic stellate cells in vitro and ameliorates inflammatory liver damage but not fibrosis in the Abcb4{sup −/−} model

    Energy Technology Data Exchange (ETDEWEB)

    Reiter, Florian P., E-mail: florian.reiter@med.uni-muenchen.de [Department of Medicine II, Liver Center Munich, University of Munich, Marchioninistr. 15, D-81377 Munich (Germany); Hohenester, Simon; Nagel, Jutta M.; Wimmer, Ralf; Artmann, Renate; Wottke, Lena [Department of Medicine II, Liver Center Munich, University of Munich, Marchioninistr. 15, D-81377 Munich (Germany); Makeschin, Marie-Christine; Mayr, Doris [Institute of Pathology, University of Munich, Thalkirchner Str. 36, D-80337 Munich (Germany); Rust, Christian [Department of Medicine I, Krankenhaus Barmherzige Brüder, Romanstr. 93, D-80639 Munich (Germany); Trauner, Michael [Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna (Austria); Denk, Gerald U. [Department of Medicine II, Liver Center Munich, University of Munich, Marchioninistr. 15, D-81377 Munich (Germany)

    2015-04-03

    Background/Purpose of the study: Vitamin D{sub 3}-deficiency is common in patients with chronic liver-disease and may promote disease progression. Vitamin D{sub 3}-administration has thus been proposed as a therapeutic approach. Vitamin D{sub 3} has immunomodulatory effects and may modulate autoimmune liver-disease such as primary sclerosing cholangitis. Although various mechanisms of action have been proposed, experimental evidence is limited. Here we test the hypothesis that active 1,25-(OH){sub 2}-vitamin D{sub 3} inhibits activation of hepatic stellate cells (HSC) in vitro and modulates liver-injury in vivo. Methods: Proliferation and activation of primary murine HSC were assessed by BrdU- and PicoGreen{sup ®}-assays, immunoblotting, immunofluorescence-microscopy, quantitative-PCR, and zymography following calcitriol-treatment. Wild-type and ATP-binding cassette transporter b4{sup −/−} (Abcb4{sup −/−})-mice received calcitriol for 4 weeks. Liver-damage, inflammation, and fibrosis were assessed by serum liver-tests, Sirius-red staining, quantitative-PCR, immunoblotting, immunohistochemistry and hydroxyproline quantification. Results: In vitro, calcitriol inhibited activation and proliferation of murine HSC as shown by reduced α-smooth muscle actin and platelet-derived growth factor-receptor-β-protein-levels, BrdU and PicoGreen®-assays. Furthermore, mRNA-levels and activity of matrix metalloproteinase 13 were profoundly increased. In vivo, calcitriol ameliorated inflammatory liver-injury reflected by reduced levels of alanine aminotransferase in Abcb4{sup −/−}-mice. In accordance, their livers had lower mRNA-levels of F4/80, tumor necrosis factor-receptor 1 and a lower count of portal CD11b positive cells. In contrast, no effect on overall fibrosis was observed. Conclusion: Calcitriol inhibits activation and proliferation of HSCs in vitro. In Abcb4{sup −/−}-mice, administration of calcitriol ameliorates inflammatory liver-damage but has

  12. Esculetin ameliorates hepatic fibrosis in high fat diet induced non-alcoholic fatty liver disease by regulation of FoxO1 mediated pathway.

    Science.gov (United States)

    Pandey, Anuradha; Raj, Priyank; Goru, Santosh Kumar; Kadakol, Almesh; Malek, Vajir; Sharma, Nisha; Gaikwad, Anil Bhanudas

    2017-08-01

    Non-alcoholic fatty liver disease (NAFLD), a chronic metabolic disorder is associated with oxidative stress, inflammation and fibrotic cascades. In this study, we aimed to examine the effects of Esculetin, a well-known anti-oxidant on TGF-β1 mediated liver fibrosis and FoxO1 activity. A non-genetic murine model for NAFLD was developed by chronic high fat diet (HFD) (58% calories from fats) feeding in Wistar rats. The plasma biochemical parameters, liver function tests, oxidative stress, and histopathological alterations were assessed. The alterations in extracellular matrix (ECM) deposition and FoxO1 activity were assessed by immunohistochemistry. The aberrations in plasma parameters, liver functioning, morphometric and microscopic changes in liver structure of HFD fed rats were significantly improved by treatment with Esculetin. Liver fibrosis, identified in the form of collagen deposition and expression of fibrotic proteins like TGF-β1 and fibronectin was also markedly controlled by Esculetin. The expression of phospho-FoxO1 was found to be reduced in HFD fed rats' liver, showing an increase in activation of FoxO1 under insulin resistant and hyperglycemic states. Esculetin treatment could improve phospho-FoxO1 expression, thus showing its ability to act on Akt/PI3K/FoxO1 pathway. As per the previous studies, a potential therapy for NAFLD may be the one with multi-faceted actions on insulin resistance, oxidative stress, inflammation and fibrosis. This study demonstrates the efficiency of Esculetin in improving liver fibrosis in HFD induced NAFLD. Copyright © 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  13. G Protein-Coupled Receptor-G-Protein βγ-Subunit Signaling Mediates Renal Dysfunction and Fibrosis in Heart Failure.

    Science.gov (United States)

    Kamal, Fadia A; Travers, Joshua G; Schafer, Allison E; Ma, Qing; Devarajan, Prasad; Blaxall, Burns C

    2017-01-01

    Development of CKD secondary to chronic heart failure (CHF), known as cardiorenal syndrome type 2 (CRS2), clinically associates with organ failure and reduced survival. Heart and kidney damage in CRS2 results predominantly from chronic stimulation of G protein-coupled receptors (GPCRs), including adrenergic and endothelin (ET) receptors, after elevated neurohormonal signaling of the sympathetic nervous system and the downstream ET system, respectively. Although we and others have shown that chronic GPCR stimulation and the consequent upregulated interaction between the G-protein βγ-subunit (Gβγ), GPCR-kinase 2, and β-arrestin are central to various cardiovascular diseases, the role of such alterations in kidney diseases remains largely unknown. We investigated the possible salutary effect of renal GPCR-Gβγ inhibition in CKD developed in a clinically relevant murine model of nonischemic hypertrophic CHF, transverse aortic constriction (TAC). By 12 weeks after TAC, mice developed CKD secondary to CHF associated with elevated renal GPCR-Gβγ signaling and ET system expression. Notably, systemic pharmacologic Gβγ inhibition by gallein, which we previously showed alleviates CHF in this model, attenuated these pathologic renal changes. To investigate a direct effect of gallein on the kidney, we used a bilateral ischemia-reperfusion AKI mouse model, in which gallein attenuated renal dysfunction, tissue damage, fibrosis, inflammation, and ET system activation. Furthermore, in vitro studies showed a key role for ET receptor-Gβγ signaling in pathologic fibroblast activation. Overall, our data support a direct role for GPCR-Gβγ in AKI and suggest GPCR-Gβγ inhibition as a novel therapeutic approach for treating CRS2 and AKI. Copyright © 2016 by the American Society of Nephrology.

  14. Tanshinol ameliorates CCl4-induced liver fibrosis in rats through the regulation of Nrf2/HO-1 and NF-κB/IκBα signaling pathway

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    Wang R

    2018-05-01

    Full Text Available Rong Wang,* Jing Wang,* Fuxing Song, Shengnan Li, Yongfang Yuan Department of Pharmacy, Shanghai 9th People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China *These authors contributed equally to this work Abstract: Tanshinol, a water-soluble component isolated from Salvia miltiorrhiza Bunge, has a variety of biological activities involving anti-fibrotic effect. However, the exact role and the underlying mechanisms remain largely unclear. This study mainly focused on the anti-hepatic fibrotic activities and mechanisms of tanshinol on carbon tetrachloride (CCl4-induced liver fibrosis in rats via anti-oxidative and anti-inflammation pathways. The rats were divided into 4 groups as follows: control, model, tanshinol 20 mg/kg, and tanshinol 40 mg/kg. Except for the control group, CCl4 was used to induce liver fibrosis processing for 8 weeks, meanwhile rats in tanshinol groups were intraperitoneally injected with additional tanshinol. Control group simultaneously received the same volumes of olive oil and saline. The potentially protective effect and mechanisms of tanshinol on liver fibrosis in rats were evaluated. The serum levels of alanine aminotransferase, aspartate aminotransferase, and total bilirubin were obviously lower in the tanshinol treatment groups related to model group. Compared with the model group, the levels of hyaluronic acid, type IV collagen, Laminin (LN, and procollagen III peptide (PIIIP in serum were significantly decreased after tanshinol treatment. Furthermore, tanshinol could regulate Nrf2/HO-1 signaling pathway and increase the level of superoxide dismutase (SOD and glutathione peroxidase (GSH-Px, and also decrease the level of malondialdehyde (MDA to against damage induced by oxidative stress. Simultaneously tanshinol could regulate nuclear factor kappa B signaling pathway to inhibit expression of inflammation factors, including transforming growth factor-β, tumor necrosis factor-α, Cox-2

  15. Post-radiational ureteric fibrosis with extrarenal renal failure as a rare complication after adjuvant treatment of gastric cancer - a case report

    International Nuclear Information System (INIS)

    Swieboda-Sadlej, A.; Staszewska-Skurczynska, M.; Piyush Vyas; Zurawinska, E.; Heleniak, H.; Kocik, J.; Danek, A.; Tragarz, E.

    2008-01-01

    The principles of chemoradiotherapy for treating patients with radically resected gastric cancer are not fully established. In many oncological centres patients with unfavourable prognostic factors who previously had radical gastrectomy are treated with Macdonald regimen which includes combined fluorouracil with radiotherapy. Statistics indicate that more then 30% patients treated with chemoradiotherapy suffer from serious complication. In this article we describe a case of a patient who developed ureteric fibrosis with consequent renal failure as a rare life threatening complication of Macdonald regimen. The patient received chemoradiotherapy because of unfavourable prognostic factors and good performance status however he was in advanced age and with other comorbidities. These data support the notion of the high toxicity of this regimen and suggest that selection of patients for this treatment should be done very carefully. This is discussed in the context of other available therapies in gastric cancer. (author)

  16. Exercise Ameliorates Renal Cell Apoptosis in Chronic Kidney Disease by Intervening in the Intrinsic and the Extrinsic Apoptotic Pathways in a Rat Model

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    Kuan-Chou Chen

    2013-01-01

    Full Text Available We hypothesized that doxorubicin (DR induced chronic kidney disease (CKD could trigger the intrinsic and the extrinsic renal cell apoptotic pathways, while treadmill exercise could help prevent adverse effects. Male Sprague-Dawley rats were subjected to treadmill running exercise at a speed of 30 m/min, 30 or 60 min/day, 3 times per week, for a total period of 11 weeks. The physiological and biochemical parameters were seen substantially improved (DR-CKD control, 30 min, 60 min exercise: the ratio of kidney weight/body weight (0.89, 0.74, and 0.72; the WBC (1.35, 1.08, and 1.42 × 104 cells/μL; RBC (5.30, 6.38, and 6.26 × 106 cells/μL; the platelet count (15.1, 12.8, and 11.3 × 105/μL; serum cholesterol (659, 360, and 75 mg/dL; serum triglyceride (542, 263, and 211 mg/dL; BUN (37, 25, and 22 mg/dL. Bcl-2 and intramitochondrial cytochrome c were upregulated, while the levels of Bax, SOD, MDA, cleaved caspases 9, 3, 8, 12, and calpain were all downregulated in DRCKD groups with exercise. CHOP (GADD153 and GRP78 were totally unaffected. FAS (CD95 was only slightly suppressed in the 60 min exercise DRCKD group. Conclusively, exercise can ameliorate CKD through the regulation of the intrinsic and extrinsic apoptosis pathways. The 60 min exercise yields more beneficial effect than the 30 min counterpart.

  17. Alpha8 Integrin (Itga8 Signalling Attenuates Chronic Renal Interstitial Fibrosis by Reducing Fibroblast Activation, Not by Interfering with Regulation of Cell Turnover.

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    Ines Marek

    Full Text Available The α8 integrin (Itga8 chain contributes to the regulation of cell proliferation and apoptosis in renal glomerular cells. In unilateral ureteral obstruction Itga8 is de novo expressed in the tubulointerstitium and a deficiency of Itga8 results in more severe renal fibrosis after unilateral ureteral obstruction. We hypothesized that the increased tubulointerstitial damage after unilateral ureteral obstruction observed in mice deficient for Itga8 is associated with altered tubulointerstitial cell turnover and apoptotic mechanisms resulting from the lack of Itga8 in cells of the tubulointerstitium. Induction of unilateral ureteral obstruction was achieved by ligation of the right ureter in mice lacking Itga8. Unilateral ureteral obstruction increased proliferation and apoptosis rates of tubuloepithelial and interstitial cells, however, no differences were observed in the tubulointerstitium of mice lacking Itga8 and wild type controls regarding fibroblast or proliferating cell numbers as well as markers of endoplasmic reticulum stress and apoptosis after unilateral ureteral obstruction. In contrast, unilateral ureteral obstruction in mice lacking Itga8 led to more pronounced tubulointerstitial cell activation i.e. to the appearance of more phospho-SMAD2/3-positive cells and more α-smooth muscle actin-positive cells in the tubulointerstitium. Furthermore, a more severe macrophage and T-cell infiltration was observed in these animals compared to controls. Thus, Itga8 seems to attenuate tubulointerstitial fibrosis in unilateral ureteral obstruction not via regulation of cell turnover, but via regulation of TGF-β signalling, fibroblast activation and/or immune cell infiltration.

  18. Interferon-γ production by tubulointerstitial human CD56bright natural killer cells contributes to renal fibrosis and chronic kidney disease progression.

    Science.gov (United States)

    Law, Becker M P; Wilkinson, Ray; Wang, Xiangju; Kildey, Katrina; Lindner, Mae; Rist, Melissa J; Beagley, Kenneth; Healy, Helen; Kassianos, Andrew J

    2017-07-01

    Natural killer (NK) cells are a population of lymphoid cells that play a significant role in mediating innate immune responses. Studies in mice suggest a pathological role for NK cells in models of kidney disease. In this study, we characterized the NK cell subsets present in native kidneys of patients with tubulointerstitial fibrosis, the pathological hallmark of chronic kidney disease. Significantly higher numbers of total NK cells (CD3 - CD56 + ) were detected in renal biopsies with tubulointerstitial fibrosis compared with diseased biopsies without fibrosis and healthy kidney tissue using multi-color flow cytometry. At a subset level, both the CD56 dim NK cell subset and particularly the CD56 bright NK cell subset were elevated in fibrotic kidney tissue. However, only CD56 bright NK cells significantly correlated with the loss of kidney function. Expression of the tissue-retention and -activation molecule CD69 on CD56 bright NK cells was significantly increased in fibrotic biopsy specimens compared with non-fibrotic kidney tissue, indicative of a pathogenic phenotype. Further flow cytometric phenotyping revealed selective co-expression of activating receptor CD335 (NKp46) and differentiation marker CD117 (c-kit) on CD56 bright NK cells. Multi-color immunofluorescent staining of fibrotic kidney tissue localized the accumulation of NK cells within the tubulointerstitium, with CD56 bright NK cells (NKp46 + CD117 + ) identified as the source of pro-inflammatory cytokine interferon-γ within the NK cell compartment. Thus, activated interferon-γ-producing CD56 bright NK cells are positioned to play a key role in the fibrotic process and progression to chronic kidney disease. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

  19. Oral administration of Saccharomyces boulardii ameliorates carbon tetrachloride-induced liver fibrosis in rats via reducing intestinal permeability and modulating gut microbial composition.

    Science.gov (United States)

    Li, Ming; Zhu, Lin; Xie, Ao; Yuan, Jieli

    2015-02-01

    To investigate the effects of orally administrated Saccharomyces boulardii (S. boulardii) on the progress of carbon tetrachloride (CCl4)-induced liver fibrosis, 34 male Wistar rats were randomly divided into four experimental groups including the control group (n = 8), the cirrhotic group (n = 10), the preventive group (n = 8), and the treatment group (n = 8). Results showed that the liver expression levels of collagen, type I, alpha 1 (Col1A1), alpha smooth muscle actin (αSMA), transforming growth factor beta (TGF-β) and the serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and malondialdehyde (MDA) increased significantly in cirrhotic rats compared with control and decreased by S. boulardii administration. Treatment of S. boulardii also attenuated the increased endotoxin levels and pro-inflammatory cytokines in CCl4-treated rats. And, these were associated with the changes of intestinal permeability and fecal microbial composition. Our study suggested that oral administration of S. boulardii can promote the liver function of CCl4-treated rats, and the preventive treatment of this probiotic yeast may decelerate the progress of liver fibrosis.

  20. D-Saccharic acid 1,4-lactone protects diabetic rat kidney by ameliorating hyperglycemia-mediated oxidative stress and renal inflammatory cytokines via NF-κB and PKC signaling

    Energy Technology Data Exchange (ETDEWEB)

    Bhattacharya, Semantee [Department of Life Sciences and Biotechnology, Jadavpur University, 188, Raja S C Mullick Road, Kolkata 700 032 (India); Manna, Prasenjit [Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata-700054 (India); Gachhui, Ratan [Department of Life Sciences and Biotechnology, Jadavpur University, 188, Raja S C Mullick Road, Kolkata 700 032 (India); Sil, Parames C., E-mail: parames@bosemain.boseinst.ac.in [Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata-700054 (India)

    2013-02-15

    Increasing evidence suggests that oxidative stress is involved in the pathogenesis of diabetic nephropathy (DN) and this can be attenuated by antioxidants. D-Saccharic acid 1,4-lactone (DSL) is known for its detoxifying and antioxidant properties. Our early investigation showed that DSL can ameliorate alloxan (ALX) induced diabetes mellitus and oxidative stress in rats by inhibiting pancreatic β-cell apoptosis. In the present study we, therefore, investigated the protective role of DSL against renal injury in ALX induced diabetic rats. ALX exposure (at a dose of 120 mg/kg body weight, i. p., once) elevated the blood glucose level, serum markers related to renal injury, the production of reactive oxygen species (ROS), and disturbed the intra-cellular antioxidant machineries. Oral administration of DSL (80 mg/kg body weight) restored all these alterations close to normal. In addition, DSL could also normalize the aldose reductase activity which was found to increase in the diabetic rats. Investigating the mechanism of its protective activity, we observed the activation of different isoforms of PKC along with the accumulation of matrix proteins like collagen and fibronectin. The diabetic rats also showed nuclear translocation of NF-κB and increase in the concentration of inflammatory cytokines in the renal tissue. The activation of mitochondria dependent apoptotic pathway was observed in the diabetic rat kidneys. However, treatment of diabetic rats with DSL counteracted all these changes. These findings, for the first time, demonstrated that DSL could ameliorate renal dysfunction in diabetic rats by suppressing the oxidative stress related signalling pathways. - Highlights: ► Sustained hyperglycemia and oxidative stress lead to diabetic renal injury. ► D-saccharic acid 1,4-lactone prevents renal damage in alloxan-induced diabetes. ► It restores intra-cellular antioxidant machineries and kidney apoptosis. ► DSL reduces hyperglycemia-mediated oxidative stress

  1. Tacrolimus increases Nox4 expression in human renal fibroblasts and induces fibrosis-related genes by aberrant TGF-beta receptor signalling.

    Directory of Open Access Journals (Sweden)

    Georg Kern

    Full Text Available Chronic nephrotoxicity of immunosuppressives is one of the main limiting factors in the long-term outcome of kidney transplants, leading to tissue fibrosis and ultimate organ failure. The cytokine TGF-β is considered a key factor in this process. In the human renal fibroblast cell line TK-173, the macrolide calcineurin inhibitor tacrolimus (FK-506 induced TGF-β-like effects, manifested by increased expression of NAD(PH-oxidase 4 (Nox4, transgelin, tropomyosin 1, and procollagen α1(V mRNA after three days. The macrolide mTOR inhibitor rapamycin had similar effects, while cyclosporine A did not induce fibrose-related genes. Concentration dependence curves were sigmoid, where mRNA expression was induced already at low nanomolar levels of tacrolimus, and reached saturation at 100-300 nM. The effects were independent of extracellular TGF-β as confirmed by the use of neutralizing antibodies, and thus most likely caused by aberrant TGF-β receptor signaling, where binding of tacrolimus to the regulatory FKBP12 protein results in a "leaky" TGF-β receptor. The myofibroblast marker α-smooth muscle actin was neither induced by tacrolimus nor by TGF-β1, indicating an incomplete activation of TK-173 fibroblasts under culture conditions. Tacrolimus- and TGF-β1-induced Nox4 protein upregulation was confirmed by Western blotting, and was accompanied by a rise in intracellular H2O2 concentration. Si-RNA mediated knock-down of Nox4 expression prevented up-regulation of procollagen α1(V mRNA in tacrolimus-treated cells, but induced procollagen α1(V expression in control cells. Nox4 knock-down had no significant effect on the other genes tested. TGF-β is a key molecule in fibrosis, and the constant activation of aberrant receptor signaling by tacrolimus might contribute to the long-term development of interstitial kidney fibrosis in immunosuppressed patients. Nox4 levels possibly play a regulatory role in these processes.

  2. Inhibition of canonical WNT signaling pathway by β-catenin/CBP inhibitor ICG-001 ameliorates liver fibrosis in vivo through suppression of stromal CXCL12.

    Science.gov (United States)

    Akcora, Büsra Öztürk; Storm, Gert; Bansal, Ruchi

    2018-03-01

    Quiescent hepatic stellate cells (HSCs), in response to liver injury, undergo characteristic morphological transformation into proliferative, contractile and ECM-producing myofibroblasts. In this study, we investigated the implication of canonical Wnt signaling pathway in HSCs and liver fibrogenesis. Canonical Wnt signaling pathway activation and inhibition using β-catenin/CBP inhibitor ICG001 was examined in-vitro in TGFβ-activated 3T3, LX2, primary human HSCs, and in-vivo in CCl 4 -induced acute liver injury mouse model. Fibroblasts-conditioned medium studies were performed to assess the Wnt-regulated paracrine factors involved in crosstalk between HSCs-macrophages and HSCs-endothelial cells. Canonical Wnt signaling pathway components were significantly up-regulated in-vitro and in-vivo. In-vitro, ICG-001 significantly inhibited fibrotic parameters, 3D-collagen contractility and wound healing. Conditioned medium induced fibroblasts-mediated macrophage and endothelial cells activation was significantly inhibited by ICG-001. In-vivo, ICG-001 significantly attenuated collagen accumulation and HSC activation. Interestingly, ICG-001 drastically inhibited macrophage infiltration, intrahepatic inflammation and angiogenesis. We further analyzed the paracrine factors involved in Wnt-mediated effects and found CXCL12 was significantly suppressed both in-vitro and in-vivo following Wnt inhibition. Wnt-regulated CXCL12 secretion from activated HSCs potentiated macrophage infiltration and activation, and angiogenesis. Pharmacological inhibition of canonical Wnt signaling pathway via suppression of stromal CXCL12 suggests a potential therapeutic approach targeting activated HSCs in liver fibrosis. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

  3. Nephrogenic systemic fibrosis

    DEFF Research Database (Denmark)

    Khurram, Misbah; Skov, Lone; Rossen, Kristian

    2007-01-01

    Nephrogenic systemic fibrosis (NSF) is a fibrotic disease seen in renal failure patients that may lead to severe physical disability. It has been demonstrated in recent studies that NSF can be caused by some gadolinium-containing MRI contrast agents. In this report we present one of a total of 26...

  4. Evaluation of the incidence of nephrogenic systemic fibrosis in patients with moderate renal insufficiency administered gadobenate dimeglumine for MRI

    International Nuclear Information System (INIS)

    Bryant, B.J.; Im, K.; Broome, D.R.

    2009-01-01

    Aim: To determine the incidence of nephrogenic systemic fibrosis (NSF) in stage 3 chronic kidney disease patients following intravenous exposure to gadobenate dimeglumine. Materials and methods: A prospective study was performed on 168 consecutive patients at a single institution with stage 3 chronic kidney disease who underwent clinically-indicated contrast-enhanced magnetic resonance imaging (MRI) examinations with gadobenate dimeglumine from January 2007 to March 2008. All patients were contacted by phone by investigators 3 months after MRI to verify the presence or absence of NSF signs or symptoms. If signs or symptoms suggestive of NSF developed, dermatologic referral was made and confirmatory skin biopsy performed if indicated. Results: One hundred and eighty contrast-enhanced MRI examinations with gadobenate dimeglumine were performed on the 168 patients. Twenty patients were lost to follow-up, but 160 incidents of contrast medium exposure were followed up for 3-months and 105 incidents were followed up for 6 months. The mean contrast medium dose per weight was 0.093 mmol/kg (range 0.042-0.153 mmol/kg). The mean estimated creatinine clearance was 50.4 ml/min/1.73 m 2 (range from 30-59 ml/min/1.73 m 2 ). Ten patients developed skin rashes during the 3-month follow-up period, but none were confirmed to represent NSF (0% prevalence rate). No other signs or symptoms of NSF were reported. Conclusion: Based on this limited study, NSF does not appear to occur in patients with stage 3 chronic kidney disease exposed to intravenous gadobenate dimeglumine for MRI at standard dosing of ∼0.1 mmol/kg.

  5. Correlation of serum and urinary matrix metalloproteases/tissue inhibitors of metalloproteases with subclinical allograft fibrosis in renal transplantation.

    Science.gov (United States)

    Hirt-Minkowski, Patricia; Marti, Hans-Peter; Hönger, Gideon; Grandgirard, Denis; Leib, Stephen L; Amico, Patrizia; Schaub, Stefan

    2014-01-01

    Progressive interstitial fibrosis and tubular atrophy (IF/TA) is a leading cause of chronic allograft dysfunction. Increased extracellular matrix remodeling regulated by matrix metalloproteases (MMPs) and their inhibitors (TIMPs) has been implicated in the development of IF/TA. The aim of this study was to investigate whether urinary/serum MMPs/TIMPs correlate with subclinical IF/TA detected in surveillance biopsies within the first 6months post-transplant. We measured eight different MMPs/TIMPs simultaneously in urine and serum samples from patients classified as normal histology (n=15), IF/TA 1 (n=15) and IF/TA 2-3 (n=10). There was no difference in urinary MMPs/TIMPs among the three groups, and only 1/8 serum MMPs/TIMPs (i.e. MMP-1) was significantly elevated in biopsies with IF/TA 2-3 (p=0.01). In addition, urinary/serum MMPs/TIMPs were not different between surveillance biopsies demonstrating an early development of IF/TA (i.e. delta IF/TA≥1 compared to a previous biopsy obtained three months before; n=11) and stable grade of IF/TA (i.e. delta IF/TA=0; n=20). Next, we investigated whether urinary/serum MMP/TIMP levels are elevated during acute subclinical tubulitis in surveillance biopsies obtained within the first 6months post-transplant (n=25). Compared to biopsies with normal histology, serum MMPs/TIMPs were not different; however, all urinary MMP/TIMP levels were numerically higher during subclinical tubulitis (MMP-1, MMP-7, TIMP-1 with p≤0.04). We conclude that urinary/serum MMPs/TIMPs do hardly correlate with existing or early developing IF/TA in surveillance biopsies obtained within the first 6months post-transplant. This could be explained by the dynamic process of extracellular matrix remodeling, which seems to be active during acute tubulo-interstitial injury/inflammation, but not in quiescent IF/TA. Copyright © 2013 Elsevier B.V. All rights reserved.

  6. Nephrogenic systemic fibrosis

    DEFF Research Database (Denmark)

    Marckmann, Peter

    2008-01-01

    PURPOSE OF REVIEW: The aim of this article is to outline the history of nephrogenic systemic fibrosis, a new and serious disease of patients with renal failure, and to give an update on its aetiology and prevalence. RECENT FINDINGS: Epidemiological and histochemical studies demonstrated....... Increasingly poor renal function, aberrations in calcium-phosphate metabolism and erythropoietin treatment seem to increase the risk of the disease and its severity. Up to 25-30% of patients with renal failure exposed to gadolinium-based contrast agents may develop nephrogenic systemic disease. The figure...... that gadolinium-containing contrast agents used for magnetic resonance imaging have an essential causative role in most, if not all, cases of nephrogenic systemic fibrosis. One particular agent, gadodiamide, caused the majority of cases, but gadopentetate dimeglumine has also been implicated in several cases...

  7. Acute Kidney Injury in Heart Failure Revisited-The Ameliorating Impact of "Decongestive Diuresis" on Renal Dysfunction in Type 1 Acute Cardiorenal Syndrome: Accelerated Rising Pro B Naturetic Peptide Is a Predictor of Good Renal Prognosis.

    Science.gov (United States)

    Onuigbo, Macaulay Amechi Chukwukadibia; Agbasi, Nneoma; Sengodan, Mohan; Rosario, Karen Flores

    2017-08-29

    There is mounting evidence that forward heart failure as manifested by low cardiac output alone does not define the degree of renal dysfunction in cardiorenal syndrome. As a result, the term "congestive renal failure" was coined in 2012 by Ross to depict the role of renal venous hypertension in type 1 acute cardiorenal syndrome. If so, aggressive decongestive therapies, either through mechanical ultrafiltration with dialysis machines or pharmacologic ultrafiltration with potent diuretics, would lead to improved cardio and renal outcomes. Nevertheless, as recently as 2012, a review of this literature had concluded that a renal venous hypertension-directed approach using diuretics to manage cardio-renal syndrome was yet to be fully investigated. We, in this review, with three consecutive case series, describe our experience with pharmacologic decongestive diuresis in this paradigm of care and argue for studies of such therapeutic interventions in the management of cardiorenal syndrome. Finally, based on our observations in the Renal Unit, Mayo Clinic Health System, in Northwestern Wisconsin, we have hypothesized that patients with cardiorenal syndrome presenting with accelerated rising Pro B Naturetic Peptide levels appear to represent a group that would have good cardio- and renal-outcomes with such decongestive pharmacologic therapies.

  8. The Flavonoid Apigenin Ameliorates Cisplatin-Induced Nephrotoxicity through Reduction of p53 Activation and Promotion of PI3K/Akt Pathway in Human Renal Proximal Tubular Epithelial Cells

    Directory of Open Access Journals (Sweden)

    Sung Min Ju

    2015-01-01

    Full Text Available Apigenin is a member of the flavone subclass of flavonoids present in fruits and vegetables. Apigenin has long been considered to have various biological activities, such as antioxidant, anti-inflammatory, and antitumorigenic properties, in various cell types. Cisplatin was known to exhibit cytotoxic effect to renal cells by inducing apoptosis through activation of p53. The present study investigated the antiapoptotic effects of apigenin on the cisplatin-treated human renal proximal tubular epithelial (HK-2 cells. HK-2 cells were pretreated with apigenin (5, 10, 20 μM for 1 h and then treated with 40 μM cisplatin for various times. Apigenin inhibited the cisplatin-induced apoptosis of HK-2 cells. Interestingly, apigenin itself exerted cytostatic activity because of its ability to induce cell cycle arrest. Apigenin inhibited caspase-3 activity and PARP cleavage in cisplatin-treated cells. Apigenin reduced cisplatin-induced phosphorylation and expression of p53, with no significant influence on production of ROS that is known to induce p53 activation. Furthermore, apigenin promoted cisplatin-induced Akt phosphorylation, suggesting that enhanced Akt activation may be involved in cytoprotection. Taken together, these results suggest that apigenin ameliorates cisplatin-induced apoptosis through reduction of p53 activation and promotion of PI3K/Akt pathway in HK-2 cells.

  9. Conversion to Sirolimus Ameliorates Cyclosporine-Induced Nephropathy in the Rat: Focus on Serum, Urine, Gene, and Protein Renal Expression Biomarkers

    Directory of Open Access Journals (Sweden)

    José Sereno

    2014-01-01

    Full Text Available Protocols of conversion from cyclosporin A (CsA to sirolimus (SRL have been widely used in immunotherapy after transplantation to prevent CsA-induced nephropathy, but the molecular mechanisms underlying these protocols remain nuclear. This study aimed to identify the molecular pathways and putative biomarkers of CsA-to-SRL conversion in a rat model. Four animal groups (n=6 were tested during 9 weeks: control, CsA, SRL, and conversion (CsA for 3 weeks followed by SRL for 6 weeks. Classical and emergent serum, urinary, and kidney tissue (gene and protein expression markers were assessed. Renal lesions were analyzed in hematoxylin and eosin, periodic acid-Schiff, and Masson’s trichrome stains. SRL-treated rats presented proteinuria and NGAL (serum and urinary as the best markers of renal impairment. Short CsA treatment presented slight or even absent kidney lesions and TGF-β, NF-κβ, mTOR, PCNA, TP53, KIM-1, and CTGF as relevant gene and protein changes. Prolonged CsA exposure aggravated renal damage, without clear changes on the traditional markers, but with changes in serums TGF-β and IL-7, TBARs clearance, and kidney TGF-β and mTOR. Conversion to SRL prevented CsA-induced renal damage evolution (absent/mild grade lesions, while NGAL (serum versus urine seems to be a feasible biomarker of CsA replacement to SRL.

  10. Camel Milk Ameliorates 5-Fluorouracil-Induced Renal Injury in Rats: Targeting MAPKs, NF-κB and PI3K/Akt/eNOS Pathways

    Directory of Open Access Journals (Sweden)

    Hany H. Arab

    2018-04-01

    Full Text Available Background/Aims: The clinical utility of 5-fluorouracil (5-FU is limited by its nephrotoxicity. Camel milk (CM has previously displayed beneficial effects in toxicant-induced nephropathies. The current study aimed to investigate the potential of CM to attenuate 5-FU-induced nephrotoxicity in rats. Methods: Renal tissues were studied in terms of oxidative stress, inflammation and apoptosis. The levels of renal injury markers, inflammatory cytokines along with NOX-1, Nrf-2 and HO-1 were assessed by ELISA. The expression of MMP-2, MMP-9, NF-κBp65, p53, Bax and PCNA were detected by Immunohistochemistry. To gain an insight into the molecular signaling mechanisms, we determined the effect of CM on MAPKs, NF-κB and PI3K/Akt/eNOS pathways by Western blotting. Results: CM lowered 5-FU-triggered increase of creatinine, BUN, Kim-1 and NGAL renal injury biomarkers and attenuated the histopathological aberrations. It suppressed oxidative stress and augmented renal antioxidant armory (GSH, SOD, GPx, TAC with restoration of NOX-1, Nrf-2 and HO-1 levels. CM also suppressed renal inflammation as indicated by inhibition of MPO, TNF-α, IL-1β, IL-18 and MCP-1 proinflammatory mediators and downregulation of MMP-2 and MMP-9 expression with boosting of IL-10. Regarding MAPKs signaling, CM suppressed the phosphorylation of p38 MAPK, JNK1/2 and ERK1/2 and inhibited NF-κB activation. For apoptosis, CM downregulated p53, Bax, CytC and caspase-3 proapoptotic signals with enhancement of Bcl-2 and PCNA. It also enhanced PI3K p110α, phospho-Akt and phospho-eNOS levels with augmentation of renal NO, favoring cell survival. Equally important, CM preconditioning enhanced 5-FU cytotoxicity in MCF-7, HepG-2, HCT-116 and PC-3 cells, thus, justifying their concomitant use. Conclusion: The current findings pinpoint, for the first time, the marked renoprotective effects of CM that were mediated via ROS scavenging, suppression of MAPKs and NF-κB along with activation of PI3K

  11. Antigen-specific immature dendritic cell vaccine ameliorates anti-dsDNA antibody-induced renal damage in a mouse model.

    Science.gov (United States)

    Xia, Yumin; Jiang, Shan; Weng, Shenhong; Lv, Xiaochun; Cheng, Hong; Fang, Chunhong

    2011-12-01

    Dendritic cells (DCs) can inhibit immune response by clonal anergy when immature. Recent studies have shown that immature DCs (iDCs) may serve as a live cell vaccine after specific antigen pulse based on its potential of blocking antibody production. In this study, we aimed to investigate the effects of nuclear antigen-pulsed iDCs in the treatment of lupus-like renal damages induced by anti-dsDNA antibodies. iDCs were generated from haemopoietic stem cells in bone marrow and then pulsed in vitro with nuclear antigen. The iDC vaccine and corresponding controls were injected into mice with lupus-like renal damages. The evaluation of disease was monitored by biochemical parameters and histological scores. Anti-dsDNA antibody isotypes and T-lymphocyte-produced cytokines were analysed for elucidating therapeutic mechanisms. RESULTS; The mice treated with antigen-pulsed iDCs had a sustained remission of renal damage compared with those injected with non-pulsed iDCs or other controls, including decreased anti-dsDNA antibody level, less proteinuria, lower blood urea nitrogen and serum creatinine values, and improved histological evaluation. Analysis on isotypes of anti-dsDNA antibody showed that iDC vaccine preferentially inhibited the production of IgG3, IgG2b and IgG2a. Furthermore, administration of antigen-treated iDCs to mice resulted in significantly reduced IL-2, IL-4 and IL-12 and IFN-γ produced by T-memory cells. Conversely, the vaccination of antigen-pulsed mature DCs led to increased anti-dsDNA antibody production and an aggravation of lupus-like disease in the model. CONCLUSIONS; These results suggested the high potency of iDC vaccine in preventing lupus-like renal injuries induced by pathogenic autoantibodies.

  12. Dipeptidyl peptidase-4 inhibitor ameliorates early renal injury through its anti-inflammatory action in a rat model of type 1 diabetes

    Energy Technology Data Exchange (ETDEWEB)

    Kodera, Ryo, E-mail: kodera@cc.okayama-u.ac.jp [Center for Innovative Clinical Medicine, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558 (Japan); Shikata, Kenichi [Center for Innovative Clinical Medicine, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558 (Japan); Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558 (Japan); Takatsuka, Tetsuharu; Oda, Kaori; Miyamoto, Satoshi; Kajitani, Nobuo; Hirota, Daisho; Ono, Tetsuichiro [Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558 (Japan); Usui, Hitomi Kataoka [Department of Primary Care and Medical Education, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558 (Japan); Makino, Hirofumi [Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558 (Japan)

    2014-01-17

    Highlights: •DPP-4 inhibitor decreased urinary albumin excretion in a rat of type 1 diabetes. •DPP-4 inhibitor ameliorated histlogical changes of diabetic nephropathy. •DPP-4 inhibitor has reno-protective effects through anti-inflammatory action. •DPP-4 inhibitor is beneficial on diabetic nephropathy besides lowering blood glucose. -- Abstract: Introduction: Dipeptidyl peptidase-4 (DPP-4) inhibitors are incretin-based drugs in patients with type 2 diabetes. In our previous study, we showed that glucagon-like peptide-1 (GLP-1) receptor agonist has reno-protective effects through anti-inflammatory action. The mechanism of action of DPP-4 inhibitor is different from that of GLP-1 receptor agonists. It is not obvious whether DPP-4 inhibitor prevents the exacerbation of diabetic nephropathy through anti-inflammatory effects besides lowering blood glucose or not. The purpose of this study is to clarify the reno-protective effects of DPP-4 inhibitor through anti-inflammatory actions in the early diabetic nephropathy. Materials and methods: Five-week-old male Sprague–Dawley (SD) rats were divided into three groups; non-diabetes, diabetes and diabetes treated with DPP-4 inhibitor (PKF275-055; 3 mg/kg/day). PKF275-055 was administered orally for 8 weeks. Results: PKF275-055 increased the serum active GLP-1 concentration and the production of urinary cyclic AMP. PKF275-055 decreased urinary albumin excretion and ameliorated histological change of diabetic nephropathy. Macrophage infiltration was inhibited, and inflammatory molecules were down-regulated by PKF275-055 in the glomeruli. In addition, nuclear factor-κB (NF-κB) activity was suppressed in the kidney. Conclusions: These results indicate that DPP-4 inhibitor, PKF275-055, have reno-protective effects through anti-inflammatory action in the early stage of diabetic nephropathy. The endogenous biological active GLP-1 might be beneficial on diabetic nephropathy besides lowering blood glucose.

  13. Dipeptidyl peptidase-4 inhibitor ameliorates early renal injury through its anti-inflammatory action in a rat model of type 1 diabetes

    International Nuclear Information System (INIS)

    Kodera, Ryo; Shikata, Kenichi; Takatsuka, Tetsuharu; Oda, Kaori; Miyamoto, Satoshi; Kajitani, Nobuo; Hirota, Daisho; Ono, Tetsuichiro; Usui, Hitomi Kataoka; Makino, Hirofumi

    2014-01-01

    Highlights: •DPP-4 inhibitor decreased urinary albumin excretion in a rat of type 1 diabetes. •DPP-4 inhibitor ameliorated histlogical changes of diabetic nephropathy. •DPP-4 inhibitor has reno-protective effects through anti-inflammatory action. •DPP-4 inhibitor is beneficial on diabetic nephropathy besides lowering blood glucose. -- Abstract: Introduction: Dipeptidyl peptidase-4 (DPP-4) inhibitors are incretin-based drugs in patients with type 2 diabetes. In our previous study, we showed that glucagon-like peptide-1 (GLP-1) receptor agonist has reno-protective effects through anti-inflammatory action. The mechanism of action of DPP-4 inhibitor is different from that of GLP-1 receptor agonists. It is not obvious whether DPP-4 inhibitor prevents the exacerbation of diabetic nephropathy through anti-inflammatory effects besides lowering blood glucose or not. The purpose of this study is to clarify the reno-protective effects of DPP-4 inhibitor through anti-inflammatory actions in the early diabetic nephropathy. Materials and methods: Five-week-old male Sprague–Dawley (SD) rats were divided into three groups; non-diabetes, diabetes and diabetes treated with DPP-4 inhibitor (PKF275-055; 3 mg/kg/day). PKF275-055 was administered orally for 8 weeks. Results: PKF275-055 increased the serum active GLP-1 concentration and the production of urinary cyclic AMP. PKF275-055 decreased urinary albumin excretion and ameliorated histological change of diabetic nephropathy. Macrophage infiltration was inhibited, and inflammatory molecules were down-regulated by PKF275-055 in the glomeruli. In addition, nuclear factor-κB (NF-κB) activity was suppressed in the kidney. Conclusions: These results indicate that DPP-4 inhibitor, PKF275-055, have reno-protective effects through anti-inflammatory action in the early stage of diabetic nephropathy. The endogenous biological active GLP-1 might be beneficial on diabetic nephropathy besides lowering blood glucose

  14. Nephrogenic systemic fibrosis

    DEFF Research Database (Denmark)

    Marckmann, Peter; Skov, Lone; Rossen, Kristian

    2006-01-01

    Nephrogenic systemic fibrosis is a new, rare disease of unknown cause that affects patients with renal failure. Single cases led to the suspicion of a causative role of gadodiamide that is used for magnetic resonance imaging. This study therefore reviewed all of the authors' confirmed cases...... of nephrogenic systemic fibrosis (n = 13) with respect to clinical characteristics, gadodiamide exposure, and subsequent clinical course. It was found that all had been exposed to gadodiamide before the development of nephrogenic systemic fibrosis. The delay from exposure to first sign of the disease was 2 to 75...... d (median 25 d). Odds ratio for acquiring the disease when gadodiamide exposed was 32.5 (95% confidence interval 1.9 to 549.2; P

  15. Dietary docosahexaenoic acid ameliorates, but rapeseed oil and safflower oil accelerate renal injury in stroke-prone spontaneously hypertensive rats as compared with soybean oil, which is associated with expression for renal transforming growth factor-beta, fibronectin and renin.

    Science.gov (United States)

    Miyazaki, M; Takemura, N; Watanabe, S; Hata, N; Misawa, Y; Okuyama, H

    2000-01-03

    We have noted that n-3 fatty acid-rich oils, such as fish oil, perilla oil and flaxseed oil as well as ethyl docosahexaenoate (DHA) prolonged the survival time of stroke-prone spontaneously hypertensive rats (SHRSP) rats by approximately 10% as compared with linoleate (n-6)-rich safflower oil. Rapeseed oil with a relatively low n-6/n-3 ratio unusually shortened the survival time by approximately 40%, suggesting the presence of minor components unfavorable to SHRSP rats. This study examined the effects of dietary oils and DHA on renal injury and gene expression related to renal injury in SHRSP rats. Rats fed rapeseed oil- and safflower oil-supplemented diets developed more severe proteinuria than those fed soybean oil-supplemented diet used as a control, but there were no significant differences in blood pressure. In contrast, the DHA-supplemented diet inhibited the development of proteinuria and suppressed hypertension. The mRNA levels for renal TGF-beta, fibronectin and renin were higher in the rapeseed oil and safflower oil groups after 9 weeks of feeding of the experimental diet than in the soybean oil and DHA groups. The fatty acid composition of kidney phospholipids was markedly affected by these diets. These results indicate that the renal injury observed in the groups fed safflower oil with a high n-6/n-3 ratio and rapeseed oil with presumed minor components is accompanied by increased expression of the TGF-beta, renin and fibronectin genes, and that dietary DHA suppresses renal injury and gene expression as compared with soybean oil.

  16. Augmenter of liver regeneration inhibits TGF-β1-induced renal tubular epithelial-to-mesenchymal transition via suppressing TβR II expression in vitro

    International Nuclear Information System (INIS)

    Liao, Xiao-hui; Zhang, Ling; Chen, Guo-tao; Yan, Ru-yu; Sun, Hang; Guo, Hui; Liu, Qi

    2014-01-01

    Tubular epithelial-to-mesenchymal transition (EMT) plays a crucial role in the progression of renal tubular interstitial fibrosis (TIF), which subsequently leads to chronic kidney disease (CKD) and eventually, end-stage renal disease (ESRD). We propose that augmenter of liver regeneration (ALR), a member of the newly discovered ALR/Erv1 protein family shown to ameliorate hepatic fibrosis, plays a similar protective role in renal tubular cells and has potential as a new treatment option for CKD. Here, we showed that recombinant human ALR (rhALR) inhibits EMT in renal tubular cells by antagonizing activation of the transforming growth factor-β1 (TGF-β1) signaling pathway. Further investigation revealed that rhALR suppresses the expression of TGF-β receptor type II (TβR II) and significantly alleviates TGF-β1-induced phosphorylation of Smad2 and nuclear factor-κB (NF-κB). No apparent adverse effects were observed upon the addition of rhALR alone to cells. These findings collectively suggest that ALR plays a role in inhibiting progression of renal tubular EMT, supporting its potential utility as an effective antifibrotic strategy to reverse TIF in CKD. - Highlights: • ALR is involved in the pathological progression of renal EMT in NRK-52E cells. • ALR suppresses the expression of TβRII and the phosphorylation of Smad2 and NF-κB. • ALR plays a role in inhibiting progression of renal tubular EMT

  17. Augmenter of liver regeneration inhibits TGF-β1-induced renal tubular epithelial-to-mesenchymal transition via suppressing TβR II expression in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Liao, Xiao-hui [Department of Nephrology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010 (China); Zhang, Ling, E-mail: lindazhang8508@hotmail.com [Department of Nephrology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010 (China); Chen, Guo-tao; Yan, Ru-yu [Department of Nephrology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010 (China); Sun, Hang; Guo, Hui [Institute for Viral Hepatitis, Key Laboratory of Molecular Biology for Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010 (China); Liu, Qi, E-mail: txzzliuqi@163.com [Institute for Viral Hepatitis, Key Laboratory of Molecular Biology for Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010 (China)

    2014-10-01

    Tubular epithelial-to-mesenchymal transition (EMT) plays a crucial role in the progression of renal tubular interstitial fibrosis (TIF), which subsequently leads to chronic kidney disease (CKD) and eventually, end-stage renal disease (ESRD). We propose that augmenter of liver regeneration (ALR), a member of the newly discovered ALR/Erv1 protein family shown to ameliorate hepatic fibrosis, plays a similar protective role in renal tubular cells and has potential as a new treatment option for CKD. Here, we showed that recombinant human ALR (rhALR) inhibits EMT in renal tubular cells by antagonizing activation of the transforming growth factor-β1 (TGF-β1) signaling pathway. Further investigation revealed that rhALR suppresses the expression of TGF-β receptor type II (TβR II) and significantly alleviates TGF-β1-induced phosphorylation of Smad2 and nuclear factor-κB (NF-κB). No apparent adverse effects were observed upon the addition of rhALR alone to cells. These findings collectively suggest that ALR plays a role in inhibiting progression of renal tubular EMT, supporting its potential utility as an effective antifibrotic strategy to reverse TIF in CKD. - Highlights: • ALR is involved in the pathological progression of renal EMT in NRK-52E cells. • ALR suppresses the expression of TβRII and the phosphorylation of Smad2 and NF-κB. • ALR plays a role in inhibiting progression of renal tubular EMT.

  18. Unusual Presentation Of Idiopathic Retroperitoneal Fibrosis: Case ...

    African Journals Online (AJOL)

    Idiopathic retroperitoneal fibrosis (IRF) is an uncommon entity described as progressive proliferation of connective tissues leading to a fibrous plaque-like lesions that encases the aorta and inferior vena cava inferior to the level of the renal arteries. Mass forming retroperitoneal fibrosis is rare. We present a rare case of a ...

  19. Introduction to Pulmonary Fibrosis

    Science.gov (United States)

    ... page: Introduction to Pulmonary Fibrosis What Is Pulmonary Fibrosis? Pulmonary fibrosis is a disease where there is scarring ... of pulmonary fibrosis. Learn more How Is Pulmonary Fibrosis Diagnosed? Pulmonary fibrosis can be difficult to diagnose, so it ...

  20. Overlap of Post-obstructive Diuresis and Unmasked Diabetes Insipidus in a Case of IgG4-related Retroperitoneal Fibrosis and Tuberoinfundibular Hypophysitis: A Case Report and Review of the Literature.

    Science.gov (United States)

    Sasaki Yatabe, Midori; Watanabe, Kimio; Hayashi, Yoshimitsu; Yatabe, Junichi; Morimoto, Satoshi; Ichihara, Atsuhiro; Nakayama, Masaaki; Watanabe, Tsuyoshi

    The clinical picture of IgG4-related disease (IgG4-RD) is diverse because various organs can be affected. We describe the case of a 56-year-old man with acute renal failure and tuberoinfundibular hypophysitis due to IgG4-RD. Steroid therapy lowered the serum IgG4 level and ameliorated renal dysfunction, bilateral hydronephrosis and retroperitoneal fibrosis. However, polyuria from post-obstructive diuresis and unmasked central diabetes insipidus ensued. The patient's polyuria continued despite the administration of a therapeutic dose of glucocorticoid; the patient's pituitary swelling and anterior pituitary dysfunction were partially ameliorated. The pituitary swelling recurred seven months later. In patients with IgG4-RD, the manifestation of polyuria after steroid therapy should prompt suspicion of post-obstructive diuresis and the unmasking of central diabetes insipidus.

  1. Mitochondrial Modulation by Epigallocatechin 3-Gallate Ameliorates Cisplatin Induced Renal Injury through Decreasing Oxidative/Nitrative Stress, Inflammation and NF-kB in Mice

    Science.gov (United States)

    Wang, Xueping; Wang, Ping; Fu, Guanghou; Meng, Hongzhou; Wang, Yimin; Jin, Baiye

    2015-01-01

    Cancer chemotherapy drug cisplatin is known for its nephrotoxicity. The aim of this study is to investigate whether Epigallocatechin 3-Gallate (EGCG) can reduce cisplatin mediated side effect in kidney and to understand its mechanism of protection against tissue injury. We used a well-established 3-day cisplatin induced nephrotoxicity mice model where EGCG were administered. EGCG is a major active compound in Green Tea and have strong anti-oxidant and anti-inflammatory properties. EGCG protected against cisplatin induced renal dysfunction as measured by serum creatinine and blood urea nitrogen (BUN). EGCG improved cisplatin induced kidney structural damages such as tubular dilatation, cast formation, granulovaculoar degeneration and tubular cell necrosis as evident by PAS staining. Cisplatin induced kidney specific mitochondrial oxidative stress, impaired activities of mitochondrial electron transport chain enzyme complexes, impaired anti-oxidant defense enzyme activities such as glutathione peroxidase (GPX) and manganese superoxide dismutase (MnSOD) in mitochondria, inflammation (tumor necrosis factor α and interleukin 1β), increased accumulation of NF-κB in nuclear fraction, p53 induction, and apoptotic cell death (caspase 3 activity and DNA fragmentation). Treatment of mice with EGCG markedly attenuated cisplatin induced mitochondrial oxidative/nitrative stress, mitochondrial damages to electron transport chain activities and antioxidant defense enzyme activities in mitochondria. These mitochondrial modulations by EGCG led to protection mechanism against cisplatin induced inflammation and apoptotic cell death in mice kidney. As a result, EGCG improved renal function in cisplatin mediated kidney damage. In addition to that, EGCG attenuated cisplatin induced apoptotic cell death and mitochondrial reactive oxygen species (ROS) generation in human kidney tubular cell line HK-2. Thus, our data suggest that EGCG may represent new promising adjunct candidate for

  2. Nigella sativa oil attenuates chronic nephrotoxicity induced by oral sodium nitrite: Effects on tissue fibrosis and apoptosis.

    Science.gov (United States)

    Al-Gayyar, Mohammed M H; Hassan, Hanan M; Alyoussef, Abdullah; Abbas, Ahmed; Darweish, Mohamed M; El-Hawwary, Amany A

    2016-03-01

    Sodium nitrite, a food preservative, has been reported to increase oxidative stress indicators such as lipid peroxidation, which can affect different organs including the kidney. Here, we investigated the toxic effects of oral sodium nitrite on kidney function in rats and evaluated potential protective effects of Nigella sativa oil (NSO). Seventy adult male Sprague-Dawley rats received 80 mg/kg sodium nitrite orally in the presence or absence of NSO (2.5, 5, and 10 ml/kg) for 12 weeks. Morphological changes were assessed by hematoxylin and eosin, Mallory trichome, and periodic acid-Schiff staining. Renal tissues were used for measurements of oxidative stress markers, C-reactive protein, cytochrome C oxidase, transforming growth factor (TGF)-beta1, monocyte chemotactic protein (MCP)-1, pJNK/JNK, and caspase-3. NSO significantly reduced sodium nitrite-induced elevation in serum urea and creatinine, as well as increasing normal appearance of renal tissue. NSO also prevented reductions in glycogen levels caused by sodium nitrite alone. Moreover, NSO treatment resulted in dose-dependent significant reductions in fibrosis markers after sodium nitrite-induced 3- and 2.7-fold increase in MCP-1 and TGF-beta1, respectively. Finally, NSO partially reduced the elevated caspase-3 and pJNK/JNK. NSO ameliorates sodium nitrite-induced nephrotoxicity through blocking oxidative stress, attenuation of fibrosis/inflammation, restoration of glycogen level, amelioration of cytochrome C oxidase, and inhibition of apoptosis.

  3. Nephrogenic Systemic Fibrosis in Denmark

    DEFF Research Database (Denmark)

    Elmholdt, Tina Rask; Olesen, Anne; J�rgensen, Bettina

    2013-01-01

    Nephrogenic systemic fibrosis is a debilitating and painful disorder with an increased stimulation of the connective tissue in the skin and systemic tissues. The disease is associated with exposure to gadolinium-based contrast agent used in magnetic resonance imaging in patients with renal...

  4. The anti-inflammatory and antifibrotic effects of Coreopsis tinctoria Nutt on high-glucose-fat diet and streptozotocin-induced diabetic renal damage in rats.

    Science.gov (United States)

    Yao, Lan; Li, Linlin; Li, Xinxia; Li, Hui; Zhang, Yujie; Zhang, Rui; Wang, Jian; Mao, Xinmin

    2015-09-07

    Diabetic nephropathy is a serious complication of diabetes whose development process is associated with inflammation, renal hypertrophy, and fibrosis. Coreopsis tinctoria Nutt, traditionally used as a healthcare tea, has anti-inflammatory, anti-hyperlipidemia, and glycemic regulation activities. The aim of our study was to investigate the renal protective effect of ethyl acetate extract of C. tinctoria Nutt (AC) on high-glucose-fat diet and streptozotocin (STZ)-induced diabetic rats. A diabetic rat model was induced by high-glucose-fat diet and intraperitoneal injection of 35 mg/kg STZ. After treatment with AC at a daily dose of 150, 300 or, 600 mg/kg for 4 weeks, metabolic and renal function parameters of serum and urine were examined. Degree of renal damage, renal proinflammatory cytokines, and fibrotic protein expression were analyzed by histopathology and immunohistochemistry. Renal AMP-activated protein kinase (AMPK) and transforming growth factor (TGF)-β1/Smad signaling pathway were determined by western blotting. Diabetic rats showed obvious renal dysfunction, inflammation and fibrosis. However, AC significantly reduced levels of blood glucose, total cholesterol, triglyceride, blood urea nitrogen, serum creatinine and urinary albumin, as well as expression of kidney proinflammatory cytokines of monocyte chemoattractant protein-1 and intercellular adhesion molecule-1. AC also ameliorated renal hypertrophy and fibrosis by reducing fibronectin and collagen IV and suppressing the TGF-β1/Smad signaling pathway. Meanwhile, AMPKα as a protective cytokine was markedly stimulated by AC. In summary, AC controls blood glucose, inhibits inflammatory and fibrotic processes, suppresses the TGF-β1/Smad signaling pathway, and activates phosphorylation of AMPKα in the kidneys, which confirms the protective effects of AC in the early stage of diabetic kidney disease.

  5. Nephrogenic systemic fibrosis: epidemiology update

    DEFF Research Database (Denmark)

    Marckmann, P.

    2008-01-01

    Purpose of review The aim of this article is to outline the history of nephrogenic systemic fibrosis, a new and serious disease of patients with renal failure, and to give an update on its aetiology and prevalence. Recent findings Epidemiological and histochemical studies demonstrated....... Increasingly poor renal function, aberrations in calcium-phosphate metabolism and erythropoietin treatment seem to increase the risk of the disease and its severity. Up to 25-30% of patients with renal failure exposed to gadolinium-based contrast agents may develop nephrogenic systemic disease. The figure...... that gadolinium-containing contrast agents used for magnetic resonance imaging have an essential causative role in most, if not all, cases of nephrogenic systemic fibrosis. One particular agent, gadodiamide, caused the majority of cases, but gadopentetate dimeglumine has also been implicated in several cases...

  6. Intraperitoneal administration of the globular adiponectin gene ameliorates diabetic nephropathy in Wistar rats.

    Science.gov (United States)

    Yuan, Fang; Liu, Ying-Hong; Liu, Fu-You; Peng, You-Ming; Tian, Jun-Wei

    2014-06-01

    The present study investigated the potential effects of the long-term expression of exogenous adiponectin (ADPN) on normal and diabetic kidneys. Type 2 diabetes mellitus models were induced by high-lipid and high-sucrose feeding plus intraperitoneal injection of streptozotocin. The recombinant plasmid pIRES2-EGFP-gAd, which is able to co-express globular ADPN (gAd) and enhanced green fluorescent protein (EGFP), was intraperitoneally injected into rat models mediated by Lipofectamine. In total, 32 Wistar rats were randomly assigned into four groups: the normal control group, the diabetes group, the diabetes group treated with pIRES2-EGFP-gAd and the diabetes group treated with pIRES2-EGFP. After 12 weeks, serum biochemistry and urine albumin levels were measured. The kidneys were collected to assess the generation of reactive oxygen species (ROS) and the renal pathological changes were observed by light microcopy. The protein expression of endothelial nitric oxide synthase (eNOS), transforming growth factor-β1 (TGF-β1) and phosphorylated adenosine monophosphate-activated protein kinase (p-AMPK) were determined by an immunohistochemical staining method and western blot analysis. Intraperitoneal injection of the human gAd gene via Lipofectamine resulted in abundant ADPN protein in the kidney. In the diabetic rats, the delivery of the exogenous gAd gene ameliorated the progression of diabetic nephropathy (DN). ADPN attenuated urine albumin excretion in the diabetic rats. ADPN also mitigated glomerular mesangial expansion, reduced the generation of ROS and prevented interstitial fibrosis. In addition, the expression of gAd inhibited the renal expression of TGF-β1, promoted the protein expression of eNOS and activated the opening of the AMPK signaling pathway in the renal tissues of the diabetic rats. Despite the effects of ADPN on DN being controversial, these observations indicate that the supplementation of ADPN is beneficial in ameliorating DN in rats.

  7. Nephrogenic systemic fibrosis

    International Nuclear Information System (INIS)

    Samtleben, W.

    2007-01-01

    A scleromyxedema-like disease was recognized in 1997. In 2000 this disorder was first published and termed nephrogenic fibrosing dermopathy because all patients had advanced renal failure. In 2006 it was discovered that the patients had a history of a preceding contrast-enhanced magnetic resonance imaging (MRI). All patients had acute or chronic severe renal insufficiency with a glomerular filtration rate (GFR) 2 . So far a total of about 215 patients with this new skin disorder have been reported to international registries. The skin thickening has a typical histology and begins in the peripheral extremities and progresses proximally, including also the abdominal wall and the head in some patients. NSF involves not only the skin, but also the muscles and other organs (e.g., lungs, heart, eyes) in some patients. Therefore the term nephrogenic systemic fibrosis (NSF) was introduced. Skin fibrosis and sclerosis are usually progressive with disabling contractures of involved joints (knees, hands, feet). NSF may be lethal in up to 28% of patients. Spontaneous remissions are rare. No generally accepted treatment is available. So far, the pathogenesis is not well understood. One hypothesis supposes a role of gadolinium liberated from the contrast agents. As patients with acute or chronic advanced renal failure (GFR 2 ) including those with hepatorenal dysfunctions are at high risk to develop NSF after exposure to gadolinium-based contrast agents, contrast-enhanced MRI should be avoided in this group and alternative diagnostic procedures should be used whenever possible. (orig.) [de

  8. Bmi-1 plays a critical role in protection from renal tubulointerstitial injury by maintaining redox balance

    Science.gov (United States)

    Jin, Jianliang; Lv, Xianhui; Chen, Lulu; Zhang, Wei; Li, Jinbo; Wang, Qian; Wang, Rong; Lu, Xiang; Miao, Dengshun

    2014-01-01

    To determine whether Bmi-1 deficiency could lead to renal tubulointerstitial injury by mitochondrial dysfunction and increased oxidative stress in the kidney, 3-week-old Bmi-1-/- mice were treated with the antioxidant N-acetylcysteine (NAC, 1 mg mL−1) in their drinking water, or pyrro-quinoline quinone (PQQ, 4 mg kg−1 diet) in their diet for 2 weeks, and their renal phenotypes were compared with vehicle-treated Bmi1-/- and wild-type mice. Bmi-1 was knocked down in human renal proximal tubular epithelial (HK2) cells which were treated with 1 mm NAC for 72 or 96 h, and their phenotypes were compared with control cells. Five-week-old vehicle-treated Bmi-1-/- mice displayed renal interstitial fibrosis, tubular atrophy, and severe renal function impairment with decreased renal cell proliferation, increased renal cell apoptosis and senescence, and inflammatory cell infiltration. Impaired mitochondrial structure, decreased mitochondrial numbers, and increased oxidative stress occurred in Bmi-1-/- mice; subsequently, this caused DNA damage, the activation of TGF-β1/Smad signaling, and the imbalance between extracellular matrix synthesis and degradation. Oxidative stress-induced epithelial-to-mesenchymal transition of renal tubular epithelial cells was enhanced in Bmi-1 knocked down HK2 cells. All phenotypic alterations caused by Bmi-1 deficiency were ameliorated by antioxidant treatment. These findings indicate that Bmi-1 plays a critical role in protection from renal tubulointerstitial injury by maintaining redox balance and will be a novel therapeutic target for preventing renal tubulointerstitial injury. PMID:24915841

  9. Berberine ameliorates chronic kidney injury caused by atherosclerotic renovascular disease through the suppression of NFκB signaling pathway in rats.

    Directory of Open Access Journals (Sweden)

    Xin Wan

    Full Text Available BACKGROUND AND OBJECTIVES: Impaired renal function in atherosclerotic renovascular disease (ARD may be the result of crosstalk between atherosclerotic renovascular stenosis and amplified oxidative stress, inflammation and fibrosis. Berberine (BBR regulates cholesterol metabolism and exerts antioxidant effects. Accordingly, we hypothesized that BBR treatment may ameliorate ARD-induced kidney injury through its cholesterol-lowering effect and also suppression of the pathways involved in oxidative stress, inflammation and NFκB activation. METHODS: Male rats were subjected to unilateral renal artery stenosis with silver-irritant coil, and then fed with 12-week hypercholesterolemic diet. Rats with renal artery stenosis were randomly assigned to two groups (n = 6 each - ARD, or ARD+BBR - according to diet alone or in combination with BBR. Similarly, age-matched rats underwent sham operation and were also fed with hypercholesterolemic diet alone or in combination with BBR as two corresponding controls. Single-kidney hemodynamic metrics were measured in vivo with Doppler ultrasound to determine renal artery flow. The metrics reflecting hyperlipidemia, oxidative stress, renal structure and function, inflammation and NFκB activation were measured, respectively. RESULTS: Compared with control rats, ARD rats had a significant increase in urinary albumin, plasma cholesterol, LDL and thiobarbituric acid reactive substances (TBARS and a significant decrease in SOD activity. When exposed to 12-week BBR, ARD rats had significantly lower levels in blood pressure, LDL, urinary albumin, and TBARS. In addition, there were significantly lower expression levels of iNOS and TGF-β in the ARD+BBR group than in the ARD group, with attenuated NFκB-DNA binding activity and down-regulated protein levels of subunits p65 and p50 as well as IKKβ. CONCLUSIONS: We conclude that BBR can improve hypercholesterolemia and redox status in the kidney, eventually ameliorating

  10. Protein S is protective in pulmonary fibrosis.

    Science.gov (United States)

    Urawa, M; Kobayashi, T; D'Alessandro-Gabazza, C N; Fujimoto, H; Toda, M; Roeen, Z; Hinneh, J A; Yasuma, T; Takei, Y; Taguchi, O; Gabazza, E C

    2016-08-01

    Essentials Epithelial cell apoptosis is critical in the pathogenesis of idiopathic pulmonary fibrosis. Protein S, a circulating anticoagulant, inhibited apoptosis of lung epithelial cells. Overexpression of protein S in lung cells reduced bleomycin-induced pulmonary fibrosis. Intranasal therapy with exogenous protein S ameliorated bleomycin-induced pulmonary fibrosis. Background Pulmonary fibrosis is the terminal stage of interstitial lung diseases, some of them being incurable and of unknown etiology. Apoptosis plays a critical role in lung fibrogenesis. Protein S is a plasma anticoagulant with potent antiapoptotic activity. The role of protein S in pulmonary fibrosis is unknown. Objectives To evaluate the clinical relevance of protein S and its protective role in pulmonary fibrosis. Methods and Results The circulating level of protein S was measured in patients with pulmonary fibrosis and controls by the use of enzyme immunoassays. Pulmonary fibrosis was induced with bleomycin in transgenic mice overexpressing human protein S and wild-type mice, and exogenous protein S or vehicle was administered to wild-type mice; fibrosis was then compared in both models. Patients with pulmonary fibrosis had reduced circulating levels of protein S as compared with controls. Inflammatory changes, the levels of profibrotic cytokines, fibrosis score, hydroxyproline content in the lungs and oxygen desaturation were significantly reduced in protein S-transgenic mice as compared with wild-type mice. Wild-type mice treated with exogenous protein S showed significant decreases in the levels of inflammatory and profibrotic markers and fibrosis in the lungs as compared with untreated control mice. After bleomycin infusion, mice overexpressing human protein S showed significantly low caspase-3 activity, enhanced expression of antiapoptotic molecules and enhanced Akt and Axl kinase phosphorylation as compared with wild-type counterparts. Protein S also inhibited apoptosis of alveolar

  11. Nephrogenic systemic fibrosis.

    LENUS (Irish Health Repository)

    Kennedy, C

    2010-11-05

    Nephroaenic systemic fibrosis (NSF) is a potentiallv fatal dermatiological condition found exclusively in patients with advanced renal I failure. There is minimal literature regarding the epidemiology and outcomes of patients with NSF in Ireland. A retrospective chart review was performed for all patients with NSF in Ireland. Ireland\\'s experience with the disease was examined in light of international reports. There have been three cases of NSF in Ireland; an area which serves 1915 dialysis patients--giving a point prevalence among Irish end-stage kidney disease patients of 0.002. There was a large variation in disease severity between the three patients. All three patients had significant exposure to gadolinium chelate. Caution with gadolinium administration must be exercised in patients with advanced renal failure.

  12. Nephrogenic systemic fibrosis

    Directory of Open Access Journals (Sweden)

    Bhushan Madke

    2011-01-01

    Full Text Available Nephrogenic systemic fibrosis (NSF is a relatively new fibrosing disorder which has caught the attention of various specialities in the past decade. NSF is an extremely disabling and often painful condition, affecting up to 13% of the individuals with chronic kidney disease. The administration of a gadolinium chelate contrast agent has been reported to induce the development of NSF, particularly in patients who have acute or chronic renal disease with a glomerular filtration rate (GFR lower than 30-mL/min/1.73 m 2 and in those with acute renal insufficiency. Mass spectroscopy studies have demonstrated particles of gadolinium in the lesional tissue. The exact pathogenesis of this curious sclerosing condition is unknown. The role of the aberrant targeting of ′circulating fibrocytes′ to the peripheral tissues and viscera has been hypothesized. NSF has distinct clinicopathological features in the setting of renal failure and needs to be looked upon as a new entity on the block. The condition is characterized by irregular indurated plaques, with amoeba-like projections and islands of sparing, chiefly on the trunk and extremities. Flexion contractures of fingers, knees, and elbow joints are known to occur in advanced cases of NSF. The course is frequently associated with painful episodes and loss of ambulation. Histopathology shows haphazard arrangement of thickened bundles of collagen, varying amount of mucin, and increased population of fibroblast-like cells in the dermis. Immunohistochemistry shows increased deposition of type-I procollagen and CD 34+ cells having fibroblastic activity. The condition is refractory to treatment with corticosteroids and immunosuppressive agents. Various modalities of therapy such as UVA1 phototherapy, imatinib mesylate, photodynamic therapy, plasmapheresis, extracorporeal photochemotherapy, and high-dose intravenous immunoglobulin have shown a moderate degree of improvement in skin thickness scores. A prudent

  13. Pulmonary Fibrosis Foundation

    Science.gov (United States)

    ... submissions. MORE We Imagine a World Without Pulmonary Fibrosis The Pulmonary Fibrosis Foundation mobilizes people and resources to provide ... its battle against the deadly lung disease, pulmonary fibrosis (PF). PULMONARY FIBROSIS WALK SURPASSES PARTICIPATION AND FUNDRAISING GOALS Nearly ...

  14. Mitigation of TGF-β/Smad signaling pathway-associated liver fibrosis ...

    African Journals Online (AJOL)

    2112 ... PF'on Schistosomiasis japonica-induced liver fibrosis have also been ... with “National Research Council for Animal Care”. [11]. .... Smad 7 as observed following exposure to CCl4, ... Jia Z, He J. Paeoniflorin ameliorates rheumatoid arthritis.

  15. Nephrogenic systemic fibrosis (NSF) and gadolinium-based contrast ...

    African Journals Online (AJOL)

    Nephrogenic systemic fibrosis (NSF), unknown before March 1997 and first described in 2000, is a systemic disorder characterised by widespread tissue fibrosis. The first known case occurred in 1997, after the use of gadolinium-based contrast agents (GBCAs) at high doses in patients with renal failure had become routine.

  16. Icariin combined with human umbilical cord mesenchymal stem cells significantly improve the impaired kidney function in chronic renal failure.

    Science.gov (United States)

    Li, Wen; Wang, Li; Chu, Xiaoqian; Cui, Huantian; Bian, Yuhong

    2017-04-01

    At present, the main therapy for chronic renal failure (CRF) is dialysis and renal transplantation, but neither obtains satisfactory results. Human umbilical cord mesenchymal stem cells (huMSCs) are isolated from the fetal umbilical cord which has a high self-renewal and multi-directional differentiation potential. Icariin (ICA), a kidney-tonifying Chinese Medicine can enhance the multipotency of huMSCs. Therefore, this work seeks to employ the use of ICA-treated huMSCs for the treatment of chronic renal failure. Blood urea nitrogen and creatinine (Cr) analyses showed amelioration of functional parameters in ICA-treated huMSCs for the treatment of CRF rats at 3, 7, and 14 days after transplantation. ICA-treated huMSCs can obviously increase the number of cells in injured renal tissues at 3, 7, and 14 days after transplantation by optical molecular imaging system. Hematoxylin-eosin staining demonstrated that ICA-treated huMSCs reduced the levels of fibrosis in CRF rats at 14 days after transplantation. Superoxide dismutase and Malondialdehyde analyses showed that ICA-treated huMSCs reduced the oxidative damage in CRF rats. Moreover, transplantation with ICA-treated huMSCs decreased inflammatory responses, promoted the expression of growth factors, and protected injured renal tissues. Taken together, our findings suggest that ICA-treated huMSCs could improve the kidney function in CRF rats.

  17. Pulmonary fibrosis

    International Nuclear Information System (INIS)

    Yamakido, Michio; Okuzaki, Takeshi

    1992-01-01

    When the chest is exposed to x radiation and Co-60 gamma radiation, radiation damage may occur in the lungs 2 to 10 weeks after irradiation. This condition is generally referred to as radiation pneumonitis, with the incidence ranging from 5.4% to 91.8% in the literature. Then radiation pneumonitis may develop into pulmonary fibrosis associated with roentgenologically diffuse linear and ring-like shadows and strong contraction 6 months to one year after irradiation. Until recently, little attention has been paid to pulmonary pneumonitis as a delayed effect of A-bomb radiation. The recent study using the population of 9,253 A-bomb survivors have suggested that the prevalence of pulmonary fibrosis tended to be high in heavily exposed A-bomb survivors. Two other studies using the cohort of 16,956 and 42,728 A-bomb survivors, respectively, have shown that the prevalence of roentgenologically proven pulmonary fibrosis was higher in men than women (1.82% vs 0.41%), was increased with aging and had a higher tendency in heavily exposed A-bomb survivors. (N.K.)

  18. Genetic Deletion of Soluble Epoxide Hydrolase Attenuates Inflammation and Fibrosis in Experimental Obstructive Nephropathy

    Directory of Open Access Journals (Sweden)

    Chin-Wei Chiang

    2015-01-01

    Full Text Available Soluble epoxide hydrolase (sEH is abundantly expressed in kidney and plays a potent role in regulating inflammatory response in inflammatory diseases. However, the role of sEH in progression of chronic kidney diseases such as obstructive nephropathy is still elusive. In current study, wild-type (WT and sEH deficient (sEH−/− mice were subjected to the unilateral ureteral obstruction (UUO surgery and the kidney injury was evaluated by histological examination, western blotting, and ELISA. The protein level of sEH in kidney was increased in UUO-treated mice group compared to nonobstructed group. Additionally, UUO-induced hydronephrosis, renal tubular injury, inflammation, and fibrosis were ameliorated in sEH−/− mice with the exception of glomerulosclerosis. Moreover, sEH−/− mice with UUO showed lower levels of inflammation-related and fibrosis-related protein such as monocyte chemoattractant protein-1, macrophage inflammatory protein-2, interleukin-1β (IL-1β, IL-6, inducible nitric oxide synthase, collagen 1A1, and α-actin. The levels of superoxide anion radical and hydrogen peroxide as well as NADPH oxidase activity were also decreased in UUO kidneys of sEH−/− mice compared to that observed in WT mice. Collectively, our findings suggest that sEH plays an important role in the pathogenesis of experimental obstructive nephropathy and may be a therapeutic target for the treatment of obstructive nephropathy-related diseases.

  19. Familial Pulmonary Fibrosis

    Science.gov (United States)

    ... Education & Training Home Conditions Familial Pulmonary Fibrosis Familial Pulmonary Fibrosis Make an Appointment Find a Doctor Ask a ... more members within the same family have Idiopathic Pulmonary Fibrosis (IPF) or any other form of Idiopathic Interstitial ...

  20. Cyclic Nucleotide Signalling in Kidney Fibrosis

    Directory of Open Access Journals (Sweden)

    Elisabeth Schinner

    2015-01-01

    Full Text Available Kidney fibrosis is an important factor for the progression of kidney diseases, e.g., diabetes mellitus induced kidney failure, glomerulosclerosis and nephritis resulting in chronic kidney disease or end-stage renal disease. Cyclic adenosine monophosphate (cAMP and cyclic guanosine monophosphate (cGMP were implicated to suppress several of the above mentioned renal diseases. In this review article, identified effects and mechanisms of cGMP and cAMP regarding renal fibrosis are summarized. These mechanisms include several signalling pathways of nitric oxide/ANP/guanylyl cyclases/cGMP-dependent protein kinase and cAMP/Epac/adenylyl cyclases/cAMP-dependent protein kinase. Furthermore, diverse possible drugs activating these pathways are discussed. From these diverse mechanisms it is expected that new pharmacological treatments will evolve for the therapy or even prevention of kidney failure.

  1. Inhibitory Effect of NH4Cl Treatment on Renal Tgfß1 Signaling Following Unilateral Ureteral Obstruction

    Directory of Open Access Journals (Sweden)

    Martina Feger

    2015-09-01

    Full Text Available Background/Aims: Consequences of obstructive nephropathy include tissue fibrosis, a major pathophysiological mechanism contributing to development of end-stage renal disease. Transforming growth factor β 1 (Tgfβ1 is involved in the progression of renal fibrosis. According to recent observations, ammonium chloride (NH4Cl prevented phosphate-induced vascular remodeling, effects involving decrease of Tgfβ1 expression and inhibition of Tgfβ1-dependent signaling. The present study, thus, explored whether NH4Cl influences renal Tgfβ1-induced pro-fibrotic signaling in obstructive nephropathy induced by unilateral ureteral obstruction (UUO. Methods: UUO was induced for seven days in C57Bl6 mice with or without additional treatment with NH4Cl (0.28 M in drinking water. Transcript levels were determined by RT-PCR as well as protein abundance by Western blotting, blood pH was determined utilizing a blood gas and chemistry analyser. Results: UUO increased renal mRNA expression of Tgfb1, Tgfβ-activated kinase 1 (Tak1 protein abundance and Smad2 phosphorylation in the nuclear fraction of the obstructed kidney tissues, effects blunted in NH4Cl treated mice as compared to control treated mice. The mRNA levels of the transcription factors nuclear factor of activated T cells 5 (Nfat5 and SRY (sex determining region Y-box 9 (Sox9 as well as of tumor necrosis factor α (Tnfα, interleukin 6 (Il6, plasminogen activator inhibitor 1 (Pai1 and Snai1 were up-regulated in the obstructed kidney tissues following UUO, effects again significantly ameliorated following NH4Cl treatment. Furthermore, the increased protein and mRNA expression of α-smooth muscle actin (α-Sma, fibronectin and collagen type I in the obstructed kidney tissues following UUO were significantly attenuated following NH4Cl treatment. Conclusion: NH4Cl treatment ameliorates Tgfβ1-dependent pro-fibrotic signaling and renal tissue fibrosis markers following obstructive nephropathy.

  2. Cyclosporine A induces senescence in renal tubular epithelial cells

    NARCIS (Netherlands)

    Jennings, Paul; Koppelstaetter, Christian; Aydin, Sonia; Abberger, Thomas; Wolf, Anna Maria; Mayer, Gert; Pfaller, Walter

    The nephrotoxic potential of the widely used immunosuppressive agent cyclosporine A (CsA) is well recognized. However, the mechanism of renal tubular toxicity is not yet fully elucidated. Chronic CsA nephropathy and renal organ aging share some clinical features, such as renal fibrosis and tubular

  3. Ultrasonography in chronic renal failure

    International Nuclear Information System (INIS)

    Buturovic-Ponikvar, Jadranka; Visnar-Perovic, Alenka

    2003-01-01

    Many chronic renal diseases lead to the final common state of decrease in renal size, parenchymal atrophy, sclerosis and fibrosis. The ultrasound image show a smaller kidney, thinning of the parenchyma and its hyperechogenicity (reflecting sclerosis and fibrosis). The frequency of renal cysts increases with the progression of the disease. Ultrasound generally does not allow for the exact diagnosis of an underlying chronic disease (renal biopsy is usually required), but it can help to determine an irreversible disease, assess prognosis and avoid unnecessary diagnostic or therapeutic procedures. The main exception in which the ultrasound image does not show a smaller kidney with parenchymal atrophy is diabetic nephropathy, the leading cause of chronic and end-stage renal failure in developed countries in recent years. In this case, both renal size and parenchymal thickness are preserved until end-stage renal failure. Doppler study of intrarenal vessels can provide additional information about microvascular and parenchymal lesions, which is helpful in deciding for or against therapeutic intervention and timely planning for optimal renal replacement therapy option

  4. Albumin stimulates renal tubular inflammation through an HSP70-TLR4 axis in mice with early diabetic nephropathy

    Science.gov (United States)

    Jheng, Huei-Fen; Tsai, Pei-Jane; Chuang, Yi-Lun; Shen, Yi-Ting; Tai, Ting-An; Chen, Wen-Chung; Chou, Chuan-Kai; Ho, Li-Chun; Tang, Ming-Jer; Lai, Kuei-Tai A.; Sung, Junne-Ming; Tsai, Yau-Sheng

    2015-01-01

    ABSTRACT Increased urinary albumin excretion is not simply an aftermath of glomerular injury, but is also involved in the progression of diabetic nephropathy (DN). Whereas Toll-like receptors (TLRs) are incriminated in the renal inflammation of DN, whether and how albumin is involved in the TLR-related renal inflammatory response remains to be clarified. Here, we showed that both TLR2 and TLR4, one of their putative endogenous ligands [heat shock protein 70 (HSP70)] and nuclear factor-κB promoter activity were markedly elevated in the kidneys of diabetic mice. A deficiency of TLR4 but not of TLR2 alleviated albuminuria, tubulointerstitial fibrosis and inflammation induced by diabetes. The protection against renal injury in diabetic Tlr4−/− mice was associated with reduced tubular injuries and preserved cubilin levels, rather than amelioration of glomerular lesions. In vitro studies revealed that albumin, a stronger inducer than high glucose (HG), induced the release of HSP70 from proximal tubular cells. HSP70 blockade ameliorated albumin-induced inflammatory mediators. HSP70 triggered the production of inflammatory mediators in a TLR4-dependent manner. Moreover, HSP70 inhibition in vivo ameliorated diabetes-induced albuminuria, inflammatory response and tubular injury. Finally, we found that individuals with DN had higher levels of TLR4 and HSP70 in the dilated tubules than non-diabetic controls. Thus, activation of the HSP70-TLR4 axis, stimulated at least in part by albumin, in the tubular cell is a newly identified mechanism associated with induction of tubulointerstitial inflammation and aggravation of pre-existing microalbuminuria in the progression of DN. PMID:26398934

  5. Cobrotoxin from Naja naja atra Venom Ameliorates Adriamycin Nephropathy in Rats

    Directory of Open Access Journals (Sweden)

    Shu-Zhi Wang

    2015-01-01

    Full Text Available Chronic kidney disease (CKD becomes a global health problem with high morbidity and mortality. Adriamycin- (ADR- induced rodent chronic nephropathy is a classic experimental model of human minimal lesion nephrotic syndrome. The present study investigated the effect of cobrotoxin (CTX on ADR-induced nephropathy. Rats were given 6 mg/kg ADR once through the tail vein to replicate ADR nephropathy model. CTX was administered to rats daily by placing a fast dissolving CTX membrane strip under the tongue starting from 5 days prior to ADR administration until the end of experiment. The results showed that CTX ameliorated the symptoms of ADR nephropathy syndrome with reduced body weight loss, proteinuria, hypoalbuminemia, dyslipidemia, serum electrolyte imbalance, oxidative stress, renal function abnormities, and kidney pathological lesions. Anti-inflammatory cytokine IL-10 expression was elevated after CTX administration in ADR nephropathy model. CTX inhibited the phosphorylation of IκB-α and NF-κB p65 nuclear translocation. Meanwhile, CTX upregulated the protein level of podocyte-specific nephrin and downregulated the level of fibrosis-related TGF-β. These findings suggest that CTX may be a potential drug for chronic kidney diseases.

  6. Intestinal fibrosis is reduced by early elimination of inflammation in a mouse model of IBD: impact of a "Top-Down" approach to intestinal fibrosis in mice.

    Science.gov (United States)

    Johnson, Laura A; Luke, Amy; Sauder, Kay; Moons, David S; Horowitz, Jeffrey C; Higgins, Peter D R

    2012-03-01

    The natural history of Crohn's disease follows a path of progression from an inflammatory to a fibrostenosing disease, with most patients requiring surgical resection of fibrotic strictures. Potent antiinflammatory therapies reduce inflammation but do not appear to alter the natural history of intestinal fibrosis. The aim of this study was to determine the relationship between intestinal inflammation and fibrogenesis and the impact of a very early "top-down" interventional approach on fibrosis in vivo. In this study we removed the inflammatory stimulus from the Salmonella typhimurium mouse model of intestinal fibrosis by eradicating the S. typhimurium infection with levofloxacin at sequential timepoints during the infection. We evaluated the effect of this elimination of the inflammatory stimulus on the natural history of inflammation and fibrosis as determined by gross pathology, histopathology, mRNA expression, and protein expression. Fibrogenesis is preceded by inflammation. Delayed eradication of the inflammatory stimulus by antibiotic treatment represses inflammation without preventing fibrosis. Early intervention significantly ameliorates but does not completely prevent subsequent fibrosis. This study demonstrates that intestinal fibrosis develops despite removal of an inflammatory stimulus and elimination of inflammation. Early intervention ameliorates but does not abolish subsequent fibrosis, suggesting that fibrosis, once initiated, is self-propagating, suggesting that a very early top-down interventional approach may have the most impact on fibrostenosing disease. Copyright © 2011 Crohn's & Colitis Foundation of America, Inc.

  7. Long-term treatment with EGFR inhibitor erlotinib attenuates renal inflammatory cytokines but not nephropathy in Alport syndrome mouse model.

    Science.gov (United States)

    Omachi, Kohei; Miyakita, Rui; Fukuda, Ryosuke; Kai, Yukari; Suico, Mary Ann; Yokota, Tsubasa; Kamura, Misato; Shuto, Tsuyoshi; Kai, Hirofumi

    2017-12-01

    Alport syndrome (AS) is a hereditary kidney disease caused by mutation of type IV collagen. Loss of collagen network induces collapse of glomerular basement membrane (GBM) structure. The previous studies showed that upregulation of some tyrosine kinase receptors signaling accompanied GBM disorder in AS mouse model. EGFR signaling is one of the well-known receptor kinase signaling that is involved in glomerular diseases. However, whether EGFR signaling is relevant to AS progression is still uninvestigated. Here, we determined the involvement of EGFR in AS and the effect of suppressing EGFR signaling by erlotinib treatment on AS progression. Phosphorylated EGFR expression was investigated by Western blotting analysis and immunostaining of kidney tissues of Col4a5 mutant mice (a mouse model of X-linked AS). To check the effect of blocking EGFR signaling in AS, we administered erlotinib to AS mice once a day (10 mg/kg/day) orally for 18 weeks. Renal function parameters (proteinuria, serum creatinine, and BUN) and renal histology were assessed, and the gene expressions of inflammatory cytokines were analyzed in renal tissues. Phosphorylated EGFR expression was upregulated in AS mice kidney tissues. Erlotinib slightly reduced the urinary protein and suppressed the expression of renal injury markers (Lcn2, Lysozyme) and inflammatory cytokines (Il-6, Il-1β and KC). Erlotinib did not improve renal pathology, such as glomerular sclerosis and fibrosis. These findings suggest that EGFR signaling is upregulated in kidney, but although inhibiting this signaling pathway suppressed renal inflammatory cytokines, it did not ameliorate renal dysfunction in AS mouse model.

  8. PA21, a novel phosphate binder, improves renal osteodystrophy in rats with chronic renal failure.

    Science.gov (United States)

    Yaguchi, Atsushi; Tatemichi, Satoshi; Takeda, Hiroo; Kobayashi, Mamoru

    2017-01-01

    The effects of PA21, a novel iron-based and non-calcium-based phosphate binder, on hyperphosphatemia and its accompanying bone abnormality in chronic kidney disease-mineral and bone disorder (CKD-MBD) were evaluated. Rats with adenine-induced chronic renal failure (CRF) were prepared by feeding them an adenine-containing diet for four weeks. They were also freely fed a diet that contained PA21 (0.5, 1.5, and 5%), sevelamer hydrochloride (0.6 and 2%) or lanthanum carbonate hydrate (0.6 and 2%) for four weeks. Blood biochemical parameters were measured and bone histomorphometry was performed for femurs, which were isolated after drug treatment. Serum phosphorus and parathyroid hormone (PTH) levels were higher in the CRF rats. Administration of phosphate binders for four weeks decreased serum phosphorus and PTH levels in a dose-dependent manner and there were significant decreases in the AUC0-28 day of these parameters in 5% PA21, 2% sevelamer hydrochloride, and 2% lanthanum carbonate hydrate groups compared with that in the CRF control group. Moreover, osteoid volume improved significantly in 5% of the PA21 group, and fibrosis volume and cortical porosity were ameliorated in 5% PA21, 2% sevelamer hydrochloride, and 2% lanthanum carbonate hydrate groups. These results suggest that PA21 is effective against hyperphosphatemia, secondary hyperparathyroidism, and bone abnormalities in CKD-MBD as sevelamer hydrochloride and lanthanum carbonate hydrate are, and that PA21 is a new potential alternative to phosphate binders.

  9. Renal microvascular disease in an aging population: a reversible process?

    Science.gov (United States)

    Futrakul, Narisa; Futrakul, Prasit

    2008-01-01

    Renal microvascular disease and tubulointerstitial fibrosis are usually demonstrated in aging in humans and animals. It has recently been proposed that renal microvascular disease is the crucial determinant of tubulointerstitial disease or fibrosis. Enhanced circulating endothelial cell loss is a biomarker that reflects glomerular endothelial injury or renal microvascular disease, and fractional excretion of magnesium (FE Mg) is a sensitive biomarker that reflects an early stage of tubulointerstitial fibrosis. In aging in humans, both of these biomarkers are abnormally elevated. In addition, a glomerular endothelial dysfunction determined by altered hemodynamics associated with peritubular capillary flow reduction is substantiated. A correction of such hemodynamic alteration with vasodilators can effectively improve renal perfusion and restore renal function. Thus, anti-aging therapy can reverse the renal microvascular disease and dysfunction associated with the aging process.

  10. Novel Omega-3 Fatty Acid Epoxygenase Metabolite Reduces Kidney Fibrosis

    Science.gov (United States)

    Sharma, Amit; Khan, Md. Abdul Hye; Levick, Scott P.; Lee, Kin Sing Stephen; Hammock, Bruce D.; Imig, John D.

    2016-01-01

    Cytochrome P450 (CYP) monooxygenases epoxidize the omega-3 polyunsaturated fatty acid (PUFA) docosahexaenoic acid into novel epoxydocosapentaenoic acids (EDPs) that have multiple biological actions. The present study determined the ability of the most abundant EDP regioisomer, 19,20-EDP to reduce kidney injury in an experimental unilateral ureteral obstruction (UUO) renal fibrosis mouse model. Mice with UUO developed kidney tubular injury and interstitial fibrosis. UUO mice had elevated kidney hydroxyproline content and five-times greater collagen positive fibrotic area than sham control mice. 19,20-EDP treatment to UUO mice for 10 days reduced renal fibrosis with a 40%–50% reduction in collagen positive area and hydroxyproline content. There was a six-fold increase in kidney α-smooth muscle actin (α-SMA) positive area in UUO mice compared to sham control mice, and 19,20-EDP treatment to UUO mice decreased α-SMA immunopositive area by 60%. UUO mice demonstrated renal epithelial-to-mesenchymal transition (EMT) with reduced expression of the epithelial marker E-cadherin and elevated expression of multiple mesenchymal markers (FSP-1, α-SMA, and desmin). Interestingly, 19,20-EDP treatment reduced renal EMT in UUO by decreasing mesenchymal and increasing epithelial marker expression. Overall, we demonstrate that a novel omega-3 fatty acid metabolite 19,20-EDP, prevents UUO-induced renal fibrosis in mice by reducing renal EMT. PMID:27213332

  11. Ameliorative effect of antioxidants (vitamins C and E against abamectin toxicity in liver, kidney and testis of male albino rats

    Directory of Open Access Journals (Sweden)

    B. Wilson Magdy

    2016-10-01

    In conclusion, it appears that vitamins C and E, or in combination (as antioxidants ameliorate the hepato-renal and testicular toxicity of abamectin, but are not completely protective, especially in liver tissue.

  12. Glycyrrhizic acid alleviates bleomycin-induced pulmonary fibrosis in rats

    Directory of Open Access Journals (Sweden)

    Lili eGao

    2015-10-01

    Full Text Available Idiopathic pulmonary fibrosis is a progressive and lethal form of interstitial lung disease that lacks effective therapies at present. Glycyrrhizic acid (GA, a natural compound extracted from a traditional Chinese herbal medicine Glycyrrhiza glabra, was recently reported to benefit lung injury and liver fibrosis in animal models, yet whether GA has a therapeutic effect on pulmonary fibrosis is unknown. In this study, we investigated the potential therapeutic effect of GA on pulmonary fibrosis in a rat model with bleomycin (BLM-induced pulmonary fibrosis. The results indicated that GA treatment remarkably ameliorated BLM-induced pulmonary fibrosis and attenuated BLM-induced inflammation, oxidative stress, epithelial-mesenchymal transition and activation of tansforming growth factor-beta signaling pathway in the lungs. Further, we demonstrated that GA treatment inhibited proliferation of 3T6 fibroblast cells, induced cell cycle arrest and promoted apoptosis in vitro, implying that GA-mediated suppression of fibroproliferation may contribute to the anti-fibrotic effect against BLM-induced pulmonary fibrosis. In summary, our study suggests a therapeutic potential of GA in the treatment of pulmonary fibrosis.

  13. Celecoxib offsets the negative renal influences of cyclosporine via modulation of the TGF-β1/IL-2/COX-2/endothelin ET(B) receptor cascade.

    Science.gov (United States)

    El-Gowelli, Hanan M; Helmy, Maged W; Ali, Rabab M; El-Mas, Mahmoud M

    2014-03-01

    Endothelin (ET) signaling provokes nephrotoxicity induced by the immunosuppressant drug cyclosporine A (CSA). We tested the hypotheses that (i): celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, counterbalances renal derangements caused by CSA in rats and (ii) the COX-2/endothelin ET(B) receptor signaling mediates the CSA-celecoxib interaction. Ten-day treatment with CSA (20 mg/kg/day) significantly increased biochemical indices of renal function (serum urea, creatinine), inflammation (interleukin-2, IL-2) and fibrosis (transforming growth factor-β₁, TGF-β₁). Histologically, CSA caused renal tubular atrophy along with interstitial fibrosis. These detrimental renal effects of CSA were largely reduced in rats treated concurrently with celecoxib (10 mg/kg/day). We also report that cortical glomerular and medullary tubular protein expressions of COX-2 and ET(B) receptors were reduced by CSA and restored to near-control values in rats treated simultaneously with celecoxib. The importance of ET(B) receptors in renal control and in the CSA-celecoxib interaction was further verified by the findings (i) most of the adverse biochemical, inflammatory, and histopathological profiles of CSA were replicated in rats treated with the endothelin ETB receptor antagonist BQ788 (0.1 mg/kg/day, 10 days), and (ii) the BQ788 effects, like those of CSA, were alleviated in rats treated concurrently with celecoxib. Together, the data suggest that the facilitation of the interplay between the TGF-β1/IL-2/COX-2 pathway and the endothelin ET(B) receptors constitutes the cellular mechanism by which celecoxib ameliorates the nephrotoxic manifestations of CSA in rats. Copyright © 2014 Elsevier Inc. All rights reserved.

  14. Ameliorative percutaneous lumbar discectomy

    International Nuclear Information System (INIS)

    Xiao Chengjiang; Su Huanbin; He Xiaofeng; Li Yanhao

    2005-01-01

    Objective: To ameliorate the percutaneous lumbar discectomy (APLD) for improving the effectiveness and amplifying the indicative range of PLD. Methods: To ameliorate percutaneous punctured route based on classic PLD and discectomy of extracting pulp out of the herniated disc with special pulpforceps. The statistical analysis of the therapeutic results on 750 disc protrusions of 655 cases undergone APLD following up from 6 to 54 months retrospectively. Results: The effective ratios were excellent in 40.2%, good for 46.6% and bad of 13.3%. No occurrance of intervertebral inflammation and paradiscal hematoma, there were only 1 case complicated with injuried cauda equina, and 4 cases with broken appliance within disc. Conclusions: APLD is effective and safe, not only indicative for inclusion disc herniation, but also for noninclusion herniation. (authors)

  15. Cystic fibrosis: case report

    International Nuclear Information System (INIS)

    Park, Si Hyun; Lee, Hyun Ju; Kim, Ji Hye; Park, Chol Heui

    2002-01-01

    Cystic fibrosis is an autosomal recessive genetic disease. Among Caucasians, it is the most common cause of pulmonary insufficiency during the first three decades of life. The prevalence of cystic fibrosis varies according to ethnic origin: it is common among Caucasians but rare among Asians. We report a case in which cystic fibrosis with bronchiectasis and hyperaeration was revealed by high-resolution CT, and mutation of the cystic fibrosis conductance transmembrane regulator gene (CFTR) by DNA analysis

  16. Cystic fibrosis: case report

    International Nuclear Information System (INIS)

    Park, Si Hyun; Lee, Hyun Ju; Kim, Ji Hye; Park, Chol Heui

    2002-01-01

    Cystic fibrosis is a autosomal recessive genetic disease. Among caucasians, it is the most common cause of pulmonary insufficiency during the first three decades of life. The prevalence of cystic fibrosis varies according to ethnic origin: it is common among caucasians but rare among Asians. We report a case in which cystic fibrosis with bronchiectasis and hyperaeration was revealed by high-resolution CT, and mutation of the cystic fibrosis conductance transmembrane regulator gene (CFTR) by DNA analysis

  17. Cystic Fibrosis (CF): Chloride Sweat Test

    Science.gov (United States)

    ... on this topic for: Parents Kids Teens Cystic Fibrosis Cystic Fibrosis and Nutrition Cystic Fibrosis (CF) Respiratory Screen: Sputum Cystic Fibrosis: Diet and Nutrition Cystic Fibrosis Cystic Fibrosis: Diet and Nutrition View more Partner Message ...

  18. Obaculactone protects against bleomycin-induced pulmonary fibrosis in mice

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Xingqi; Ouyang, Zijun; You, Qian; He, Shuai; Meng, Qianqian; Hu, Chunhui; Wu, Xudong; Shen, Yan; Sun, Yang, E-mail: yangsun@nju.edu.cn; Wu, Xuefeng, E-mail: wuxf@nju.edu.cn; Xu, Qiang, E-mail: molpharm@163.com

    2016-07-15

    Idiopathic pulmonary fibrosis is a progressive, degenerative and almost irreversible disease. There is hardly an effective cure for lung damage due to pulmonary fibrosis. The purpose of this study was to evaluate the role of obaculactone in an already-assessed model of idiopathic pulmonary fibrosis induced by bleomycin administration. Mice were subjected to intratracheal instillation of bleomycin, and obaculactone was given orally after bleomycin instillation daily for 23 days. Treatment with obaculactone ameliorated body weight loss, lung histopathology abnormalities and pulmonary collagen deposition, with a decrease of the inflammatory cell number and the cytokine level in bronchoalveolar lavage fluid. Moreover, obaculactone inhibited the expression of icam1, vcam1, inos and cox2, and attenuated oxidative stress in bleomycin-treated lungs. Importantly, the production of collagen I and α-SMA in lung tissues as well as the levels of TGF-β1, ALK5, p-Smad2 and p-Smad3 in lung homogenates was also reduced after obaculactone treatment. Finally, the TGF-β1-induced epithelial-mesenchymal transition via Smad-dependent and Smad-independent pathways was reversed by obaculactone. Collectively, these data suggest that obaculactone may be a promising drug candidate for the treatment of idiopathic pulmonary fibrosis. - Highlights: • Obaculactone ameliorates bleomycin-induced pulmonary fibrosis in mice. • Obaculactone mitigates bleomycin-induced inflammatory response in lungs. • Obaculactone exerts inhibitory effects on TGF-β1 signaling and TGF-β1-induced EMT progress.

  19. Obaculactone protects against bleomycin-induced pulmonary fibrosis in mice

    International Nuclear Information System (INIS)

    Wang, Xingqi; Ouyang, Zijun; You, Qian; He, Shuai; Meng, Qianqian; Hu, Chunhui; Wu, Xudong; Shen, Yan; Sun, Yang; Wu, Xuefeng; Xu, Qiang

    2016-01-01

    Idiopathic pulmonary fibrosis is a progressive, degenerative and almost irreversible disease. There is hardly an effective cure for lung damage due to pulmonary fibrosis. The purpose of this study was to evaluate the role of obaculactone in an already-assessed model of idiopathic pulmonary fibrosis induced by bleomycin administration. Mice were subjected to intratracheal instillation of bleomycin, and obaculactone was given orally after bleomycin instillation daily for 23 days. Treatment with obaculactone ameliorated body weight loss, lung histopathology abnormalities and pulmonary collagen deposition, with a decrease of the inflammatory cell number and the cytokine level in bronchoalveolar lavage fluid. Moreover, obaculactone inhibited the expression of icam1, vcam1, inos and cox2, and attenuated oxidative stress in bleomycin-treated lungs. Importantly, the production of collagen I and α-SMA in lung tissues as well as the levels of TGF-β1, ALK5, p-Smad2 and p-Smad3 in lung homogenates was also reduced after obaculactone treatment. Finally, the TGF-β1-induced epithelial-mesenchymal transition via Smad-dependent and Smad-independent pathways was reversed by obaculactone. Collectively, these data suggest that obaculactone may be a promising drug candidate for the treatment of idiopathic pulmonary fibrosis. - Highlights: • Obaculactone ameliorates bleomycin-induced pulmonary fibrosis in mice. • Obaculactone mitigates bleomycin-induced inflammatory response in lungs. • Obaculactone exerts inhibitory effects on TGF-β1 signaling and TGF-β1-induced EMT progress.

  20. Renal rescue of dopamine D2 receptor function reverses renal injury and high blood pressure

    Science.gov (United States)

    Konkalmatt, Prasad R.; Asico, Laureano D.; Zhang, Yanrong; Yang, Yu; Drachenberg, Cinthia; Zheng, Xiaoxu; Han, Fei; Jose, Pedro A.; Armando, Ines

    2016-01-01

    Dopamine D2 receptor (DRD2) deficiency increases renal inflammation and blood pressure in mice. We show here that long-term renal-selective silencing of Drd2 using siRNA increases renal expression of proinflammatory and profibrotic factors and blood pressure in mice. To determine the effects of renal-selective rescue of Drd2 expression in mice, the renal expression of DRD2 was first silenced using siRNA and 14 days later rescued by retrograde renal infusion of adeno-associated virus (AAV) vector with DRD2. Renal Drd2 siRNA treatment decreased the renal expression of DRD2 protein by 55%, and DRD2 AAV treatment increased the renal expression of DRD2 protein by 7.5- to 10-fold. Renal-selective DRD2 rescue reduced the expression of proinflammatory factors and kidney injury, preserved renal function, and normalized systolic and diastolic blood pressure. These results demonstrate that the deleterious effects of renal-selective Drd2 silencing on renal function and blood pressure were rescued by renal-selective overexpression of DRD2. Moreover, the deleterious effects of 45-minute bilateral ischemia/reperfusion on renal function and blood pressure in mice were ameliorated by a renal-selective increase in DRD2 expression by the retrograde ureteral infusion of DRD2 AAV immediately after the induction of ischemia/reperfusion injury. Thus, 14 days after ischemia/reperfusion injury, the renal expression of profibrotic factors, serum creatinine, and blood pressure were lower in mice infused with DRD2 AAV than in those infused with control AAV. These results indicate an important role of renal DRD2 in limiting renal injury and preserving normal renal function and blood pressure. PMID:27358912

  1. (Pro)renin Receptor Is an Amplifier of Wnt/β-Catenin Signaling in Kidney Injury and Fibrosis.

    Science.gov (United States)

    Li, Zhen; Zhou, Lili; Wang, Yongping; Miao, Jinhua; Hong, Xue; Hou, Fan Fan; Liu, Youhua

    2017-08-01

    The (pro)renin receptor (PRR) is a transmembrane protein with multiple functions. However, its regulation and role in the pathogenesis of CKD remain poorly defined. Here, we report that PRR is a downstream target and an essential component of Wnt/ β -catenin signaling. In mouse models, induction of CKD by ischemia-reperfusion injury (IRI), adriamycin, or angiotensin II infusion upregulated PRR expression in kidney tubular epithelium. Immunohistochemical staining of kidney biopsy specimens also revealed induction of renal PRR in human CKD. Overexpression of either Wnt1 or β -catenin induced PRR mRNA and protein expression in vitro Notably, forced expression of PRR potentiated Wnt1-mediated β -catenin activation and augmented the expression of downstream targets such as fibronectin, plasminogen activator inhibitor 1, and α -smooth muscle actin ( α -SMA). Conversely, knockdown of PRR by siRNA abolished β -catenin activation. PRR potentiation of Wnt/ β -catenin signaling did not require renin, but required vacuolar H + ATPase activity. In the mouse model of IRI, transfection with PRR or Wnt1 expression vectors promoted β -catenin activation, aggravated kidney dysfunction, and worsened renal inflammation and fibrotic lesions. Coexpression of PRR and Wnt1 had a synergistic effect. In contrast, knockdown of PRR expression ameliorated kidney injury and fibrosis after IRI. These results indicate that PRR is both a downstream target and a crucial element in Wnt signal transmission. We conclude that PRR can promote kidney injury and fibrosis by amplifying Wnt/ β -catenin signaling. Copyright © 2017 by the American Society of Nephrology.

  2. An integrated lipidomics and metabolomics reveal nephroprotective effect and biochemical mechanism of Rheum officinale in chronic renal failure

    Science.gov (United States)

    Zhang, Zhi-Hao; Vaziri, Nosratola D.; Wei, Feng; Cheng, Xian-Long; Bai, Xu; Zhao, Ying-Yong

    2016-01-01

    Chronic renal failure (CRF) is a major public health problem worldwide. Earlier studies have revealed salutary effects of rhubarb extracts in CRF. In this study, we employed lipidomic and metabolomic approaches to identify the plasma biomarkers and to determine the effect of treatment with petroleum ether, ethyl acetate and n-butanol extracts of rhubarb in a rat model of CRF with adenine-induced chronic tubulointerstitial nephropathy. In addition, clinical biochemistry, histological evaluation and pro-fibrotic protein expression were analyzed. Significant changes were found between the CRF and control groups representing characteristic phenotypes of rats with CRF. Treatment with the three rhubarb extracts improved renal injury and dysfunction, either fully or partially reversed the plasma metabolites abnormalities and attenuated upregulation of pro-fibrotic proteins including TGF-β1, α-SMA, PAI-1, CTGF, FN and collagen-1. The nephroprotective effect of ethyl acetate extract was better than other extracts. The differential metabolites were closely associated with glycerophospholipid, fatty acid and amino acid metabolisms. The results revealed a strong link between renal tubulointerstitial fibrosis and glycerophospholipid metabolism and L-carnitine metabolism in the development of CRF. Amelioration of CRF with the three rhubarb extracts was associated with the delayed development and/or reversal the disorders in key metabolites associated with adenine-induced CRF. PMID:26903149

  3. Hypogonadism and renal failure: An update.

    Science.gov (United States)

    Thirumavalavan, Nannan; Wilken, Nathan A; Ramasamy, Ranjith

    2015-01-01

    The prevalence of both hypogonadism and renal failure is increasing. Hypogonadism in men with renal failure carries with it significant morbidity, including anemia and premature cardiovascular disease. It remains unclear whether testosterone therapy can affect the morbidity and mortality associated with renal failure. As such, in this review, we sought to evaluate the current literature addressing hypogonadism and testosterone replacement, specifically in men with renal failure. The articles chosen for this review were selected by performing a broad search using Pubmed, Embase and Scopus including the terms hypogonadism and renal failure from 1990 to the present. This review is based on both primary sources as well as review articles. Hypogonadism in renal failure has a multifactorial etiology, including co-morbid conditions such as diabetes, hypertension, old age and obesity. Renal failure can lead to decreased luteinizing hormone production and decreased prolactin clearance that could impair testosterone production. Given the increasing prevalence of hypogonadism and the potential morbidity associated with hypogonadism in men with renal failure, careful evaluation of serum testosterone would be valuable. Testosterone replacement therapy should be considered in men with symptomatic hypogonadism and renal failure, and may ameliorate some of the morbidity associated with renal failure. Patients with all stages of renal disease are at an increased risk of hypogonadism that could be associated with significant morbidity. Testosterone replacement therapy may reduce some of the morbidity of renal failure, although it carries risk.

  4. Inhibition of WISE preserves renal allograft function.

    Science.gov (United States)

    Qian, Xueming; Yuan, Xiaodong; Vonderfecht, Steven; Ge, Xupeng; Lee, Jae; Jurisch, Anke; Zhang, Li; You, Andrew; Fitzpatrick, Vincent D; Williams, Alexia; Valente, Eliane G; Pretorius, Jim; Stevens, Jennitte L; Tipton, Barbara; Winters, Aaron G; Graham, Kevin; Harriss, Lindsey; Baker, Daniel M; Damore, Michael; Salimi-Moosavi, Hossein; Gao, Yongming; Elkhal, Abdallah; Paszty, Chris; Simonet, W Scott; Richards, William G; Tullius, Stefan G

    2013-01-01

    Wnt-modulator in surface ectoderm (WISE) is a secreted modulator of Wnt signaling expressed in the adult kidney. Activation of Wnt signaling has been observed in renal transplants developing interstitial fibrosis and tubular atrophy; however, whether WISE contributes to chronic changes is not well understood. Here, we found moderate to high expression of WISE mRNA in a rat model of renal transplantation and in kidneys from normal rats. Treatment with a neutralizing antibody against WISE improved proteinuria and graft function, which correlated with higher levels of β-catenin protein in kidney allografts. In addition, treatment with the anti-WISE antibody reduced infiltration of CD68(+) macrophages and CD8(+) T cells, attenuated glomerular and interstitial injury, and decreased biomarkers of renal injury. This treatment reduced expression of genes involved in immune responses and in fibrogenic pathways. In summary, WISE contributes to renal dysfunction by promoting tubular atrophy and interstitial fibrosis.

  5. Antiangiogenic treatment diminishes renal injury and dysfunction via regulation of local AKT in early experimental diabetes.

    Science.gov (United States)

    Bai, Xiaoyan; Li, Xiao; Tian, Jianwei; Zhou, Zhanmei

    2014-01-01

    In view of increased vascular endothelial growth factor-A (VEGF-A) expression and renal dysfunction in early diabetes, we designed a study to test whether VEGF-A inhibition can prevent early renal injury and dysfunction. We investigated the relationship and mechanism between VEGF-A and AKT regulation. In vitro, VEGF-A small interfering RNA (siRNA) and AKT inhibitor MK-2206 were employed to podocytes and NRK-52 cells cultured in high glucose (30 mM). In vivo, the antiangiogenic drug endostatin was administered in 12 week-old streptozotocin-induced male Sprague Dawley rats. The levels of VEGF-A, AKT, phosphorylated Ser⁴⁷³-AKT, phosphorylated Thr³⁰⁸-AKT, nephrin, angiotensin II (Ang II), angiotensin type II receptor 1 (ATR1) were examined using quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR), Western blot analysis and immunohistochemistry. Interactions between phosphorylated Thr³⁰⁸-AKT and either nephrin in podocytes or Ang II in renal tubules were studied, respectively, using confocal immunofluorescence microscopy and immunoprecipitation. Silencing VEGF-A in podocytes upregulated phosphorylated Thr³⁰⁸-AKT and nephrin. Silencing VEGF-A in NRK-52E cells upregulated phosphorylated Thr³⁰⁸-AKT while downregulated Ang II and ATR1. MK-2206 enhanced VEGF-A expression in both podocytes and NRK-52E cells by inhibiting AKT activities. In diabetic rat kidneys, VEGF-A was upregulated and phosphorylated Thr³⁰⁸-AKT colocalized with either nephrin in podocytes or Ang II in renal tubules. With the endostatin treatment, the level of VEGF-A decreased while phosphorylated Thr³⁰⁸-AKT increased in both glomeruli and renal tubules. Treatment with endostatin upregulated nephrin in podocytes while downregulated Ang II and AT1R in renal tubules. Glomerular mesangial expansion was attenuated by the endostatin treatment, however, differences did not reach statistical significance. Endostatin ameliorated the interstitial fibrosis

  6. Antiangiogenic treatment diminishes renal injury and dysfunction via regulation of local AKT in early experimental diabetes.

    Directory of Open Access Journals (Sweden)

    Xiaoyan Bai

    Full Text Available In view of increased vascular endothelial growth factor-A (VEGF-A expression and renal dysfunction in early diabetes, we designed a study to test whether VEGF-A inhibition can prevent early renal injury and dysfunction. We investigated the relationship and mechanism between VEGF-A and AKT regulation. In vitro, VEGF-A small interfering RNA (siRNA and AKT inhibitor MK-2206 were employed to podocytes and NRK-52 cells cultured in high glucose (30 mM. In vivo, the antiangiogenic drug endostatin was administered in 12 week-old streptozotocin-induced male Sprague Dawley rats. The levels of VEGF-A, AKT, phosphorylated Ser⁴⁷³-AKT, phosphorylated Thr³⁰⁸-AKT, nephrin, angiotensin II (Ang II, angiotensin type II receptor 1 (ATR1 were examined using quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR, Western blot analysis and immunohistochemistry. Interactions between phosphorylated Thr³⁰⁸-AKT and either nephrin in podocytes or Ang II in renal tubules were studied, respectively, using confocal immunofluorescence microscopy and immunoprecipitation. Silencing VEGF-A in podocytes upregulated phosphorylated Thr³⁰⁸-AKT and nephrin. Silencing VEGF-A in NRK-52E cells upregulated phosphorylated Thr³⁰⁸-AKT while downregulated Ang II and ATR1. MK-2206 enhanced VEGF-A expression in both podocytes and NRK-52E cells by inhibiting AKT activities. In diabetic rat kidneys, VEGF-A was upregulated and phosphorylated Thr³⁰⁸-AKT colocalized with either nephrin in podocytes or Ang II in renal tubules. With the endostatin treatment, the level of VEGF-A decreased while phosphorylated Thr³⁰⁸-AKT increased in both glomeruli and renal tubules. Treatment with endostatin upregulated nephrin in podocytes while downregulated Ang II and AT1R in renal tubules. Glomerular mesangial expansion was attenuated by the endostatin treatment, however, differences did not reach statistical significance. Endostatin ameliorated the

  7. Curcumin ameliorates epithelial-to-mesenchymal transition of podocytes in vivo and in vitro via regulating caveolin-1.

    Science.gov (United States)

    Sun, Li-na; Chen, Zhi-xin; Liu, Xiang-chun; Liu, Hai-ying; Guan, Guang-ju; Liu, Gang

    2014-10-01

    Epithelial-mesenchymal transition (EMT) is recognized to play a key role in diabetic nephropathy (DN). Curcumin, the main active component of turmeric extracted from the roots of the Curcuma longa plant, has been reported for its anti-fibrotic effects in kidney fibrosis. The purpose of our study was to investigate the effects of curcumin in reversing epithelial-to-mesenchymal transition (EMT) of podocytes in vivo and in vitro. In vivo streptozotocin (STZ)-induced diabetic rats received vehicle or curcumin, and podocytes were treated with high glucose (HG) in the presence or absence of curcumin in vitro. And we investigated the effect of curcumin on HG-induced phosphorylation of cav-1 on the stability cav-1 and β-catenin using immunoprecipitation and fluorescence microscopy analysis. Curcumin treatment dramatically ameliorated metabolic parameters, renal function, morphological parameters in diabetic rats. We found that HG treatment led to significant down-regulation of p-cadherin and synaptopodin, as well as remarkable up-regulation of α-SMA and FSP-1 in vivo and in vitro. Furthermore, curcumin inhibited HG-induced caveolin-1 (cav-1) Tyr(14) phosphorylation associating with the suppression of stabilization of cav-1 and β-catenin. In summary, these findings suggest that curcumin prevents EMT of podocytes, proteinuria, and kidney injury in DN by suppressing the phosphorylation of cav-1, and increasing stabilization of cav-1 and β-catenin. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  8. The proximal tubular cell, a key player in renal damage

    NARCIS (Netherlands)

    Timmeren, Mirjan Miranda van

    2008-01-01

    A decline in renal function is associated with the degree of proteinuria and with histological findings of glomerulosclerosis and interstitial fibrosis. Proteinuria is not only a marker of renal damage, but ultrafiltered proteins can be toxic to the kidney, thereby contributing to

  9. Upregulation of Interleukin-33 in obstructive renal injury

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Wei-Yu, E-mail: wychen624@cgmh.org.tw [Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan (China); Chang, Ya-Jen [Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan (China); Su, Chia-Hao [Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan (China); Tsai, Tzu-Hsien [Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan (China); Chen, Shang-Der [Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan (China); Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Kaohsiung, Taiwan (China); Hsing, Chung-Hsi [Department of Anesthesiology, Chi-Mei Medical Center, Tainan, Taiwan (China); Yang, Jenq-Lin, E-mail: jyang@adm.cgmh.org.tw [Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan (China)

    2016-05-13

    Interstitial fibrosis and loss of parenchymal tubular cells are the common outcomes of progressive renal diseases. Pro-inflammatory cytokines have been known contributing to the damage of tubular cells and fibrosis responses after renal injury. Interleukin (IL)-33 is a tissue-derived nucleus alarmin that drives inflammatory responses. The regulation and function of IL-33 in renal injury, however, is not well understood. To investigate the involvement of cytokines in the pathogenesis of renal injury and fibrosis, we performed the mouse renal injury model induced by unilateral urinary obstruction (UUO) and analyze the differentially upregulated genes between the obstructed and the contralateral unobstructed kidneys using RNA sequencing (RNAseq). Our RNAseq data identified IL33 and its receptor ST2 were upregulated in the UUO kidney. Quantitative analysis confirmed that transcripts of IL33 and ST2 were upregulated in the obstructed kidneys. Immunofluorescent staining revealed that IL-33 was upregulated in Vimentin- and alpha-SMA-positive interstitial cells. By using genetically knockout mice, deletion of IL33 reduced UUO-induced renal fibrosis. Moreover, in combination with BrdU labeling technique, we observed that the numbers of proliferating tubular epithelial cells were increased in the UUO kidneys from IL33-or ST2-deficient mice compared to wild type mice. Collectively, our study demonstrated the upregulation of IL-33/ST2 signaling in the obstructed kidney may promote tubular cell injury and interstitial fibrosis. IL-33 may serve as a biomarker to detect renal injury and that IL-33/ST2 signaling may represent a novel target for treating renal diseases. -- Highlights: •Interleukin (IL)-33 was upregulated in obstructed kidneys. •Interstitial myofibroblasts expressed IL-33 after UUO-induced renal injury. •Deficiency of IL33 reduced interstitial fibrosis and promoted tubular cell proliferation.

  10. The Interplay between Inflammation and Fibrosis in Kidney Transplantation

    Directory of Open Access Journals (Sweden)

    Irina B. Torres

    2014-01-01

    Full Text Available Serial surveillance renal allograft biopsies have shown that early subclinical inflammation constitutes a risk factor for the development of interstitial fibrosis. More recently, it has been observed that persistent inflammation is also associated with fibrosis progression and chronic humoral rejection, two histological conditions associated with poor allograft survival. Treatment of subclinical inflammation with steroid boluses prevents progression of fibrosis and preserves renal function in patients treated with a cyclosporine-based regimen. Subclinical inflammation has been reduced after the introduction of tacrolimus based regimens, and it has been shown that immunosuppressive schedules that are effective in preventing acute rejection and subclinical inflammation may prevent the progression of fibrosis and chronic humoral rejection. On the other hand, minimization protocols are associated with progression of fibrosis, and noncompliance with the immunosuppressive regime constitutes a major risk factor for chronic humoral rejection. Thus, adequate immunosuppressive treatment, avoiding minimization strategies and reinforcing educational actions to prevent noncompliance, is at present an effective approach to combat the progression of fibrosis.

  11. Nitro-oleic acid ameliorates oxygen and glucose deprivation/re-oxygenation triggered oxidative stress in renal tubular cells via activation of Nrf2 and suppression of NADPH oxidase.

    Science.gov (United States)

    Nie, Huibin; Xue, Xia; Liu, Gang; Guan, Guangju; Liu, Haiying; Sun, Lina; Zhao, Long; Wang, Xueling; Chen, Zhixin

    2016-01-01

    Nitroalkene derivative of oleic acid (OA-NO 2 ), due to its ability to mediate revisable Michael addition, has been demonstrated to have various biological properties and become a therapeutic agent in various diseases. Though its antioxidant properties have been reported in different models of acute kidney injury (AKI), the mechanism by which OA-NO 2 attenuates intracellular oxidative stress is not well investigated. Here, we elucidated the anti-oxidative mechanism of OA-NO 2 in an in vitro model of renal ischemia/reperfusion (I/R) injury. Human tubular epithelial cells were subjected to oxygen and glucose deprivation/re-oxygenation (OGD/R) injury. Pretreatment with OA-NO 2 (1.25 μM, 45 min) attenuated OGD/R triggered reactive oxygen species (ROS) generation and subsequent mitochondrial membrane potential disruption. This action was mediated via up-regulating endogenous antioxidant defense components including superoxide dismutase (SOD1), heme oxygenase 1 (HO-1), and γ-glutamyl cysteine ligase modulatory subunits (GCLM). Moreover, subcellular fractionation analyses demonstrated that OA-NO 2 promoted nuclear translocation of nuclear factor-E2- related factor-2 (Nrf2) and Nrf2 siRNA partially abrogated these protective effects. In addition, OA-NO 2 inhibited NADPH oxidase activation and NADPH oxidase 4 (NOX4), NADPH oxidase 2 (NOX2) and p22 phox up-regulation after OGD/R injury, which was not relevant to Nrf2. These results contribute to clarify that the mechanism of OA-NO 2 reno-protection involves both inhibition of NADPH oxidase activity and induction of SOD1, Nrf2-dependent HO-1, and GCLM.

  12. Klotho ameliorates cyclosporine A-induced nephropathy via PDLIM2/NF-kB p65 signaling pathway.

    Science.gov (United States)

    Jin, Meihua; Lv, Pengfei; Chen, Guanyu; Wang, Peng; Zuo, Zhongfu; Ren, Lili; Bi, Jing; Yang, Chul-Woo; Mei, Xifan; Han, Donghe

    2017-04-29

    Klotho, an antiaging protein, can extend the lifespan and modulate cellular responses to inflammation and oxidative stress which can ameliorate chronic kidney diseases (CKD). To investigate the molecular mechanism of Klotho on inflammation in cyclosporine A (CsA) induced nephropathy, the mice were transfected with adenovirus mediated Klotho gene and treated with cyclosporine A (CsA; 30 mg/kg/day) for 4 weeks. Also, primary human renal proximal tubule epithelial cells (RPTECs) were treated with soluble Klotho protein and LPS. The results showed that Ad-klotho significantly reduced serum creatinine (Scr) and blood urea nitrogen (BUN) caused by CsA, and significantly increased creatinine clearance. Tubule interstitial fibrosis score (TIF), renal 8-OHdG excretion, macrophage infiltration and MCP-1 were decreased after Ad-klotho gene transfer. In addition, the overexpression of Klotho led to increase in the expression of PDLIM2, decreased in the amount of NF-kB p65, and inhibited the production of inflammatory cytokines (TNFα, IL-6, IL-12) and iNOS. Accordingly, in vitro results showed, Klotho enhanced PDLIM2 expression and reduced NF-kB p65 expression, while PDLIM2 siRNA could block the inhibitory effects of Klotho on expression of NF-kB p65. Secretion of inflammatory cytokines was also inhibited by Klotho treatment, and PDLIM2 siRNA hindered regulatory effects of Klotho on the cytokines. Real-time PCR and Luciferase assay showed that Klotho markedly increased expression of PDLIM2 mRNA and PDLIM2 reporter activity in a dose-dependent manner. These findings suggest that Klotho can modulate inflammation via PDLIM2/NF-kB p65 pathway in CsA-induced nephropathy. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Renal Osteodystrophy

    Directory of Open Access Journals (Sweden)

    Aynur Metin Terzibaşoğlu

    2004-12-01

    Full Text Available Chronic renal insufficiency is a functional definition which is characterized by irreversible and progressive decreasing in renal functions. This impairment is in collaboration with glomeruler filtration rate and serum creatinine levels. Besides this, different grades of bone metabolism disorders develop in chronic renal insufficiency. Pathologic changes in bone tissue due to loss of renal paranchyme is interrelated with calcium, phosphorus vitamine-D and parathyroid hormone. Clinically we can see high turnover bone disease, low turnover bone disease, osteomalacia, osteosclerosis and osteoporosis in renal osteodystropy. In this article we aimed to review pathology of bone metabolism disorders due to chronic renal insufficiency, clinic aspects and treatment approaches briefly.

  14. Neonatal cystic fibrosis screening test

    Science.gov (United States)

    Cystic fibrosis screening - neonatal; Immunoreactive trypsinogen; IRT test; CF - screening ... Cystic fibrosis is a disease passed down through families. CF causes thick, sticky mucus to build up in ...

  15. Renal venogram

    Science.gov (United States)

    ... be black. Other structures will be shades of gray. Veins are not normally seen in an x- ... Venogram - kidney; Renal vein thrombosis - venogram Images Kidney anatomy Kidney - blood and urine flow Renal veins References ...

  16. Cystic fibrosis in adults

    Directory of Open Access Journals (Sweden)

    C. Damas

    2007-05-01

    Full Text Available The authors reviewed adult cystic fibrosis patients followed in the Pulmonology Unit from 1994-2004 (n = 8, five female and three male, aged 20-34 years old (median = 27 years. Patients were diagnosed at 18 months - 31 years old by sweat testing (positive in six patients and genotyping (four patients homozygous for ΔF508 mutation.Respiratory involvement was characterised by sinusitis and bronchiectasis. Pulmonary involvement was accompanied by functional abnormalities and gas exchange impairment in the majority of the patients. Bronchial tree was colonised permanently in five patients: Pseudomonas aeruginosa in four and Staphilococcus aureus in four (three patients affected by both agents simultaneously.The main causes of exacerbation were respiratory infections and haemoptysis.Non-respiratory involvement was variable. Four patients had digestive involvement (one with hepatic cirrhosis, one had renal failure and only one had a sperm count to document infertility. Four patients had osteopaenia.Treatment included chest physiotherapy, bronchodilators, dornase alfa, mucolytics, digestive enzymes, vitamins, antibiotics and oxygen therapy.At review, one had left follow-up, one had died, one was awaiting lung transplant and the others evidenced no difference in clinical characteristics.In this group of patients the severity of the pulmonary disease was not related to a late diagnosis. It can be explained by the diversity of cystic fibrosis presentation in adults Resumo: Os autores efectuaram uma revisão de doentes adultos com fibrose quística (FQ, seguidos na consulta de Pneumologia no período de 1994-2004 (n = 8: cinco mulheres e três homens, com idades compreendidas entre 20 e 34 anos (mediana  =  27 anos, cuja idade de diagnóstico variou entre os 18 meses e os 31 anos.O diagnóstico foi obtido por prova de suor (positiva em seis doentes e estudo genético (homozigotia para a mutação ΔF508 em

  17. Imaging pulmonary fibrosis

    International Nuclear Information System (INIS)

    Brauner, M.W.; Rety, F.; Naccache, J.M.; Girard, F.; Valeyre, D.F.

    2001-01-01

    Localized fibrosis of the lung is usually scar tissue while diffuse pulmonary fibrosis is more often a sign of active disease. Chronic infiltrative lung disease may be classified into four categories: idiopathic pneumonitis, collagen diseases, granulomatosis (sarcoidosis), and caused by known diseases (pneumoconiosis, hypersensitivity pneumonitis, drug-induced lung disease, radiation). (authors)

  18. Angiogenesis in liver fibrosis

    NARCIS (Netherlands)

    Adlia, Amirah

    2017-01-01

    Angiogenesis emerges in parallel with liver fibrosis, but it is still unclear whether angiogenesis is a defense mechanism of the body in response to fibrosis, or whether it aggravates the fibrotic condition. In this thesis, Amirah Adlia applied different approaches to elucidate the role of

  19. Fibrosis and Cancer

    DEFF Research Database (Denmark)

    Cox, Thomas R.; Erler, Janine T.

    2016-01-01

    The relation between fibrosis and cancer has long been debated, specifically whether desmoplasia precedes, accompanies, or succeeds tumourigenesis, progression, and metastasis. Recent reports have published opposing data, adding to the perplexity. However, what is emerging is that it is likely th...... the specific properties of the extracellular matrix (ECM) that determine the paradoxical nature of cancer-associated fibrosis....

  20. Diagnosis of cystic fibrosis

    NARCIS (Netherlands)

    H.J. Veeze

    1995-01-01

    textabstractApplying the sweat-test as the first choice of test when a diagnosis of cystic fibrosis is suspected is still common practice and advisable. Since the cloning of the CFTR gene more than 400 different cystic fibrosis (CF) mutations have already been identified. The use of CF mutation

  1. Renal perfusion scintiscan

    Science.gov (United States)

    ... Radionuclide renal perfusion scan; Perfusion scintiscan - renal; Scintiscan - renal perfusion Images Kidney anatomy Kidney - blood and urine flow Intravenous pyelogram References Rottenberg G, Andi AC. Renal ...

  2. Phosphocalcic Markers and Calcification Propensity for Assessment of Interstitial Fibrosis and Vascular Lesions in Kidney Allograft Recipients.

    Directory of Open Access Journals (Sweden)

    Lena Berchtold

    Full Text Available Renal interstitial fibrosis and arterial lesions predict loss of function in chronic kidney disease. Noninvasive estimation of interstitial fibrosis and vascular lesions is currently not available. The aim of the study was to determine whether phosphocalcic markers are associated with, and can predict, renal chronic histological changes. We included 129 kidney allograft recipients with an available transplant biopsy in a retrospective study. We analyzed the associations and predictive values of phosphocalcic markers and serum calcification propensity (T50 for chronic histological changes (interstitial fibrosis and vascular lesions. PTH, T50 and vitamin D levels were independently associated to interstitial fibrosis. PTH elevation was associated with increasing interstitial fibrosis severity (r = 0.29, p = 0.001, while T50 and vitamin D were protective (r = -0.20, p = 0.025 and r = -0.23, p = 0.009 respectively. On the contrary, fibroblast growth factor 23 (FGF23 and Klotho correlated only modestly with interstitial fibrosis (p = 0.045 whereas calcium and phosphate did not. PTH, vitamin D and T50 were predictors of extensive fibrosis (AUC: 0.73, 0.72 and 0.68 respectively, but did not add to renal function prediction. PTH, FGF23 and T50 were modestly predictive of low fibrosis (AUC: 0.63, 0.63 and 0.61 but did not add to renal function prediction. T50 decreased with increasing arterial lesions (r = -0.21, p = 0.038. The discriminative performance of T50 in predicting significant vascular lesions was modest (AUC 0.61. In summary, we demonstrated that PTH, vitamin D and T50 are associated to interstitial fibrosis and vascular lesions in kidney allograft recipients independently of renal function. Despite these associations, mineral metabolism indices do not show superiority or additive value to fibrosis prediction by eGFR and proteinuria in kidney allograft recipients, except for vascular lesions where T50 could be of relevance.

  3. Lesions in mink (Mustela vison) infected with giant kidney worm (Dioctophyma renale).

    Science.gov (United States)

    Mace, T F

    1976-01-01

    Adult Dioctophyma renale occupied the enlarged renal pelvis of the right kidney of naturally infected mink. Lesions in the kidney parenchyma consisted of connective tissue proliferation in the interstitial tissue, tubular atrophy and fibrosis, and periglomerular fibrosis. The luminal surface of the renal pelvis wall was formed of numerous papillae covered with transitional epithelium. The nematodes in the lumen were bathed in an albuminous fluid containing red blood cells, epithelial cells and D. renale eggs. The left (uninfected) kidney was 60% larger than the left kidney of normal mink.

  4. UAB HRFD Core Center: Core A: The Hepato/Renal Fibrocystic Diseases Translational Resource

    Science.gov (United States)

    2017-09-15

    Hepato/Renal Fibrocystic Disease; Autosomal Recessive Polycystic Kidney Disease; Joubert Syndrome; Bardet Biedl Syndrome; Meckel-Gruber Syndrome; Congenital Hepatic Fibrosis; Caroli Syndrome; Oro-Facial-Digital Syndrome Type I; Nephronophthisis; Glomerulocystic Kidney Disease

  5. Purinergic Signalling in Inflammatory Renal Disease

    Directory of Open Access Journals (Sweden)

    Nishkantha eArulkumaran

    2013-07-01

    Full Text Available Extracellular purines have a role in renal physiology and adaption to inflammation. However, inflammatory renal disease may be mediated by extracellular purines, resulting in renal injury. The role of purinergic signalling is dependent on the concentrations of extracellular purines. Low basal levels of purines are important in normal homeostasis and growth. Concentrations of extracellular purines are significantly elevated during inflammation and mediate either an adaptive role or propagate local inflammation. Adenosine signalling mediates alterations in regional renal blood flow by regulation of the renal microcirculation, tubulo-glomerular feedback, and tubular transport of sodium and water. Increased extracellular ATP and renal P2 receptor-mediated inflammation are associated with various renal diseases, including hypertension, diabetic nephropathy, and glomerulonephritis. Experimental data suggests P2 receptor deficiency or receptor antagonism is associated with amelioration of antibody-mediated nephritis, suggesting a pathogenic (rather than adaptive role of purinergic signalling. We discuss the role of extracellular nucleotides in adaptation to ischaemic renal injury and in the pathogenesis of inflammatory renal disease.

  6. Interleukin-22 Inhibits Bleomycin-Induced Pulmonary Fibrosis

    Directory of Open Access Journals (Sweden)

    Minrui Liang

    2013-01-01

    Full Text Available Pulmonary fibrosis is a progressive and fatal fibrotic disease of the lungs with unclear etiology. Recent insight has suggested that early injury/inflammation of alveolar epithelial cells could lead to dysregulation of tissue repair driven by multiple cytokines. Although dysregulation of interleukin- (IL- 22 is involved in various pulmonary pathophysiological processes, the role of IL-22 in fibrotic lung diseases is still unclear and needs to be further addressed. Here we investigated the effect of IL-22 on alveolar epithelial cells in the bleomycin- (BLM- induced pulmonary fibrosis. BLM-treated mice showed significantly decreased level of IL-22 in the lung. IL-22 produced γδT cells were also decreased significantly both in the tissues of lungs and spleens. Administration of recombinant human IL-22 to alveolar epithelial cell line A549 cells ameliorated epithelial to mesenchymal transition (EMT and partially reversed the impaired cell viability induced by BLM. Furthermore, blockage of IL-22 deteriorated pulmonary fibrosis, with elevated EMT marker (α-smooth muscle actin (α-SMA and overactivated Smad2. Our results indicate that IL-22 may play a protective role in the development of BLM-induced pulmonary fibrosis and may suggest IL-22 as a novel immunotherapy tool in treating pulmonary fibrosis.

  7. A novel chalcone derivative attenuates the diabetes-induced renal injury via inhibition of high glucose-mediated inflammatory response and macrophage infiltration

    International Nuclear Information System (INIS)

    Fang, Qilu; Zhao, Leping; Wang, Yi; Zhang, Yali; Li, Zhaoyu; Pan, Yong; Kanchana, Karvannan; Wang, Jingying; Tong, Chao; Li, Dan; Liang, Guang

    2015-01-01

    Inflammation plays a central role in the development and progression of diabetic nephropathy (DN). Researches on novel anti-inflammatory agents may offer new opportunities for the treatment of DN. We previously found a chalcone derivative L6H21 could inhibit LPS-induced cytokine release from macrophages. The aim of this study was to investigate whether L6H21 could ameliorate the high glucose-mediated inflammation in NRK-52E cells and attenuate the inflammation-mediated renal injury. According to the results, L6H21 showed a great inhibitory effect on the expression of pro-inflammatory cytokines, cell adhesion molecules, chemokines, and macrophage adhesion via down-regulation of NF-κB/MAPKs activity in high glucose-stimulated renal NRK-52E cells. Further, in vivo oral administration with L6H21 at a dosage of 20 mg/kg/2 days showed a decreased expression of pro-inflammatory cytokines, cell adhesion molecules, which subsequently contributed to the inhibition on renal macrophage infiltration, the reduction of serum creatinine and BUN levels, and the improvement on the fibrosis and pathological changes in the renal tissues of diabetic mice. These findings provided that chalcone derived L6H21 may be a promising anti-inflammatory agent and have the potential in the therapy of diabetic nephropathy, and importantly, MAPK/NF-κB signaling system may be a novel therapeutic target for human DN in the future. - Highlights: • Inflammation plays a central role in the development of diabetic nephropathy. • Compound L6H21 reduced the high glucose-mediated inflammation in NRK-52E cells. • Compound L6H21 attenuated the inflammation-mediated renal injury. • L6H21 exhibited anti-inflammatory effects via inactivation of NF-κB/MAPKs. • MAPKs/NF-κB may be a novel therapeutic target in diabetic nephropathy treatment

  8. A novel chalcone derivative attenuates the diabetes-induced renal injury via inhibition of high glucose-mediated inflammatory response and macrophage infiltration

    Energy Technology Data Exchange (ETDEWEB)

    Fang, Qilu [Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang (China); Zhao, Leping [Department of Pharmacy, the Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang (China); Wang, Yi; Zhang, Yali [Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang (China); Li, Zhaoyu [Department of International High School, Shanghai Jiaotong University Nanyang Affiliated (Kunshan) School, Minhang District, Shanghai (China); Pan, Yong; Kanchana, Karvannan; Wang, Jingying; Tong, Chao [Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang (China); Li, Dan, E-mail: yqyyld@163.com [Department of Nephrology, the Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang (China); Liang, Guang, E-mail: wzmcliangguang@163.com [Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang (China)

    2015-01-15

    Inflammation plays a central role in the development and progression of diabetic nephropathy (DN). Researches on novel anti-inflammatory agents may offer new opportunities for the treatment of DN. We previously found a chalcone derivative L6H21 could inhibit LPS-induced cytokine release from macrophages. The aim of this study was to investigate whether L6H21 could ameliorate the high glucose-mediated inflammation in NRK-52E cells and attenuate the inflammation-mediated renal injury. According to the results, L6H21 showed a great inhibitory effect on the expression of pro-inflammatory cytokines, cell adhesion molecules, chemokines, and macrophage adhesion via down-regulation of NF-κB/MAPKs activity in high glucose-stimulated renal NRK-52E cells. Further, in vivo oral administration with L6H21 at a dosage of 20 mg/kg/2 days showed a decreased expression of pro-inflammatory cytokines, cell adhesion molecules, which subsequently contributed to the inhibition on renal macrophage infiltration, the reduction of serum creatinine and BUN levels, and the improvement on the fibrosis and pathological changes in the renal tissues of diabetic mice. These findings provided that chalcone derived L6H21 may be a promising anti-inflammatory agent and have the potential in the therapy of diabetic nephropathy, and importantly, MAPK/NF-κB signaling system may be a novel therapeutic target for human DN in the future. - Highlights: • Inflammation plays a central role in the development of diabetic nephropathy. • Compound L6H21 reduced the high glucose-mediated inflammation in NRK-52E cells. • Compound L6H21 attenuated the inflammation-mediated renal injury. • L6H21 exhibited anti-inflammatory effects via inactivation of NF-κB/MAPKs. • MAPKs/NF-κB may be a novel therapeutic target in diabetic nephropathy treatment.

  9. RENAL CRYOABLATION

    Directory of Open Access Journals (Sweden)

    A. V. Govorov

    2012-01-01

    Full Text Available Renal cryoablation is an alternative minimally-invasive method of treatment for localized renal cell carcinoma. The main advantages of this methodology include visualization of the tumor and the forming of "ice ball" in real time, fewer complications compared with other methods of treatment of renal cell carcinoma, as well as the possibility of conducting cryotherapy in patients with concomitant pathology. Compared with other ablative technologies cryoablation has a low rate of repeat sessions and good intermediate oncological results. The studies of long-term oncological and functional results of renal cryoablation are presently under way.

  10. Case-control study of gadodiamide-related nephrogenic systemic fibrosis

    DEFF Research Database (Denmark)

    Marckmann, Peter; Skov, Lone; Rossen, Kristian

    2007-01-01

    exposed to gadodiamide develop nephrogenic systemic fibrosis. METHODS: We conducted a case-control study of 19 histologically verified cases and 19 sex- and age-matched controls. All subjects had chronic renal failure when exposed to gadodiamide. Clinical, biochemical and pharmacological data were.......02). CONCLUSIONS: Increasing cumulative gadodiamide exposure, high-dose epoietin-beta treatment, and higher serum concentrations of ionized calcium and phosphate increase the risk of gadodiamide-related nephrogenic systemic fibrosis in renal failure patients. Severe cases seem to develop primarily among patients......BACKGROUND: Nephrogenic systemic fibrosis may be caused by gadolinium (Gd)-containing magnetic resonance imaging contrast agents. Most reported cases were associated with one particular agent, gadodiamide. Yet, unidentified cofactors might explain why only a minority of renal failure patients...

  11. A moderate response to plasmapheresis in nephrogenic systemic fibrosis

    Directory of Open Access Journals (Sweden)

    Pelin Ustuner

    2011-11-01

    Full Text Available Nephrogenic systemic fibrosis (NSF is a recently identified idiopathic cutaneous fibrosing disorder that occurs in the setting of renal failure. The disease initially called nephrogenic fibrosing dermopathy is closely linked to exposure to gadolinium-based contrast media used during magnetic resonance imaging in patients with renal insufficiency. Although little is known about the pathogenesis of this disease, the increased expression of transforming growth factor-beta has been demonstrated recently. Herein, we present a case of NSF was partially treated due to a moderate and temporary response to plasmapheresis with no recurrence for 6 months, but returned at the end of 6th month.

  12. Renal cancer.

    NARCIS (Netherlands)

    Corgna, E.; Betti, M.; Gatta, G.; Roila, F.; Mulder, P.H.M. de

    2007-01-01

    In Europe, renal cancer (that is neoplasia of the kidney, renal pelvis or ureter (ICD-9 189 and ICD-10 C64-C66)) ranks as the seventh most common malignancy in men amongst whom there are 29,600 new cases each year (3.5% of all cancers). Tobacco, obesity and a diet poor in vegetables are all

  13. Renal cancer

    NARCIS (Netherlands)

    Corgna, Enrichetta; Betti, Maura; Gatta, Gemma; Roila, Fausto; De Mulder, Pieter H. M.

    2007-01-01

    In Europe, renal cancer (that is neoplasia of the kidney, renal pelvis or ureter (ICD-9 189 and ICD-10 C64-C66)) ranks as the seventh most common malignancy in men amongst whom there are 29,600 new cases each year (3.5% of all cancers). Tobacco, obesity and a diet poor in vegetables are all

  14. Endostatin and transglutaminase 2 are involved in fibrosis of the aging kidney.

    Science.gov (United States)

    Lin, Chi Hua Sarah; Chen, Jun; Zhang, Zhongtao; Johnson, Gail V W; Cooper, Arthur J L; Feola, Julianne; Bank, Alexander; Shein, Jonathan; Ruotsalainen, Heli J; Pihlajaniemi, Taina A; Goligorsky, Michael S

    2016-06-01

    Endostatin (EST), an antiangiogenic factor, is enriched in aging kidneys. EST is also an interactive partner of transglutaminase 2 (TG2), an enzyme that cross-links extracellular matrix proteins. Here we tested whether EST and TG2 play a role in the fibrosis of aging. In wild-type mice, aging kidneys exhibited a 2- to 4-fold increase in TG2 paralleled by increased cross-linked extracellular matrix proteins and fibrosis. Mice transgenic to express EST showed renal fibrosis at a young age. One-month delivery of EST via minipumps to young mice showed increased renal fibrosis that became more robust when superimposed on folic acid-induced nephropathy. Upregulated TG2 and impaired renal function were apparent with EST delivery combined with folic acid-induced nephropathy. Subcapsular injection of TG2 and/or EST into kidneys of young mice not only induced interstitial fibrosis, but also increased the proportion of senescent cells. Thus, kidney fibrosis in aging may represent a natural outcome of upregulated EST and TG2, but more likely it appears to be a result of cumulative stresses occurring on the background of synergistically acting geronic (aging) proteins, EST and TG2. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

  15. Endostatin and transglutaminase 2 are involved in fibrosis of the aging kidney

    Science.gov (United States)

    Lin, Chi Hua Sarah; Chen, Jun; Zhang, Zhongtao; Johnson, Gail; Cooper, Arthur JL; Feola, Julianne; Bank, Alexander; Shein, Jonathan; Ruotsalainen, Heli; Pihlajaniemi, Taina; Goligorsky, Michael S

    2016-01-01

    Endostatin (EST), an anti-angiogenic factor, is enriched in aging kidneys. EST is also an interactive partner of transglutaminase 2 (TG2), an enzyme that cross-links extracellular matrix proteins. Here we tested whether EST and TG2 play a role in the fibrosis of aging. In wild type mice, aging kidneys exhibited a 2–4 fold increase in TG2 paralleled by increased cross-linked extracellular matrix proteins and fibrosis. Mice transgenic to express EST showed renal fibrosis at a young age. One month delivery of EST via minipumps to young mice showed increased renal fibrosis that became more robust when superimposed on folic acid-induced nephropathy. Upregulated TG2 and impaired renal function were apparent with EST delivery combined with folic acid-induced nephropathy. Subcapsular injection of TG2 and/or EST into kidneys of young mice not only induced interstitial fibrosis, but also increased the proportion of senescent cells. Thus, kidney fibrosis in aging may represent a natural outcome of upregulated EST and TG2, but more likely it appears to be a result of cumulative stresses occurring on the background of synergistically acting geronic (aging) proteins, EST and TG2. PMID:27165830

  16. Ameliorating effect of hawthorn ( Crataegus oxyacantha ) and ...

    African Journals Online (AJOL)

    Ameliorating effect of hawthorn ( Crataegus oxyacantha ) and physical exercise on ... Conclusion: Crataegus oxyacantha extract has shown positive affect to ameliorate on ... Key words: Crataegus oxyacantha, physical activity, epilepsy, gerbil, ...

  17. Coenzyme Q10 treatment ameliorates acute cisplatin nephrotoxicity in mice

    International Nuclear Information System (INIS)

    Fouad, Amr A.; Al-Sultan, Ali Ibrahim; Refaie, Shereen M.; Yacoubi, Mohamed T.

    2010-01-01

    The nephroprotective effect of coenzyme Q10 was investigated in mice with acute renal injury induced by a single i.p. injection of cisplatin (5 mg/kg). Coenzyme Q10 treatment (10 mg/kg/day, i.p.) was applied for 6 consecutive days, starting 1 day before cisplatin administration. Coenzyme Q10 significantly reduced blood urea nitrogen and serum creatinine levels which were increased by cisplatin. Coenzyme Q10 significantly compensated deficits in the antioxidant defense mechanisms (reduced glutathione level and superoxide dismutase activity), suppressed lipid peroxidation, decreased the elevations of tumor necrosis factor-α, nitric oxide and platinum ion concentration, and attenuated the reductions of selenium and zinc ions in renal tissue resulted from cisplatin administration. Also, histopathological renal tissue damage mediated by cisplatin was ameliorated by coenzyme Q10 treatment. Immunohistochemical analysis revealed that coenzyme Q10 significantly decreased the cisplatin-induced overexpression of inducible nitric oxide synthase, nuclear factor-κB, caspase-3 and p53 in renal tissue. It was concluded that coenzyme Q10 represents a potential therapeutic option to protect against acute cisplatin nephrotoxicity commonly encountered in clinical practice.

  18. Renal complications of anaesthesia.

    Science.gov (United States)

    McKinlay, J; Tyson, E; Forni, L G

    2018-01-01

    Peri-operative acute kidney injury is common, accounting for 30-40% of all in-hospital cases of acute kidney injury. It is associated with clinically significant morbidity and mortality even with what was hitherto regarded as relatively trivial increases in serum creatinine, and carries over a 12-fold relative risk of death following major abdominal surgery. Comorbid conditions such as diabetes, hypertension, liver disease and particularly pre-existing chronic kidney disease, as well as the type and urgency of surgery, are major risk factors for the development of postoperative acute kidney injury. As yet, there are no specific treatment options for the injured kidney, although there are several modifiable risk factors of which the anaesthetist should be aware. As well as the avoidance of potential nephrotoxins and appropriate volume balance, optimal anaesthetic management should aim to reduce the risk of postoperative renal complications. This may include careful ventilatory management and blood pressure control, as well as appropriate analgesic strategies. The choice of anaesthetic agent may also influence renal outcomes. Rather than concentrate on the classical management of acute kidney injury, this review focuses on the potential development of acute kidney injury peri-operatively, and the means by which this may be ameliorated. © 2018 The Association of Anaesthetists of Great Britain and Ireland.

  19. Aldosterone as a renal growth factor.

    LENUS (Irish Health Repository)

    Thomas, Warren

    2011-04-05

    Aldosterone regulates blood pressure through its effects on the cardiovascular system and kidney. Aldosterone can also contribute to the development of hypertension that leads to chronic pathologies such as nephropathy and renal fibrosis. Aldosterone directly modulates renal cell proliferation and differentiation as part of normal kidney development. The stimulation of rapidly activated protein kinase cascades is one facet of how aldosterone regulates renal cell growth. These cascades may also contribute to myofibroblastic transformation and cell proliferation observed in pathological conditions of the kidney. Polycystic kidney disease is a genetic disorder that is accelerated by hypertension. EGFR-dependent proliferation of the renal epithelium is a factor in cyst development and trans-activation of EGFR is a key feature in initiating aldosterone-induced signalling cascades. Delineating the components of aldosterone-induced signalling cascades may identify novel therapeutic targets for proliferative diseases of the kidney.

  20. Mechanisms by which heme oxygenase rescue renal dysfunction in obesity

    Directory of Open Access Journals (Sweden)

    Joseph Fomusi Ndisang

    2014-01-01

    Collectively, these data suggest that hemin ameliorates nephropathy by potentiating the expression of proteins of repair/regeneration, abating oxidative/inflammatory mediators, reducing renal histo-pathological lesions, while enhancing nephrin, podocin, podocalyxin, CD2AP and creatinine clearance, with corresponding reduction of albuminuria/proteinuria suggesting improved renal function in hemin-treated ZFs. Importantly, the concomitant potentiation regeneration proteins and podocyte cytoskeletal proteins are novel mechanisms by which hemin rescue nephropathy in obesity.

  1. Renal pathological implications in type 2 diabetes mellitus patients with renal involvement.

    Science.gov (United States)

    Li, Li; Zhang, Xiuhui; Li, Zhicheng; Zhang, Rui; Guo, Ruikun; Yin, Qinghua; Yang, Lichuan; Yue, Rongzheng; Su, Baihai; Huang, Songmin; Xu, Huan; He, Cijiang; Liu, Fang

    2017-01-01

    To investigate the renal pathological implications in type 2 diabetes mellitus patients with renal involvement. A total of 328 type 2 diabetes mellitus (T2DM) patients with renal involvement who underwent a renal biopsy and received follow-up for at least one year were recruited in our study. The patients were divided into the diabetic nephropathy (DN), non-diabetic renal disease (NDRD), and NDRD superimposed on DN groups based on the pathological diagnosis. Renal outcomes were defined by the initiation of renal replacement therapy or doubling of the serum creatinine. Kaplan-Meier analysis was used to compare renal survival, and Cox proportional hazard analysis was used to determine the predictors of renal outcomes in the DN group. Renal biopsy findings revealed that 188 patients (57.32%) had pure DN, 121 patients (36.89%) had NDRD alone, and 19 patients (5.79%) had NDRD superimposed on DN. The most frequent subclassification of NDRD was membranous nephropathy (MN). Compared with the NDRD and NDRD superimposed on DN groups, patients with pure DN had poorer renal function and lower renal survival rates. In the DN group, the five-year renal survival rates of glomerular classes of I, IIa, IIb, III and IV were 100%, 84.62%, 60%, 47.5% and 33.33%, respectively. Multivariate Cox proportional hazard analysis showed that the glomerular lesions, proteinuria and serum creatinine were independent risk factors for renal outcomes, while interstitial fibrosis/inflammation and arteriolar hyalinosis were not independently associated with renal outcomes in the DN group. Making an accurate pathologic diagnosis by renal biopsy is crucial for diabetes mellitus (DM) patients with renal involvement. The findings of our present study indicated that patients with pure DN had poorer renal outcomes than patients with NDRD or NDRD superimposed on DN. The classification of glomerular lesions, proteinuria and serum creatinine were independent risk factors for renal outcomes in the DN group

  2. A new perspective on the pathogenesis of chronic renal disease in captive cheetahs (Acinonyx jubatus).

    Science.gov (United States)

    Mitchell, Emily P; Prozesky, Leon; Lawrence, John

    2018-01-01

    The sustainability of captive cheetah populations is limited by high mortality due to chronic renal disease. This necropsy study, conducted on 243 captive cheetahs from one institution, investigated the relationships between focal palatine erosions, gastritis, enterocolitis, glomerulosclerosis, chronic renal infarcts, renal cortical and medullary fibrosis, and renal medullary amyloidosis at death. Associations between the individual renal lesions and death due to chronic renal disease and comparisons of lesion prevalence between captive bred and wild born and between normal and king coated cheetahs were also assessed. All lesions were significantly positively correlated with age at death. Renal medullary fibrosis was the only lesion associated with the likelihood of death being due to chronic renal disease, and cheetahs with this lesion were younger, on average, than cheetahs with other renal lesions. Alimentary tract lesions were not associated with amyloidosis. All lesions, except for palatine erosions, were more common in wild born than in captive bred cheetahs; the former were older at death than the latter. Having a king coat had no clear effect on disease prevalence. These results suggest that age and renal medullary fibrosis are the primary factors influencing the pathogenesis of chronic renal disease in captive cheetahs. Apart from amyloidosis, these findings are analogous to those described in chronic renal disease in domestic cats, which is postulated to result primarily from repetitive hypoxic injury of renal tubules, mediated by age and stress. Cheetahs may be particularly susceptible to acute renal tubular injury due to their propensity for stress and their extended life span in captivity, as well as their adaptation for fecundity (rather than longevity) and adrenaline-mediated high speed prey chases. The presence of chronic renal disease in subadult cheetahs suggests that prevention, identification and mitigation of stress are critical to the

  3. Syndecans in heart fibrosis.

    Science.gov (United States)

    Lunde, Ida G; Herum, Kate M; Carlson, Cathrine C; Christensen, Geir

    2016-09-01

    Heart disease is a deadly syndrome affecting millions worldwide. It reflects an unmet clinical need, and the disease mechanisms are poorly understood. Cardiac fibrosis is central to heart disease. The four-membered family of transmembrane proteoglycans, syndecan-1 to -4, is believed to regulate fibrosis. We review the current literature concerning syndecans in cardiac fibrosis. Syndecan expression is up-regulated in response to pro-inflammatory stimuli in various forms of heart disease with fibrosis. Mice lacking syndecan-1 and -4 show reduced activation of pro-fibrotic signaling and increased cardiac rupture upon infarction indicating an important role for these molecules. Whereas the short cytoplasmic tail of syndecans regulates signaling, their extracellular part, substituted with heparan sulfate glycosaminoglycan chains, binds a plethora of extracellular matrix (ECM) molecules involved in fibrosis, e.g., collagens, growth factors, cytokines, and immune cell adhesion proteins. Full-length syndecans induce pro-fibrotic signaling, increasing the expression of collagens, myofibroblast differentiation factors, ECM enzymes, growth factors, and immune cell adhesion molecules, thereby also increasing cardiac stiffness and preventing cardiac rupture. Upon pro-inflammatory stimuli, syndecan ectodomains are enzymatically released from heart cells (syndecan shedding). Shed ectodomains affect the expression of ECM molecules, promoting ECM degradation and cardiac rupture upon myocardial infarction. Blood levels of shed syndecan-1 and -4 ectodomains are associated with hospitalization, mortality, and heart remodeling in patients with heart failure. Improved understanding of syndecans and their modifying enzymes in cardiac fibrosis might contribute to the development of compounds with therapeutic potential, and enzymatically shed syndecan ectodomains might constitute a future prognostic tool for heart diseases with fibrosis. Graphical Abstract Graphical abstract summarizing

  4. Endomyocardial fibrosis in infancy

    Directory of Open Access Journals (Sweden)

    Jatene Marcelo Biscegli

    2003-01-01

    Full Text Available The patient was a 4-month-old infant, who underwent persistent ductus arteriosus interruption with titanium clips at the age of 13 days and, since the age of 2 months, had crises of hypoxia and hypertonicity. After clinical investigation, the presence of pulmonary hypertension was confirmed and left ventricular inflow tract obstruction was suspected. The patient underwent surgical treatment at the age of 4 months, during which right and left ventricular endocardial fibrosis was identified. The fibrosis was resected, but the infant had an unfavorable clinical evolution with significant diastolic restriction and died on the sixth postoperative day. Anatomicopathological and surgical findings suggested endomyocardial fibrosis, although that pathology is very rare at the patient's age.

  5. Involvement of endoplasmic reticulum stress in albuminuria induced inflammasome activation in renal proximal tubular cells.

    Directory of Open Access Journals (Sweden)

    Li Fang

    Full Text Available Albuminuria contributes to the progression of tubulointerstitial fibrosis. Although it has been demonstrated that ongoing albuminuria leads to tubular injury manifested by the overexpression of numerous proinflammatory cytokines, the mechanism remains largely unknown. In this study, we found that the inflammasome activation which has been recognized as one of the cornerstones of intracellular surveillance system was associated with the severity of albuminuria in the renal biopsies specimens. In vitro, bovine serum albumin (BSA could also induce the activation of NLRP3 inflammasome in the cultured kidney epithelial cells (NRK-52E. Since there was a significant overlap of NLRP3 with the ER marker calreticulin, the ER stress provoked by BSA seemed to play a crucial role in the activation of inflammasome. Here, we demonstrated that the chemical chaperone taurine-conjugated ursodeoxycholic acid (TUDCA which was proved to be an enhancer for the adaptive capacity of ER could attenuate the inflammasome activation induced by albuminuria not only in vitro but also in diabetic nephropathy. Taken together, these data suggested that ER stress seemed to play an important role in albuminuria-induced inflammasome activation, elimination of ER stress via TUDCA might hold promise as a novel avenue for preventing inflammasome activation ameliorating kidney epithelial cells injury induced by albuminuria.

  6. Tubular overexpression of gremlin induces renal damage susceptibility in mice.

    Directory of Open Access Journals (Sweden)

    Alejandra Droguett

    Full Text Available A growing number of patients are recognized worldwide to have chronic kidney disease. Glomerular and interstitial fibrosis are hallmarks of renal progression. However, fibrosis of the kidney remains an unresolved challenge, and its molecular mechanisms are still not fully understood. Gremlin is an embryogenic gene that has been shown to play a key role in nephrogenesis, and its expression is generally low in the normal adult kidney. However, gremlin expression is elevated in many human renal diseases, including diabetic nephropathy, pauci-immune glomerulonephritis and chronic allograft nephropathy. Several studies have proposed that gremlin may be involved in renal damage by acting as a downstream mediator of TGF-β. To examine the in vivo role of gremlin in kidney pathophysiology, we generated seven viable transgenic mouse lines expressing human gremlin (GREM1 specifically in renal proximal tubular epithelial cells under the control of an androgen-regulated promoter. These lines demonstrated 1.2- to 200-fold increased GREM1 expression. GREM1 transgenic mice presented a normal phenotype and were without proteinuria and renal function involvement. In response to the acute renal damage cause by folic acid nephrotoxicity, tubule-specific GREM1 transgenic mice developed increased proteinuria after 7 and 14 days compared with wild-type treated mice. At 14 days tubular lesions, such as dilatation, epithelium flattening and hyaline casts, with interstitial cell infiltration and mild fibrosis were significantly more prominent in transgenic mice than wild-type mice. Tubular GREM1 overexpression was correlated with the renal upregulation of profibrotic factors, such as TGF-β and αSMA, and with increased numbers of monocytes/macrophages and lymphocytes compared to wild-type mice. Taken together, our results suggest that GREM1-overexpressing mice have an increased susceptibility to renal damage, supporting the involvement of gremlin in renal damage

  7. Oral Pirfenidone in patients with chronic fibrosis resulting from radiotherapy: a pilot study

    International Nuclear Information System (INIS)

    Simone, Nicole L; Soule, Benjamin P; Gerber, Lynn; Augustine, Elizabeth; Smith, Sharon; Altemus, Rosemary M; Mitchell, James B; Camphausen, Kevin A

    2007-01-01

    Fibrosis is a common side effect after treatment with ionizing radiation. Several methods to ameliorate debilitating fibrosis have been employed but without consistent results. The goal of this pilot study is to determine if Pirfenidone, a novel regulator of cytokine gene expression, has the potential to ameliorate established radiation-induced fibrosis. Open label, prospective pilot study of 800 mg three times/day, orally administered Pirfenidone was administered to enrolled patients who were had completed radiation therapy and who had established radiation-induced fibrosis. Range of motion (ROM) was assessed using standard measures, and subjective measures of pain, fatigue, disability and global health were measured every three months. Seven patients were enrolled of whom 3 had ROM assessments of 1 site and 2 had ROM assessments of 2 sites. Of these assessments, 6 revealed increased ROM during drug intervention while 1 revealed a decreased ROM. There was an overall improvement in the mental composite score of the SF36 while physical composite score was decreased and the vitality score was unchanged. Two patients were removed from the study because of syncopal episodes. Several patients experienced improved function of at least 25% and reported subjective improvement. Pirfenidone may benefit patients with radiation-induced fibrosis and is worthy of a larger well controlled trial

  8. Comparison of trichostatin A and valproic acid treatment regimens in a mouse model of kidney fibrosis

    International Nuclear Information System (INIS)

    Van Beneden, Katrien; Geers, Caroline; Pauwels, Marina; Mannaerts, Inge; Wissing, Karl M.; Van den Branden, Christiane; Grunsven, Leo A. van

    2013-01-01

    Histone deacetylase (HDAC) inhibitors are promising new compounds for the therapy of fibrotic diseases. In this study we compared the effect of two HDAC inhibitors, trichostatin A and valproic acid, in an experimental model of kidney fibrosis. In mice, doxorubicin (adriamycin) can cause nephropathy characterized by chronic proteinuria, glomerular damage and interstitial inflammation and fibrosis, as seen in human focal segmental glomerulosclerosis. Two treatment regimens were applied, treatment was either started prior to the doxorubicin insult or delayed until a significant degree of proteinuria and fibrosis was present. Pre-treatment of trichostatin A significantly hampered glomerulosclerosis and tubulointerstitial fibrosis, as did the pre-treatment with valproic acid. In contrast, the development of proteinuria was only completely inhibited in the pre-treated valproic acid group, and not in the pre-treated trichostatin A animals. In the postponed treatment with valproic acid, a complete resolution of established doxorubicin-induced proteinuria was achieved within three days, whereas trichostatin A could not correct proteinuria in such a treatment regimen. However, both postponed regimens have comparable efficacy in maintaining the kidney fibrosis to the level reached at the start of the treatments. Moreover, not only the process of fibrosis, but also renal inflammation was attenuated by both HDAC inhibitors. Our data confirm a role for HDACs in renal fibrogenesis and point towards a therapeutic potential for HDAC inhibitors. The effect on renal disease progression and manifestation can however be different for individual HDAC inhibitors. - Highlights: • Valproic acid is a potent antiproteinuric drug, whereas trichostatin A is not. • Trichostatin A and valproic acid reduce kidney fibrosis in doxorubicin nephropathy. • Both valproic acid and trichostatin A attenuate renal inflammation

  9. Comparison of trichostatin A and valproic acid treatment regimens in a mouse model of kidney fibrosis

    Energy Technology Data Exchange (ETDEWEB)

    Van Beneden, Katrien, E-mail: kvbenede@vub.ac.be [Department of Human Anatomy, Liver Cell Biology Lab, Vrije Universiteit Brussel, Brussels (Belgium); Geers, Caroline [Department of Pathology, Universitair Ziekenhuis Brussel, Brussels (Belgium); Pauwels, Marina [Department of Human Anatomy, Liver Cell Biology Lab, Vrije Universiteit Brussel, Brussels (Belgium); Mannaerts, Inge [Department of Cell Biology, Liver Cell Biology Lab, Vrije Universiteit Brussel, Brussels (Belgium); Wissing, Karl M. [Department of Nephrology, Universitair Ziekenhuis Brussel, Brussels (Belgium); Van den Branden, Christiane [Department of Human Anatomy, Liver Cell Biology Lab, Vrije Universiteit Brussel, Brussels (Belgium); Grunsven, Leo A. van, E-mail: lvgrunsv@vub.ac.be [Department of Cell Biology, Liver Cell Biology Lab, Vrije Universiteit Brussel, Brussels (Belgium)

    2013-09-01

    Histone deacetylase (HDAC) inhibitors are promising new compounds for the therapy of fibrotic diseases. In this study we compared the effect of two HDAC inhibitors, trichostatin A and valproic acid, in an experimental model of kidney fibrosis. In mice, doxorubicin (adriamycin) can cause nephropathy characterized by chronic proteinuria, glomerular damage and interstitial inflammation and fibrosis, as seen in human focal segmental glomerulosclerosis. Two treatment regimens were applied, treatment was either started prior to the doxorubicin insult or delayed until a significant degree of proteinuria and fibrosis was present. Pre-treatment of trichostatin A significantly hampered glomerulosclerosis and tubulointerstitial fibrosis, as did the pre-treatment with valproic acid. In contrast, the development of proteinuria was only completely inhibited in the pre-treated valproic acid group, and not in the pre-treated trichostatin A animals. In the postponed treatment with valproic acid, a complete resolution of established doxorubicin-induced proteinuria was achieved within three days, whereas trichostatin A could not correct proteinuria in such a treatment regimen. However, both postponed regimens have comparable efficacy in maintaining the kidney fibrosis to the level reached at the start of the treatments. Moreover, not only the process of fibrosis, but also renal inflammation was attenuated by both HDAC inhibitors. Our data confirm a role for HDACs in renal fibrogenesis and point towards a therapeutic potential for HDAC inhibitors. The effect on renal disease progression and manifestation can however be different for individual HDAC inhibitors. - Highlights: • Valproic acid is a potent antiproteinuric drug, whereas trichostatin A is not. • Trichostatin A and valproic acid reduce kidney fibrosis in doxorubicin nephropathy. • Both valproic acid and trichostatin A attenuate renal inflammation.

  10. Renal scan

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/003790.htm Renal scan To use the sharing features on this ... anaphylaxis . Alternative Names Renogram; Kidney scan Images Kidney anatomy Kidney - blood and urine flow References Chernecky CC, ...

  11. Retroperitoneal fibrosis with pancreatic involvement – radiological appearance

    International Nuclear Information System (INIS)

    Zielonko, Joanna; Obołończyk, Łukasz

    2011-01-01

    Retroperitoneal fibrosis or Ormond’s disease is an uncommon process characterized by fibrous tissue proliferation in the retroperitoneum, usually involving the aorta, inferior vena cava and iliac vessels. Obstructive hydronephrosis is often observed due to ureteral entrapment. This report presents a case of the peripancreatic location of the disease. The role of CT and MRI in establishing diagnosis of retroperitoneal fibrosis in an atypical site is discussed. A 52-year-old woman with Hashimoto’s thyroiditis was admitted to hospital because of pain suggesting renal colic. The patient was subjected to ultrasound, CT, and MRI which did not confirm urolithiasis but revealed pancreatic infiltration. Partial pancreatectomy, left-sided adrenalectomy and splenectomy were performed. Retroperitoneal fibrosis was diagnosed in the histopathological examination. A few weeks after surgery, a complication such as pancreatitis developed. Repeat CT confirmed it and showed right hydronephrosis secondary to ureteral involvement by a mass adjacent to the common iliac artery (defined as a typical manifestation of retroperitoneal fibrosis). Nephrostomy and conservative treatment improved the clinical state of the patient. No progression of the process was observed in the follow-up examinations. Atypical retroperitoneal fibrosis remains a diagnostic challenge. Imaging techniques CT and MRI are useful tools for evaluating the extent of Ormond’s disease. An unusual distribution of the process (e.g. peripancreatic location reported in this study) requires histopathological assessment to establish the final diagnosis

  12. Renal Hemangiopericytoma

    Directory of Open Access Journals (Sweden)

    İbrahim Halil Bozkurt

    2015-03-01

    Full Text Available Hemangiopericytoma is an uncommon perivascular tumor originating from pericytes in the pelvis, head and tneck, and the meninges; extremely rarely in the urinary system. We report a case of incidentally detected renal mass in which radiologic evaluation was suggestive of renal cell carcinoma. First, we performed partial nephrectomy, and then, radical nephrectomy because of positive surgical margins and the pathological examination of the surgical specimen that revealed a hemangiopericytoma. No additional treatment was administered.

  13. Placental extract ameliorates non-alcoholic steatohepatitis (NASH by exerting protective effects on endothelial cells

    Directory of Open Access Journals (Sweden)

    Akihiro Yamauchi

    2017-09-01

    Full Text Available Non-alcoholic steatohepatitis (NASH is a severe form of fatty liver disease that is defined by the presence of inflammation and fibrosis, ultimately leading to cirrhosis and hepatocellular carcinoma. Treatment with human placental extract (HPE reportedly ameliorates the hepatic injury. We evaluated the effect of HPE treatment in a mouse model of NASH. In the methione- and choline-deficient (MCD diet-induced liver injury model, fibrosis started from regions adjacent to the sinusoids. We administered the MCD diet with high-salt loading (8% NaCl in the drinking water to mice deficient in the vasoprotective molecule RAMP2 for 5 weeks, with or without HPE. In both the HPE and control groups, fibrosis was seen in regions adjacent to the sinusoids, but the fibrosis was less pronounced in the HPE-treated mice. Levels of TNF-α and MMP9 expression were also significantly reduced in HPE-treated mice, and oxidative stress was suppressed in the perivascular region. In addition, HPE dose-dependently increased survival of cultured endothelial cells exposed to 100 μM H2O2, and it upregulated expression of eNOS and the anti-apoptotic factors bcl-2 and bcl-xL. From these observations, we conclude that HPE ameliorates NASH-associated pathologies by suppressing inflammation, oxidative stress and fibrosis. These beneficially effects of HPE are in part attributable to its protective effects on liver sinusoidal endothelial cells. HPE could thus be an attractive therapeutic candidate with which to suppress progression from simple fatty liver to NASH.

  14. Hibiscus sabdariffa polyphenols alleviate insulin resistance and renal epithelial to mesenchymal transition: a novel action mechanism mediated by type 4 dipeptidyl peptidase.

    Science.gov (United States)

    Peng, Chiung-Huei; Yang, Yi-Sun; Chan, Kuei-Chuan; Wang, Chau-Jong; Chen, Mu-Lin; Huang, Chien-Ning

    2014-10-08

    The epithelial to mesenchymal transition (EMT) is important in renal fibrosis. Ser307 phosphorylation of insulin receptor substrate-1 (IRS-1 (S307)) is a hallmark of insulin resistance. We report that polyphenol extracts of Hibiscus sabdariffa (HPE) ameliorate diabetic nephropathy and EMT. Recently it has been observed that type 4 dipeptidyl peptidase (DPP-4) inhibitor linagliptin is effective for treating type 2 diabetes and albuminuria. We investigated if DPP-4 and insulin resistance are involved in renal EMT and explored the role of HPE. In high glucose-stimulated tubular cells, HPE, like linagliptin, inhibited DPP-4 activation, thereby regulating vimentin (EMT marker) and IRS-1 (S307). IRS-1 knockdown revealed its essential role in mediating downstream EMT. In type 2 diabetic rats, pIRS-1 (S307) abundantly surrounds the tubular region, with increased vimentin in kidney. Both the expressions were reduced by HPE. In conclusion, HPE exerts effects similar to those of linagliptin, which improves insulin resistance and EMT, and could be an adjuvant to prevent diabetic nephropathy.

  15. Renal albumin absorption in physiology and pathology.

    Science.gov (United States)

    Birn, H; Christensen, E I

    2006-02-01

    Albumin is the most abundant plasmaprotein serving multiple functions as a carrier of metabolites, hormones, vitamins, and drugs, as an acid/base buffer, as antioxidant and by supporting the oncotic pressure and volume of the blood. The presence of albumin in urine is considered to be the result of the balance between glomerular filtration and tubular reabsorption. Albuminuria has been accepted as an independent risk factor and a marker for renal as well as cardiovascular disease, and during the past decade, evidence has suggested that albumin itself may cause progression of renal disease. Thus, the reduction of proteinuria and, in particular, albuminuria has become a target in itself to prevent deterioration of renal function. Studies have shown albumin and its ligands to induce expression of inflammatory and fibrogenic mediators, and it has been hypothesized that increased filtration of albumin causes excessive tubular reabsorption, resulting in inflammation and fibrosis, resulting in the loss of renal function. In addition, it is known that tubular dysfunction in itself may cause albuminuria owing to decreased reabsorption of filtered albumin, and, recently, it has been suggested that significant amounts of albumin fragments are excreted in the urine as a result of tubular degradation. Thus, although both tubular and glomerular dysfunction influences renal handling of albumin, it appears that tubular reabsorption plays a central role in mediating the effects of albumin on renal function. The present paper will review the mechanisms for tubular albumin uptake and the possible implications for the development of renal disease.

  16. Blockade of Death Ligand TRAIL Inhibits Renal Ischemia Reperfusion Injury

    International Nuclear Information System (INIS)

    Adachi, Takaomi; Sugiyama, Noriyuki; Gondai, Tatsuro; Yagita, Hideo; Yokoyama, Takahiko

    2013-01-01

    Renal ischemia-reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI). Many investigators have reported that cell death via apoptosis significantly contributed to the pathophysiology of renal IRI. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor superfamily, and induces apoptosis and inflammation. However, the role of TRAIL in renal IRI is unclear. Here, we investigated whether TRAIL contributes to renal IRI and whether TRAIL blockade could attenuate renal IRI. AKI was induced by unilateral clamping of the renal pedicle for 60 min in male FVB/N mice. We found that the expression of TRAIL and its receptors were highly upregulated in renal tubular cells in renal IRI. Neutralizing anti-TRAIL antibody or its control IgG was given 24 hr before ischemia and a half-dose booster injection was administered into the peritoneal cavity immediately after reperfusion. We found that TRAIL blockade inhibited tubular apoptosis and reduced the accumulation of neutrophils and macrophages. Furthermore, TRAIL blockade attenuated renal fibrosis and atrophy after IRI. In conclusion, our study suggests that TRAIL is a critical pathogenic factor in renal IRI, and that TRAIL could be a new therapeutic target for the prevention of renal IRI

  17. Effect of Shenkang injection combined with hemodialysis treatment on renal function, renal anemia and cytokine levels in patients with chronic renal failure

    Directory of Open Access Journals (Sweden)

    Rui Liu

    2016-10-01

    Full Text Available Objective: To study the effect of Shenkang injection combined with hemodialysis treatment on renal function, renal anemia and cytokine levels in patients with chronic renal failure. Methods: A total of 68 patients with chronic renal failure who received hemodialysis treatment in our hospital during between October 2013 and February 2016 were selected and randomly divided into two groups, the observation group received Shenkang injection treatment in the process of dialysis, and the control group only received conventional symptomatic and supportive treatment. 8 weeks after treatment, serum was collected to determine the levels of renal function indexes, nutritional status indexes, anemia indexes and cytokines, and urine was collected to determine renal function indexes. Results: β2-MG, UA, Cr, phosphorus, IL-17, IL-23, CTGF, TGF-β1, FGF-2 and FGF-23 levels in serum as well as NGAL, KIM-1 and RBP levels in urine of observation group were significantly lower than those of control group, and TP, Alb, PA, calcium, Hb, EPO, Fe, TRF and FER levels in serum were significantly higher than those of control group. Conclusion: Shenkang injection combined with hemodialysis treatment helps to improve renal function, nutritional status and renal anemia, and reduce the synthesis of inflammation and renal interstitial fibrosis-related cytokines in patients with chronic renal failure.

  18. Inhibiting core fucosylation attenuates glucose-induced peritoneal fibrosis in rats.

    Science.gov (United States)

    Li, Longkai; Shen, Nan; Wang, Nan; Wang, Weidong; Tang, Qingzhu; Du, Xiangning; Carrero, Juan Jesus; Wang, Keping; Deng, Yiyao; Li, Zhitong; Lin, Hongli; Wu, Taihua

    2018-06-01

    Ultrafiltration failure is a major complication of long-term peritoneal dialysis, resulting in dialysis failure. Peritoneal fibrosis induced by continuous exposure to high glucose dialysate is the major contributor of ultrafiltration failure, for which there is no effective treatment. Overactivation of several signaling pathways, including transforming growth factor-β1 (TGF-β1) and platelet-derived growth factor (PDGF) pathways, contribute to the development of peritoneal fibrosis. Therefore, simultaneously blocking multiple signaling pathways might be a potential novel method of treating peritoneal fibrosis. Previously, we showed that core fucosylation, an important posttranslational modification of the TGF-β1 receptors, can regulate the activation of TGF-β1 signaling in renal interstitial fibrosis. However, it remains unclear whether core fucosylation affects the progression of peritoneal fibrosis. Herein, we show that core fucosylation was enriched in the peritoneal membrane of rats accompanied by peritoneal fibrosis induced by a high glucose dialysate. Blocking core fucosylation dramatically attenuated peritoneal fibrosis in the rat model achieved by simultaneously inactivating the TGF-β1 and PDGF signaling pathways. Next the protective effects of blocking core fucosylation and imatinib (a selective PDGF receptor inhibitor) on peritoneal fibrosis were compared and found to exhibit a greater inhibitory effect over imatinib alone, suggesting that blocking activation of multiple signaling pathways may have superior inhibitory effects on the development of peritoneal fibrosis. Thus, core fucosylation is essential for the development of peritoneal fibrosis by regulating the activation of multiple signaling pathways. This may be a potential novel target for drug development to treat peritoneal fibrosis. Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

  19. An epidemic outbreak of nephrogenic systemic fibrosis in a Danish hospital

    International Nuclear Information System (INIS)

    Marckmann, Peter

    2008-01-01

    The nephrological department of Copenhagen University Hospital Herlev experienced an epidemic accumulation of patients developing nephrogenic systemic fibrosis in the period 2002-2006. Systematic studies of these patients revealed that they all had a gadodiamide-enhanced magnetic resonance examination prior to their symptoms, and that they all had severe renal insufficiency (chronic kidney disease stage 5) at the time of their exposure to gadodiamide. Besides exposure to gadodiamide, our analyses indicated that increasing cumulative gadodiamide exposure (i.e. repeated exposures), and higher serum concentrations of ionized calcium and phosphate were cofactors that raised the risk of developing nephrogenic systemic fibrosis. Higher cumulative gadodiamide exposure, higher prescribed erythropoietin dosage at exposure, and being hemodialysis patient were three factors associated with nephrogenic systemic fibrosis in its most severe form. Retrospective reviews of patients records and patient interviews revealed the large variability in symptoms and clinical course of nephrogenic systemic fibrosis, but also highlighted that the typical initial symptoms were symmetric swelling, discoloration and pain of lower legs, whereas the typical late symptoms of severely affected patients were skin thickening, stiffness, contractures, and debilitating disabilities. In conclusion, nephrogenic systemic fibrosis is a serious iatrogenic disease of patients with renal insufficiency caused by some Gd-containing contrast agents, in particular gadodiamide. Unfortunately, there is no proven curative treatment. It is therefore essential that future cases of nephrogenic systemic fibrosis are prevented

  20. Expression of hypoxia-inducible factor-1α and hepatocyte growth factor in development of fibrosis in the transplanted kidney

    DEFF Research Database (Denmark)

    Kellenberger, Terese; Marcussen, Niels; Nyengaard, Jens Randel

    2014-01-01

    Late renal graft loss is associated with interstitial fibrosis. Hypoxia-inducible factor-1α (HIF-1α) is thought to facilitate fibrosis through interaction with TGF-β1, while hepatocyte growth factor (HGF) may act antifibrotic in the kidney allograft. The aim of this study was to investigate...... transplantation, but an inverse significant correlation between the HGF expression and the fibrosis score 1 year after transplantation was shown. Even when adjusting for human leucocyte antigen mismatches, there was a significant relationship between fibrosis and HGF expression. Graft survival...... was not significantly correlated to HIF-1α or HGF at 1 year, although the trend was towards better graft survival with high HGF. HGF may have antifibrotic effects in human renal transplants. (Central.Denmark.Region.Committee number: 1-10-72-318-13)....

  1. Nephrogenic systemic fibrosis: late skin manifestations

    DEFF Research Database (Denmark)

    Bangsgaard, Nannie; Marckmann, Peter; Rossen, Kristian

    2009-01-01

    BACKGROUND: Nephrogenic systemic fibrosis (NSF) is a serious disease that occurs in patients with severe renal disease and is believed to be caused by gadolinium-containing contrast agents. A detailed description of the late skin manifestations of NSF is important to help dermatologists...... and nephrologists recognize the disease. OBSERVATIONS: We studied 17 patients with NSF late in the disease. All patients showed epidermal atrophy and hairlessness of the affected regions, primarily the lower legs. Affected areas were symmetrically distributed and hyperpigmented in most cases. Eleven patients showed......: This descriptive case series of patients with NSF gives a detailed clinical picture of the skin manifestations late in the disease. It demonstrates that the clinical picture in the late stage has a varied presentation and that NSF has a significant effect on the quality of life....

  2. Current status of nephrogenic systemic fibrosis

    International Nuclear Information System (INIS)

    Daftari Besheli, L.; Aran, S.; Shaqdan, K.; Kay, J.; Abujudeh, H.

    2014-01-01

    Nephrogenic systemic fibrosis (NSF) occurs in patients with advanced chronic kidney disease (CKD) or acute renal failure, most commonly following exposure to gadolinium-based contrast agents (GBCAs). NSF can be debilitating and associated with increased mortality. The putative association of NSF with GBCAs prompted the development of guidelines to limit the use of these contrast agents in at-risk patients. Indeed, the incidence of NSF has decreased dramatically following application of these guidelines, which appears to be the only effective means of decreasing NSF incidence. Thus, increasing clinician awareness of these updated guidelines is important. The present review introduces and compares updated guidelines for GBCA use and discusses the latest advances in the understanding of the pathogenic mechanisms and treatment of NSF

  3. Baicalin Ameliorates Experimental Liver Cholestasis in Mice by Modulation of Oxidative Stress, Inflammation, and NRF2 Transcription Factor

    Directory of Open Access Journals (Sweden)

    Kezhen Shen

    2017-01-01

    Full Text Available Experimental cholestatic liver fibrosis was performed by bile duct ligation (BDL in mice, and significant liver injury was observed in 15 days. Administration of baicalin in mice significantly ameliorates liver fibrosis. Experimental cholestatic liver fibrosis was associated with induced gene expression of fibrotic markers such as collagen I, fibronectin, alpha smooth muscle actin (SMA, and connective tissue growth factor (CTGF; increased inflammatory cytokines (TNFα, MIP1α, IL1β, and MIP2; increased oxidative stress and reactive oxygen species- (ROS- inducing enzymes (NOX2 and iNOS; dysfunctional mitochondrial electron chain complexes; and apoptotic/necrotic cell death markers (DNA fragmentation, caspase 3 activity, and PARP activity. Baicalin administration on alternate day reduced fibrosis along with profibrotic gene expression, proinflammatory cytokines, oxidative stress, and cell death whereas improving the function of mitochondrial electron transport chain. We observed baicalin enhanced NRF2 activation by nuclear translocation and induced its target genes HO-1 and GCLM, thus enhancing antioxidant defense. Interplay of oxidative stress/inflammation and NRF2 were key players for baicalin-mediated protection. Stellate cell activation is crucial for initiation of fibrosis. Baicalin alleviated stellate cell activation and modulated TIMP1, SMA, collagen 1, and fibronectin in vitro. This study indicates that baicalin might be beneficial for reducing inflammation and fibrosis in liver injury models.

  4. Imaging findings in congenital hepatic fibrosis

    International Nuclear Information System (INIS)

    Akhan, Okan; Karaosmanoglu, Ali Devrim; Ergen, Bilge

    2007-01-01

    Congenital hepatic fibrosis (CHF) is a rare congenital multisystemic disorder, mostly inherited in autosomal recessive fashion, primarily affecting renal and hepatobiliary systems. Main underlying process of the disease is the malformation of the ductal plate, the embryological precursor of the biliary system, and secondary biliary strictures and periportal fibrosis ultimately leading to portal hypertension. The natural course of the disease is highly variable ranging from minimally symptomatic disease to true cirrhosis of the liver. However, in most patients the most common manifestations of the diseases that are related to portal hypertension, particularly splenomegaly and bleeding varices. Many other disease processes may co-exist with the disease including Caroli's disease, choledochal cysts and autosomal recessive polycystic kidney disease (ARPKD) reflecting the mulstisystemic nature of the disease. The associating biliary ductal disease led the authors to think that all these entities are a continuum and different reflections of the same underlying pathophysiological process. Although, conventional method of diagnosis of CHF is the liver biopsy the advent of imaging technologies and modalities, today, may permit the correct diagnosis in a non-invasive manner. Characteristic imaging features are generally present and recognition of these findings may obviate liver biopsy while preserving the diagnostic accuracy. In this article, it is aimed to increase the awareness of the practising radiologists to the imaging findings of this uncommon clinical disorder and trail the blaze for future articles relating to this issue

  5. Imaging findings in congenital hepatic fibrosis

    Energy Technology Data Exchange (ETDEWEB)

    Akhan, Okan [Department of Radiology, Hacettepe University, School of Medicine, 06100 Ankara (Turkey)]. E-mail: akhano@tr.net; Karaosmanoglu, Ali Devrim [Department of Radiology, Hacettepe University, School of Medicine, 06100 Ankara (Turkey); Ergen, Bilge [Department of Radiology, Hacettepe University, School of Medicine, 06100 Ankara (Turkey)

    2007-01-15

    Congenital hepatic fibrosis (CHF) is a rare congenital multisystemic disorder, mostly inherited in autosomal recessive fashion, primarily affecting renal and hepatobiliary systems. Main underlying process of the disease is the malformation of the ductal plate, the embryological precursor of the biliary system, and secondary biliary strictures and periportal fibrosis ultimately leading to portal hypertension. The natural course of the disease is highly variable ranging from minimally symptomatic disease to true cirrhosis of the liver. However, in most patients the most common manifestations of the diseases that are related to portal hypertension, particularly splenomegaly and bleeding varices. Many other disease processes may co-exist with the disease including Caroli's disease, choledochal cysts and autosomal recessive polycystic kidney disease (ARPKD) reflecting the mulstisystemic nature of the disease. The associating biliary ductal disease led the authors to think that all these entities are a continuum and different reflections of the same underlying pathophysiological process. Although, conventional method of diagnosis of CHF is the liver biopsy the advent of imaging technologies and modalities, today, may permit the correct diagnosis in a non-invasive manner. Characteristic imaging features are generally present and recognition of these findings may obviate liver biopsy while preserving the diagnostic accuracy. In this article, it is aimed to increase the awareness of the practising radiologists to the imaging findings of this uncommon clinical disorder and trail the blaze for future articles relating to this issue.

  6. Experimental models of liver fibrosis.

    Science.gov (United States)

    Yanguas, Sara Crespo; Cogliati, Bruno; Willebrords, Joost; Maes, Michaël; Colle, Isabelle; van den Bossche, Bert; de Oliveira, Claudia Pinto Marques Souza; Andraus, Wellington; Alves, Venâncio Avancini Ferreira; Leclercq, Isabelle; Vinken, Mathieu

    2016-05-01

    Hepatic fibrosis is a wound healing response to insults and as such affects the entire world population. In industrialized countries, the main causes of liver fibrosis include alcohol abuse, chronic hepatitis virus infection and non-alcoholic steatohepatitis. A central event in liver fibrosis is the activation of hepatic stellate cells, which is triggered by a plethora of signaling pathways. Liver fibrosis can progress into more severe stages, known as cirrhosis, when liver acini are substituted by nodules, and further to hepatocellular carcinoma. Considerable efforts are currently devoted to liver fibrosis research, not only with the goal of further elucidating the molecular mechanisms that drive this disease, but equally in view of establishing effective diagnostic and therapeutic strategies. The present paper provides a state-of-the-art overview of in vivo and in vitro models used in the field of experimental liver fibrosis research.

  7. Radiation pneumonitis and fibrosis

    International Nuclear Information System (INIS)

    Shopova, V.; Salovsky, P.; Dancheva, V.

    2001-01-01

    The likelihood of toxic pulmonary lesions development as the result of radiation therapy for pulmonary carcinoma and breast cancer is discussed. Two possible forms of radiation induced changes are described, namely: classical radiation pneumonitis (RP) terminating with lung fibrosis circumscribed in the radiation zone, and sporadic RP giving rise to bilateral lymphatic alveolitis and manifestations outside the irradiation field. Attention is called to the fact that chemotherapy augments the risk of toxic lung damage occurrence. A number of markers for early RP diagnosis, including lactate dehydrogenase activity, KL-6, procollagen III, transforming growth factor β, C-reactive protein and partial oxygen pressure are listed. Therapeutic possibilities in coping with RP and pulmonary fibrosis are assayed. Apart from the standard therapeutic approach using corticosteroids and azatioprin, ideas are set forth concerning the application of some antioxidants, angiotensin converting enzyme inhibitors and γ-interferon. It is pointed out that radiation pneumonitis and pulmonary fibrosis treatment has an essential practical bearing on life expectancy and quality of life in a great number of cancer patients. (author)

  8. Radiotherapy of breast fibrosis

    International Nuclear Information System (INIS)

    Heibel, J.H.

    1979-01-01

    In a retrospective study radiotherapy of breast fibrosis in hormone-treated men with histologically confirmed prostate carcinoma was examined. 10 patients had received hormones even before irradiation, 113 obtained hormone administration only after irradiation. The objective size of the glandular body and the overall size of the breast were measured with a special method developed by the author. 46 patients indicated complaints. With hypertrophic mamma and hypertrophic mamilla in 67 examined patients, 127 different symptoms resulted in total. Four patients of the group who had obtained hormones before irradiation, suffered from subjective symptoms. It resulted that radiotherapy of breast fibrosis carried out during hormone treatment is no gynecomastia prophylaxis, that already existent mamma hypertrophies are irreversible, but that existent sensations were notably reduced within 6 months after irradiation therapy. These results indicate the necessity of a radiotherapy of the mamma fibrosis before the hormone treatment is begun. Particularly in cases of higher operative risks, also the possibility of preferring radiotherapy to mastectomy should be fully utilized, in view of adequate or even better therapeutic results. (orig./MG) [de

  9. Serum markers of liver fibrosis

    DEFF Research Database (Denmark)

    Veidal, Sanne Skovgård; Bay-Jensen, Anne-Christine; Tougas, Gervais

    2010-01-01

    -epitopes, may be targeted for novel biochemical marker development in fibrosis. We used the recently proposed BIPED system (Burden of disease, Investigative, Prognostic, Efficacy and Diagnostic) to characterise present serological markers. METHODS: Pubmed was search for keywords; Liver fibrosis, neo......, a systematic use of the neo-epitope approach, i.e. the quantification of peptide epitopes generated from enzymatic cleavage of proteins during extracellular remodeling, may prove productive in the quest to find new markers of liver fibrosis....

  10. "Cystic fibrotics could survive cholera, choleraics could survive cystic fibrosis"; hypothesis that explores new horizons in treatment of cystic fibrosis.

    Science.gov (United States)

    Azimi, Arsalan

    2015-12-01

    Cystic fibrosis, the most common inherited disease of white population, is a disease of CFTR channels, in which mucosal function of many organs especially respiratory tract is impaired. Decreased mucociliary clearance and accumulation of mucus in airways facilitates colonization of infectious microorganisms, followed by infection. Following chronic infection, persistent inflammation ensues, which results in airway remodeling and deterioration of mucociliary clearance and result in a vicious cycle. Here, it is hypothesized that cholera toxin (CT) could ameliorate symptoms of cystic fibrosis as CT could dilute the thickened mucus, improve mucociliary clearance and alleviate airway obstruction. CT strengthens immunity of airway mucosa and it could attenuates bacterial growth and reduce persistency of infection. CT also modulates cellular immune response and it could decrease airway inflammation, hinder airway remodeling and prevent respiratory deterioration. Thereby it is hypothesized that CT could target and ameliorate many of pathophysiologic steps of the disease and it explores new horizons in treatment of CF. Copyright © 2015 Elsevier Ltd. All rights reserved.

  11. 99mTc DMSA scintigraphic findings in renal tuberculosis

    International Nuclear Information System (INIS)

    Moon, Tae Yong; Kim, Kun Il; Yoon, Chi Soon; Lee, Suck Hong; Kim, Byung Soo

    1993-01-01

    Evaluations of residual renal function and the therapeutic effectiveness in renal tuberculosis have largely been dependent on intravenous pyelogram or Contrast-CT scan, even though, exact renal functions are not evaluate with there methods. 99m Tc- DMSA is a radiopharmaceutical that is trapped in the functioning tubular cells of the kidney and therefore, quantitative renal function could be evaluated by insuring the counts of renal radioactivity and concomitant evaluation of renal morphology could be passable with the analog images of the radioactivity. The authors retrospectively analyzed 99mTc-DMSA scans of 75 kidneys of 67 patients with confirmed renal tuberculosis. We classified the morphologies of tuberculous kidneys as 6 types. We classified the morphologies of tuberculous kidneys as 6 types such as the type with small cortical defect, with parenchymal ulcerocavernous lesions, ulcerocavernous fistula to pelvis, mass-like defects, contracted kidney with ureter visualization, and the type with non visualization of kidney, corresponding to the characters of renal tuberculous pathogenesis with abscess formation, ulcerocavernous fistula, and fibrosis, and corresponding to the renal anatomy with parenchyma, and pelvocalyceal collecting system. Their mean residual renal functions measured with 99mTc-DMSA uptake rates were 19.0%,18.4%, 7.9%, 12%, 4.1%, 3.4% respectively

  12. Microengineered in vitro model of cardiac fibrosis through modulating myofibroblast mechanotransduction

    International Nuclear Information System (INIS)

    Zhao, Hui; Li, Xiaokang; Zhao, Shan; Zeng, Yang; Ding, Haiyan; Du, Yanan; Zhao, Long; Sun, Wei

    2014-01-01

    Cardiac fibrosis greatly impairs normal heart function post infarction and there is no effective anti-fibrotic drug developed at present. The current therapies for cardiac infarction mainly take effect by eliminating occlusion in coronary artery by thrombolysis drugs, vascular stent grafting or heart bypass operation, which are capable to provide sufficient blood flow for intact myocardium yet showed subtle efficacy in ameliorating fibrosis condition. The advances of in vitro cell/tissue models open new avenues for drug assessment due to the low cost, good controllability and availability as well as the convenience for operation as compared to the animal models. To our knowledge, no proper biomimetic in vitro cardiac fibrosis model has been reported yet. Here we engineered an in vitro cardiac fibrosis model using heart-derived fibroblasts, and the fibrogenesis was recapitulated by patterning the substrate rigidity which mimicked the mechanical heterogeneity of myocardium post-infarction. Various biomarkers for cardiac fibrosis were assayed to validate the biomimicry of the engineered platform. Subsequent addition of Rho-associated protein kinase (ROCK) pathway inhibitor reduced the ratio of myofibroblasts, indicating the feasibility of applying this platform in screening anti-fibrosis drugs. (paper)

  13. Hyponatremia-associated rhabdomyolysis following exercise in an adolescent with cystic fibrosis.

    Science.gov (United States)

    Kaskavage, Jillian; Sklansky, Daniel

    2012-07-01

    Adolescents with well-controlled cystic fibrosis, including good lung function and appropriate growth, commonly participate in competitive athletic activities. We present the case of an adolescent male with cystic fibrosis, hyponatremia, dehydration, and rhabdomyolysis after participating in football practice on a summer morning. The patient presented with severe myalgia and serum sodium of 129 mmol/L, chloride 90 mmol/L, and creatine phosphokinase 1146 U/L. Aggressive hydration with intravenous 0.9% saline resulted in clinical improvement with no renal or muscular sequelae. Health care providers need to educate patients with cystic fibrosis about maintaining adequate hydration and sodium repletion during exercise. Research is needed regarding the appropriate amount and composition of oral rehydration fluids in exercising individuals with cystic fibrosis, as the physiology encountered in these patients provides a unique challenge to maintaining electrolyte balance and stimulation of thirst.

  14. Renal Protective Effects of Low Molecular Weight of Inonotus obliquus Polysaccharide (LIOP on HFD/STZ-Induced Nephropathy in Mice

    Directory of Open Access Journals (Sweden)

    Yen-Jung Chou

    2016-09-01

    Full Text Available Diabetic nephropathy (DN is the leading cause of end-stage renal disease in diabetes mellitus. Oxidative stress, insulin resistance and pro-inflammatory cytokines have been shown to play an important role in pathogeneses of renal damage on type 2 diabetes mellitus (DM. Inonotus obliquus (IO is a white rot fungus that belongs to the family Hymenochaetaceae; it has been used as an edible mushroom and exhibits many biological activities including anti-tumor, anti-oxidant, anti-inflammatory and anti-hyperglycemic properties. Especially the water-soluble Inonotus obliquus polysaccharides (IOPs have been previously reported to significantly inhibit LPS-induced inflammatory cytokines in mice and protect from streptozotocin (STZ-induced diabetic rats. In order to identify the nephroprotective effects of low molecular weight of IOP fraction (LIOP, from the fruiting bodies of Inonotus obliquus, high-fat diet (HFD plus STZ-induced type 2-like diabetic nephropathy C57BL/6 mice were investigated in this study. Our data showed that eight weeks of administration of 10–100 kDa, LIOP (300 mg/kg had progressively increased their sensitivity to glucose (less insulin tolerance, reduced triglyceride levels, elevated the HDL/LDL ratio and decreased urinary albumin/creatinine ratio(ACR compared to the control group. By pathological and immunohistochemical examinations, it was indicated that LIOP can restore the integrity of the glomerular capsules and increase the numbers of glomerular mesangial cells, associated with decreased expression of TGF-β on renal cortex in mice. Consistently, three days of LIOP (100 μg/mL incubation also provided protection against STZ + AGEs-induced glucotoxicity in renal tubular cells (LLC-PK1, while the levels of NF-κB and TGF-β expression significantly decreased in a dose-dependent manner. Our findings demonstrate that LIOP treatment could ameliorate glucolipotoxicity-induced renal fibrosis, possibly partly via the inhibition of NF

  15. Leptospira Interrogans Induces Fibrosis in the Mouse Kidney through Inos-Dependent, TLR- and NLR-Independent Signaling Pathways

    Science.gov (United States)

    Fanton d'Andon, Martine; Quellard, Nathalie; Fernandez, Béatrice; Ratet, Gwenn; Lacroix-Lamandé, Sonia; Vandewalle, Alain; Boneca, Ivo G.; Goujon, Jean-Michel; Werts, Catherine

    2014-01-01

    Background Leptospira (L.) interrogans are bacteria responsible for a worldwide reemerging zoonosis. Rodents carry L. interrogans asymptomatically in their kidneys and excrete bacteria in the urine, contaminating the environment. Humans get infected through skin contact and develop a mild or severe leptospirosis that may lead to renal failure and fibrosis. L. interrogans provoke an interstitial nephritis, but the induction of fibrosis caused by L. interrogans has not been studied in murine models. Innate immune receptors from the TLR and NLR families have recently been shown to play a role in the development and progression of tissue fibrosis in the lung, liver and kidneys under different pathophysiological situations. We recently showed that TLR2, TLR4, and NLRP3 receptors were crucial in the defense against leptospirosis. Moreover, infection of a human cell line with L. interrogans was shown to induce TLR2-dependent production of fibronectin, a component of the extracellular matrix. Therefore, we thought to assess the presence of renal fibrosis in L. interrogans infected mice and to analyze the contribution of some innate immune pathways in this process. Methodology/principal findings Here, we characterized by immunohistochemical studies and quantitative real-time PCR, a model of Leptospira-infected C57BL/6J mice, with chronic carriage of L. interrogans inducing mild renal fibrosis. Using various strains of transgenic mice, we determined that the renal infiltrates of T cells and, unexpectedly, TLR and NLR receptors, are not required to generate Leptospira-induced renal fibrosis. We also show that the iNOS enzyme, known to play a role in Leptospira-induced interstitial nephritis, also plays a role in the induction of renal fibrosis. Conclusion/significance To our knowledge, this work provides the first experimental murine model of sustained renal fibrosis induced by a chronic bacterial infection that may be peculiar, since it does not rely on TLR or NLR receptors

  16. Higher Anti-Liver Fibrosis Effect of Cordyceps militaris-Fermented Product Cultured with Deep Ocean Water via Inhibiting Proinflammatory Factors and Fibrosis-Related Factors Expressions

    Directory of Open Access Journals (Sweden)

    Yu-Ping Hung

    2017-06-01

    Full Text Available Deep ocean water (DOW has been shown to enhance the functional components of fungi, resulting in increased health benefits. Therefore, using DOW for culturing fungi can enhance the cordycepin and adenosine of Cordyceps militaris (CM and its protective effects on the liver. In this study, the antiliver fibrosis effects and mechanisms of ultrapure water-cultured CM (UCM, DOW-cultured CM (DCM, synthetic water-cultured CM, DOW, cordycepin, and adenosine were compared in the liver fibrosis mice induced by intraperitoneal injections of thioacetamide (TAA. The results indicated that DCM exhibited superior performance in reducing liver collagen accumulation, mitigating liver injuries, inhibiting proinflammatory factors and fibrosis-related factor (TGF-β1, Smad2/3, α-SMA, COL1A1 expression compared with UCM. DOW, cordycepin, and adenosine also performed antiliver fibrosis effect. Therefore, because DCM is rich in DOW and functional components, it can achieve anti-liver fibrosis effects through multiple pathways. These ameliorative effects are considerably superior to those of UCM.

  17. Higher Anti-Liver Fibrosis Effect of Cordyceps militaris-Fermented Product Cultured with Deep Ocean Water via Inhibiting Proinflammatory Factors and Fibrosis-Related Factors Expressions.

    Science.gov (United States)

    Hung, Yu-Ping; Lee, Chun-Lin

    2017-06-08

    Deep ocean water (DOW) has been shown to enhance the functional components of fungi, resulting in increased health benefits. Therefore, using DOW for culturing fungi can enhance the cordycepin and adenosine of Cordyceps militaris (CM) and its protective effects on the liver. In this study, the antiliver fibrosis effects and mechanisms of ultrapure water-cultured CM (UCM), DOW-cultured CM (DCM), synthetic water-cultured CM, DOW, cordycepin, and adenosine were compared in the liver fibrosis mice induced by intraperitoneal injections of thioacetamide (TAA). The results indicated that DCM exhibited superior performance in reducing liver collagen accumulation, mitigating liver injuries, inhibiting proinflammatory factors and fibrosis-related factor (TGF-β1, Smad2/3, α-SMA, COL1A1) expression compared with UCM. DOW, cordycepin, and adenosine also performed antiliver fibrosis effect. Therefore, because DCM is rich in DOW and functional components, it can achieve anti-liver fibrosis effects through multiple pathways. These ameliorative effects are considerably superior to those of UCM.

  18. Imaging from cystic fibrosis

    International Nuclear Information System (INIS)

    Schmidt, H.; Posselt, H.G.

    2008-01-01

    Cystic fibrosis (CF) is the most frequent metabolic disorder with autosomal recessive inheritance in the Caucasian population. The gene defect is located on the long arm of chromosome 7. In Germany today, the actual median survival is 37 years. The genetic defect caused by chloride anion disturbances affects multiple body systems but the morbidity and mortality is due to lung disease. The secretion of highly viscous mucus promotes viral and bacterial pulmonary infections leading to airway obstruction and consecutive destruction of the lung parenchyma. This article will review and discuss both the clinical aspects of the disease and the diagnostic methods, referring in particular to new imaging strategies. (orig.)

  19. Renal candidiasis

    International Nuclear Information System (INIS)

    Khanna, S.; Malik, N.; Khandelwal, N.

    1990-01-01

    Most fungal infections of the urinary tract are caused by Candida albicans, a yeast-like saprophytic fungus which may become apathogen under various conditions which lower the host resistance. The use of computed tomography in the diagnosis of renal fungus balls is the subject of this communication with emphasis on the radiologists role in the recognition of this entity. (H.W.). 6 refs.; 2 figs

  20. Renal hemangioma

    Directory of Open Access Journals (Sweden)

    Theodorico F. da Costa Neto

    2004-06-01

    Full Text Available INTRODUCTION: Renal hemangioma is a relatively rare benign tumor, seldom diagnosed as a cause of hematuria. CASE REPORT: A female 40-year old patient presented with continuous gross hematuria, anemia and episodic right lumbar pain, with onset about 3 months previously. The patient underwent multiple blood transfusions during her hospital stay and extensive imaging propedeutics was performed. Semi-rigid ureterorenoscopy evidenced a bleeding focus in the upper calix of the right kidney, with endoscopic treatment being unfeasible. The patient underwent right upper pole nephrectomy and presented a favorable outcome. Histopathological analysis of the surgical specimen showed that it was a renal hemangioma. COMMENTS: Imaging methods usually employed for diagnostic investigation of hematuria do not have good sensitivity for renal hemangioma. However, they are important to exclude the most frequent differential diagnoses. The ureterorenoscopy is the diagnostic method of choice and endoscopic treatment can be feasible when the lesion is accessible and electrocautery or laser are available. We emphasize the open surgical treatment as a therapeutic option upon failure of less invasive methods.

  1. Obesity and renal hemodynamics

    NARCIS (Netherlands)

    Bosma, R. J.; Krikken, J. A.; van der Heide, J. J. Homan; de Jong, P. E.; Navis, G. J.

    2006-01-01

    Obesity is a risk factor for renal damage in native kidney disease and in renal transplant recipients. Obesity is associated with several renal risk factors such as hypertension and diabetes that may convey renal risk, but obesity is also associated with an unfavorable renal hemodynamic profile

  2. Radiopharmaceuticals for renal studies

    International Nuclear Information System (INIS)

    Verdera, Silvia

    1994-01-01

    Between the diagnostic techniques using radiopharmaceuticals in nuclear medicine it find renal studies.A brief description about renal glomerular filtration(GFR) and reliability renal plasma flux (ERPF),renal blood flux measurement agents (RBF),renal scintillation agents and radiation dose estimates by organ physiology was given in this study.tabs

  3. Specific immunotherapy ameliorates ulcerative colitis.

    Science.gov (United States)

    Cai, Min; Zeng, Lu; Li, Lin-Jing; Mo, Li-Hua; Xie, Rui-Di; Feng, Bai-Sui; Zheng, Peng-Yuan; Liu, Zhi-Gang; Liu, Zhan-Ju; Yang, Ping-Chang

    2016-01-01

    Hypersensitivity reaction to certain allergens plays a role in the pathogenesis of inflammatory bowel disease (IBD). This study aims to observe the effect of specific immunotherapy in a group of IBD patients. Patients with both ulcerative colitis (UC) and food allergy were recruited into this study. Food allergy was diagnosed by skin prick test and serum specific IgE. The patients were treated with specific immunotherapy (SIT) and Clostridium butyricum (CB) capsules. After treating with SIT and CB, the clinical symptoms of UC were markedly suppressed as shown by reduced truncated Mayo scores and medication scores. The serum levels of specific IgE, interleukin (IL)-4 and tumor necrosis factor (TNF)-α were also suppressed. Treating with SIT alone or CB alone did not show appreciable improvement of the clinical symptoms of UC. UC with food allergy can be ameliorated by administration with SIT and butyrate-production probiotics.

  4. Histochemical Analysis of Renal Dysplasia with Ureteral Atresia

    International Nuclear Information System (INIS)

    Kawate, Toyoko; Kawamura, Ryuki; Uchida, Takenori; Takahashi, Kyosuke; Hasegawa, Tomohiro; Futamata, Haruo; Katoh, Ryohei; Takeda, Sen

    2009-01-01

    Unilateral small kidney with ureteral obstruction was discovered in a 74-year-old female cadaver during an anatomical dissection course. In order to elucidate the histogenesis of renal dysplasia, we carried out histochemical and immunohistochemical analyses. On macroscopic view, the kidney was approximately 3 cm in length, 2 cm in width and weighed only 9 g. Although the ureter ran from the renal hilus to the bladder, its width was under 2 mm. The renal parenchyma was extremely thin and there was a large congested vein in the renal sinus. On microscopic examination of the kidney, we observed that numerous developing renal tubules had cytokeratin-positive epithelia, most of which were surrounded by concentric fibrosis. However, we could not detect any structures resembling the collecting duct, renal tubules, renal pelvis, or glomeruli. The concentric mesencymal fibrous tissue surrounding the immature renal tubules contained the smooth muscles that were positive for h-caldesmon. Serial sections of the ureter revealed several small and discontinuous lacunae lined by cuboidal and transitional epithelium, which did not constitute a patent lumen through the bladder. This case is a rare case of renal dysplasia with defect in recanalization of the ureteral bud during the early developmental stage

  5. Idiopathic pulmonary fibrosis.

    Science.gov (United States)

    Xaubet, Antoni; Ancochea, Julio; Molina-Molina, María

    2017-02-23

    Idiopathic pulmonary fibrosis is a fibrosing interstitial pneumonia associated with the radiological and/or histological pattern of usual interstitial pneumonia. Its aetiology is unknown, but probably comprises the action of endogenous and exogenous micro-environmental factors in subjects with genetic predisposition. Its diagnosis is based on the presence of characteristic findings of high-resolution computed tomography scans and pulmonary biopsies in absence of interstitial lung diseases of other aetiologies. Its clinical evolution is variable, although the mean survival rate is 2-5 years as of its clinical presentation. Patients with idiopathic pulmonary fibrosis may present complications and comorbidities which modify the disease's clinical course and prognosis. In the mild-moderate disease, the treatment consists of the administration of anti-fibrotic drugs. In severe disease, the best therapeutic option is pulmonary transplantation. In this paper we review the diagnostic and therapeutic aspects of the disease. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

  6. Endostatin and kidney fibrosis in aging: a case for antagonistic pleiotropy?

    Science.gov (United States)

    Lin, Chi Hua Sarah; Chen, Jun; Ziman, Bruce; Marshall, Shannon; Maizel, Julien; Goligorsky, Michael S

    2014-06-15

    A recurring theme of a host of gerontologic studies conducted in either experimental animals or in humans is related to documenting the functional decline with age. We hypothesize that elevated circulating levels of a powerful antiangiogenic peptide, endostatin, represent one of the potent systemic causes for multiorgan microvascular rarefaction and functional decline due to fibrosis. It is possible that during the life span of an organism there is an accumulation of dormant transformed cells producing antiangiogenic substances (endostatin) that maintain the dormancy of such scattered malignant cells. The proof of this postulate cannot be obtained by physically documenting these scattered cells, and it rests exclusively on the detection of sequelae of shifted pro- and antiangiogenic balance toward the latter. Here we compared circulating levels of endostatin in young and aging mice of two different strains and showed that endostatin levels are elevated in the latter. Renal expression of endostatin increased ~5.6-fold in aging animals. This was associated with microvascular rarefaction and progressive tubulointerstitial fibrosis. In parallel, the levels of sirtuins 1 and 3 were significantly suppressed in aging mice in conjunction with the expression of markers of senescence. Treating young mice with endostatin for 28 days showed delayed recovery of circulation after femoral artery ligation and reduced patency of renal microvasculature but no fibrosis. In conclusion, the findings are consistent with the hypothesis on elevation of endostatin levels and parallel microvascular rarefaction and induction of renal fibrosis in aging mice. Copyright © 2014 the American Physiological Society.

  7. Acute rejection after kidney transplantation promotes graft fibrosis with elevated adenosine level in rat.

    Directory of Open Access Journals (Sweden)

    Mingliang Li

    Full Text Available Chronic allograft nephropathy is a worldwide issue with the major feature of progressive allograft fibrosis, eventually ending with graft loss. Adenosine has been demonstrated to play an important role in process of fibrosis. Our study aimed to investigate the relationship between adenosine and fibrosis in renal allograft acute rejection in rat.Wistar rats and SD rats were selected as experimental animals. Our study designed two groups. In the allograft transplantation group, kidneys of Wistar rats were orthotopically transplanted into SD rat recipients, the same species but not genetically identical, to induce acute rejection. Kidney transplantations of SD rats to SD rats which were genetically identical were served as the control. We established rat models and detected a series of indicators. All data were analyzed statistically. P<0.05 was considered statistically significant.Compared with the control group, levels of adenosine increased significantly in the allograft transplantation group, in which acute rejection was induced (P<0.05. Progressive allograft fibrosis as well as collagen deposition were observed.These findings suggested that level of adenosine was upregulated in acute rejection after kidney allograft transplantation in rat. Acute rejection may promote renal allograft fibrosis via the adenosine signaling pathways.

  8. Tissue Inhibitor of Matrix Metalloproteinase-1 Promotes Myocardial Fibrosis by Mediating CD63-Integrin β1 Interaction.

    Science.gov (United States)

    Takawale, Abhijit; Zhang, Pu; Patel, Vaibhav B; Wang, Xiuhua; Oudit, Gavin; Kassiri, Zamaneh

    2017-06-01

    Myocardial fibrosis is excess accumulation of the extracellular matrix fibrillar collagens. Fibrosis is a key feature of various cardiomyopathies and compromises cardiac systolic and diastolic performance. TIMP1 (tissue inhibitor of metalloproteinase-1) is consistently upregulated in myocardial fibrosis and is used as a marker of fibrosis. However, it remains to be determined whether TIMP1 promotes tissue fibrosis by inhibiting extracellular matrix degradation by matrix metalloproteinases or via an matrix metalloproteinase-independent pathway. We examined the function of TIMP1 in myocardial fibrosis using Timp1 -deficient mice and 2 in vivo models of myocardial fibrosis (angiotensin II infusion and cardiac pressure overload), in vitro analysis of adult cardiac fibroblasts, and fibrotic myocardium from patients with dilated cardiomyopathy (DCM). Timp1 deficiency significantly reduced myocardial fibrosis in both in vivo models of cardiomyopathy. We identified a novel mechanism for TIMP1 action whereby, independent from its matrix metalloproteinase-inhibitory function, it mediates an association between CD63 (cell surface receptor for TIMP1) and integrin β1 on cardiac fibroblasts, initiates activation and nuclear translocation of Smad2/3 and β-catenin, leading to de novo collagen synthesis. This mechanism was consistently observed in vivo, in cultured cardiac fibroblasts, and in human fibrotic myocardium. In addition, after long-term pressure overload, Timp1 deficiency persistently reduced myocardial fibrosis and ameliorated diastolic dysfunction. This study defines a novel matrix metalloproteinase-independent function of TIMP1 in promoting myocardial fibrosis. As such targeting TIMP1 could prove to be a valuable approach in developing antifibrosis therapies. © 2017 American Heart Association, Inc.

  9. Thoracic periaortal fibrosis and Ormond's disease

    International Nuclear Information System (INIS)

    Kacl, G.M.; Bino, M.; Salomon, F.; Risti, B.; Marincek, B.

    1995-01-01

    Two cases of thoracic periaortal fibrosis as a manifestation of retroperitoneal fibrosis (Ormond's disease) are shown on CT and MRI. Thoracic periaortal fibrosis can result in an inflammatory aneurysmo with chronic dissection. Manifestation of thoracic periaortal fibrosis may typically occur intermittently over decades. (orig.) [de

  10. [Plasma cell dyscrasias and renal damage].

    Science.gov (United States)

    Pasquali, Sonia; Iannuzzella, Francesco; Somenzi, Danio; Mattei, Silvia; Bovino, Achiropita; Corradini, Mattia

    2012-01-01

    Kidney damage caused by immunoglobulin free light chains in the setting of plasma cell dyscrasias is common and may involve all renal compartments, from the glomerulus to the tubulointerstitium, in a wide variety of histomorphological and clinical patterns. The knowledge of how free light chains can promote kidney injury is growing: they can cause functional changes, be processed and deposited, mediate inflammation, apoptosis and fibrosis, and obstruct nephrons. Each clone of the free light chain is unique and its primary structure and post-translation modification can determine the type of renal disease. Measurement of serum free light chain concentrations and calculation of the serum kappa/lambda ratio, together with renal biopsy, represent essential diagnostic tools. An early and correct diagnosis of renal lesions due to plasma cell dyscrasias will allow early initiation of disease-specific treatment strategies. The treatment of free light chain nephropathies is evolving and knowledge of the pathways that promote renal damage should lead to further therapeutic developments.

  11. Bilateral renal artery variation

    OpenAIRE

    Üçerler, Hülya; Üzüm, Yusuf; İkiz, Z. Aslı Aktan

    2014-01-01

    Each kidney is supplied by a single renal artery, although renal artery variations are common. Variations of the renal arteryhave become important with the increasing number of renal transplantations. Numerous studies describe variations in renalartery anatomy. Especially the left renal artery is among the most critical arterial variations, because it is the referred side forresecting the donor kidney. During routine dissection in a formalin fixed male cadaver, we have found a bilateral renal...

  12. Renal tuberculosis

    Directory of Open Access Journals (Sweden)

    Džamić Zoran

    2016-01-01

    Full Text Available Tuberculosis is still a significant health problem in the world, mostly in developing countries. The special significance lies in immunocompromised patients, particularly those suffering from the HIV. Urogenital tuberculosis is one of the most common forms of extrapulmonary tuberculosis, while the most commonly involved organ is the kidney. Renal tuberculosis occurs by hematogenous dissemination of mycobacterium tuberculosis from a primary tuberculosis foci in the body. Tuberculosis is characterized by the formation of pathognomonic lesions in the tissues - granulomata. These granulomata may heal spontaneously or remain stable for years. In certain circumstances in the body associated with immunosuppression, the disease may be activated. Central caseous necrosis occurs within tuberculoma, leading to formation of cavities that destroy renal parenchyma. The process may gain access to the collecting system, forming the caverns. In this way, infection can be spread distally to renal pelvis, ureter and bladder. Scaring of tissue by tuberculosis process may lead to development of strictures of the urinary tract. The clinical manifestations are presented by nonspecific symptoms and signs, so tuberculosis can often be overlooked. Sterile pyuria is characteristic for urinary tuberculosis. Dysuric complaints, flank pain or hematuria may be presented in patients. Constitutional symptoms of fever, weight loss and night sweats are presented in some severe cases. Diagnosis is made by isolation of mycobacterium tuberculosis in urine samples, by cultures carried out on standard solid media optimized for mycobacterial growth. Different imaging studies are used in diagnostics - IVU, CT and NMR are the most important. Medical therapy is the main modality of tuberculosis treatment. The first line anti-tuberculosis drugs include isoniazid, rifampicin, pyrazinamide and ethambutol. Surgical treatment is required in some cases, to remove severely damaged kidney, if

  13. Localized bilateral perirenal fibrosis, a rare cause of idiopathic retroperitoneal fibrosis

    Directory of Open Access Journals (Sweden)

    Maja Kveder

    2014-08-01

    Full Text Available Background: Idiopathic retroperitoneal fibrosis is an infrequent process of unknown aetiology characterised by fibrous tissue proliferation in the retroperitoneum. Even less frequent is a localized form of this disease by a proliferation of fibrous tissue around single or both kidneys.Case report: We describe a case of 46-year old man in whom medical management was started for accidentally discovered arterial hypertension, which turned out to be difficult to control.   During diagnostic work-up of hypertension, an abdominal ultrasound was obtained a year later demonstrating slight bilateral caliectasis without obvious visible cause for it. Laboratory exams have shown significantly impaired renal function, normocytic anaemia, slightly higher sedimentation rate, increased CRP and normal urinalysis. Nephrologist has decided for hospitalisation during which magnetic resonance imaging was performed  showing a few mm wide tissue coats surrounding both kidneys with fluid lying between the coat and kidney capsule. A biopsy of perirenal mass has confirmed a dense cellular lesion consisted of interweaved fascicles of spindle-shaped cells. After exclusion of tumours and other causes, a diagnosis of retroperitoneal fibrosis was confirmed. Clinical picture and laboratory data corresponded to idiopathic form of this disease. A treatment with tamoxifen was started after patient refused treatment with methylprednisolone. During tamoxifen monotherapy, there was gradual significant improvement of general symptoms, notable decline in inflammation markers, improvement of anaemia, normalisation of kidney function, and normalisation of blood pressure. Conclusion: Retroperitoneal fibrosis is still an obscure and multifaceted disease. A proper selection of diagnostic methods is the key to correct and fast diagnosis as well as good grounding for proper treatment.

  14. Metabolic alkalosis with multiple salt unbalance: an atypical onset of cystic fibrosis in a child

    Directory of Open Access Journals (Sweden)

    Dimitri Poddighe

    2017-12-01

    Full Text Available Dehydration with multiple salt abnormalities is frequently encountered in the paediatric emergency department, during acute illnesses complicated by loss of body fluids. Metabolic alkalosis is not a common finding in dehydrated children. The presence of unusual electrolyte unbalance, such as metabolic alkalosis, hyponatremia, hypochloremia and hypokalemia, without evidence of renal tubular defects, is named as pseudo-Bartter syndrome. It can occur in several clinical settings and, in infancy, it is described as a potential complication of cystic fibrosis. We report a case of pseudo-Bartter syndrome representing the onset of cystic fibrosis in childhood.

  15. Tubule-Derived Wnts Are Required for Fibroblast Activation and Kidney Fibrosis.

    Science.gov (United States)

    Zhou, Dong; Fu, Haiyan; Zhang, Lu; Zhang, Ke; Min, Yali; Xiao, Liangxiang; Lin, Lin; Bastacky, Sheldon I; Liu, Youhua

    2017-08-01

    Cell-cell communication via Wnt ligands is necessary in regulating embryonic development and has been implicated in CKD. Because Wnt ligands are ubiquitously expressed, the exact cellular source of the Wnts involved in CKD remains undefined. To address this issue, we generated two conditional knockout mouse lines in which Wntless (Wls), a dedicated cargo receptor that is obligatory for Wnt secretion, was selectively ablated in tubular epithelial cells or interstitial fibroblasts. Blockade of Wnt secretion by genetic deletion of Wls in renal tubules markedly inhibited myofibroblast activation and reduced renal fibrosis after unilateral ureteral obstruction. This effect associated with decreased activation of β -catenin and downstream gene expression and preserved tubular epithelial integrity. In contrast, fibroblast-specific deletion of Wls exhibited little effect on the severity of renal fibrosis after obstructive or ischemia-reperfusion injury. In vitro , incubation of normal rat kidney fibroblasts with tubule-derived Wnts promoted fibroblast proliferation and activation. Furthermore, compared with kidney specimens from patients without CKD, biopsy specimens from patients with CKD also displayed increased expression of multiple Wnt proteins, predominantly in renal tubular epithelium. These results illustrate that tubule-derived Wnts have an essential role in promoting fibroblast activation and kidney fibrosis via epithelial-mesenchymal communication. Copyright © 2017 by the American Society of Nephrology.

  16. Renal denervation

    DEFF Research Database (Denmark)

    Olsen, Lene Kjær; Kamper, Anne-Lise; Svendsen, Jesper Hastrup

    2015-01-01

    PURPOSE OF REVIEW: Renal denervation (RDN) has, within recent years, been suggested as a novel treatment option for patients with resistant hypertension. This review summarizes the current knowledge on this procedure as well as limitations and questions that remain to be answered. RECENT FINDINGS...... selection, anatomical and physiological effects of RDN as well as possible beneficial effects on other diseases with increased sympathetic activity. The long awaited Symplicity HTN-3 (2014) results illustrated that the RDN group and the sham-group had similar reductions in BP. SUMMARY: Initial studies...

  17. Renal denervation prevents long-term sequelae of ischemic renal injury

    Science.gov (United States)

    Kim, Jinu; Padanilam, Babu J.

    2014-01-01

    Signals that drive interstitial fibrogenesis after renal ischemia reperfusion injury remain undefined. Sympathetic activation is manifest even in the early clinical stages of chronic kidney disease and is directly related to disease severity. A role for renal nerves in renal interstitial fibrogenesis in the setting of ischemia reperfusion injury has not been studied. In male 129S1/SvImJ mice, ischemia reperfusion injury induced tubulointerstitial fibrosis as indicated by collagen deposition and profibrotic protein expression 4 to 16 days after the injury.. Leukocyte influx, proinflammatory protein expression, oxidative stress, apoptosis, and cell cycle arrest at G2/M phase were enhanced after ischemia reperfusion injury. Renal denervation at the time of injury or up to 1 day post-injury improved histology, decreased proinflammatory/profibrotic responses and apoptosis, and prevented G2/M cell cycle arrest in the kidney. Treatment with afferent nerve-derived calcitonin gene-related peptide (CGRP) or efferent nerve-derived norepinephrine in denervated and ischemia reperfusion injury-induced kidneys mimicked innervation, restored inflammation and fibrosis, induced G2/M arrest, and enhanced TGF-β1 activation. Blocking norepinephrine or CGRP function using respective receptor blockers prevented these effects. Consistent with the in vivo study, treatment with either norepinephrine or CGRP induced G2/M cell cycle arrest in HK-2 proximal tubule cells, whereas antagonists against their respective receptors prevented G2/M arrest. Thus, renal nerve stimulation is a primary mechanism and renal nerve-derived factors drive epithelial cell cycle arrest and the inflammatory cascade causing interstitial fibrogenesis after ischemia reperfusion injury. PMID:25207878

  18. Renal papillary necrosis

    Science.gov (United States)

    ... asking your provider. Alternative Names Necrosis - renal papillae; Renal medullary necrosis Images Kidney anatomy Kidney - blood and urine flow References Bushinsky DA, Monk RD. Nephrolithiasis and nephrocalcinosis. ...

  19. Gastrointestinal Manifestations of Cystic Fibrosis

    Science.gov (United States)

    2016-01-01

    Cystic fibrosis has historically been considered a pulmonary disease, but with the increasing life expectancy of these patients, gastrointestinal manifestations are becoming more important. Furthermore, nutritional status is closely linked to pulmonary function and, thus, overall mortality. This article discusses gastrointestinal manifestations (which involve nutritional, pancreatic, hepatobiliary, and, in particular, gastrointestinal tract issues) of cystic fibrosis as well as management of the disease. In addition, the article discusses studies that have been critical to our understanding of gastrointestinal manifestations of cystic fibrosis. PMID:27330503

  20. Green Tea Polyphenols, Mimicking the Effects of Dietary Restriction, Ameliorate High-Fat Diet-Induced Kidney Injury via Regulating Autophagy Flux

    Directory of Open Access Journals (Sweden)

    Xiao Xie

    2017-05-01

    Full Text Available Epidemiological and experimental studies reveal that Western dietary patterns contribute to chronic kidney disease, whereas dietary restriction (DR or dietary polyphenols such as green tea polyphenols (GTPs can ameliorate the progression of kidney injury. This study aimed to investigate the renal protective effects of GTPs and explore the underlying mechanisms. Sixty Wistar rats were randomly divided into 6 groups: standard diet (STD, DR, high-fat diet (HFD, and three diets plus 200 mg/kg(bw/day GTPs, respectively. After 18 weeks, HFD group exhibited renal injuries by increased serum cystatin C levels and urinary N-acetyl-β-d-glucosaminidase activity, which can be ameliorated by GTPs. Meanwhile, autophagy impairment as denoted by autophagy-lysosome related proteins, including LC3-II, Beclin-1, p62, cathepsin B, cathepsin D and LAMP-1, was observed in HFD group, whereas DR or GTPs promoted renal autophagy activities and GTPs ameliorated HFD-induced autophagy impairment. In vitro, autophagy flux suppression was detected in palmitic acid (PA-treated human proximal tubular epithelial cells (HK-2, which was ameliorated by epigallocatechin-3-gallate (EGCG. Furthermore, GTPs (or EGCG elevated phosphorylation of AMP-activated protein kinase in the kidneys of HFD-treated rats and in PA-treated HK-2 cells. These findings revealed that GTPs mimic the effects of DR to induce autophagy and exert a renal protective effect by alleviating HFD-induced autophagy suppression.

  1. Profile of cystic fibrosis

    Directory of Open Access Journals (Sweden)

    Mona M. El-Falaki

    2014-09-01

    Full Text Available It was generally believed that Cystic fibrosis (CF is rare among Arabs; however, the few studies available from Egypt and other Arabic countries suggested the presence of many undiagnosed patients. The aim of the present study was to determine the frequency of CF patients out of the referred cases in a single referral hospital in Egypt. A total of 100 patients clinically suspected of having CF were recruited from the CF clinic of the Allergy and Pulmonology Unit, Children’s Hospital, Cairo University, Egypt, throughout a 2 year period. Sweat chloride testing was done for all patients using the Wescor macroduct system for collection of sweat. Quantitative analysis for chloride was then done by the thiocyanate colorimetric method. Patients positive for sweat chloride (⩾60 mmol/L were tested for the ΔF508 mutation using primer specific PCR for cystic fibrosis transmembrane conductance regulator (CFTR gene. Thirty-six patients (36% had a positive sweat chloride test. The main clinical presentations in patients were chronic cough in 32 (88.9%, failure to thrive in 27 (75%, steatorrhea in 24 (66.7%, and hepatobiliary involvement in 5 (13.9%. Positive consanguinity was reported in 50% of CF patients. Thirty-two patients were screened for ΔF508 mutation. Positive ΔF508 mutation was detected in 22 (68.8% patients, 8 (25% were homozygous, 14 (43.8% were heterozygous, and 10 (31.3% tested were negative. CF was diagnosed in more than third of patients suspected of having the disease on clinical grounds. This high frequency of CF among referred patients indicates that a high index of suspicion and an increasing availability of diagnostic tests lead to the identification of a higher number of affected individuals.

  2. Radiotherapy and pulmonary fibrosis

    Energy Technology Data Exchange (ETDEWEB)

    Sone, S; Miyata, Y; Tachiiri, H [Osaka Univ. (Japan). Faculty of Medicine

    1975-04-01

    Clinical findings of radiation pneumonitis and pulmonary fibrosis were outlined, and the relationship between occurence of these disorders and radiotherapy, clinical findings and X-ray picture were studied. Standard radiation dose as cell lethal response of carcinoma of the lung were 4,500 to 5,500 rad in 4 to 5.5 weeks in undifferentiated carcinoma, 6,000 to 7,000 rad in 6 to 7 weeks in squamous cell carcinoma, 7,000 to 9,000 rad in 7 to 9 weeks in adenocarcinoma, 4,500 to 5,000 rad in 4 to 5 weeks in the large sized cancer of the esophagus, 6,500 to 7,000 rad in 5 to 7 weeks in the small sized cancer of the esophagus, and irradiation of these amount of dose caused hazards in pulmonary function. Pathological and clinical findings of pulmonary hazards within 6 month period after irradiation, factors causing them and changes in X-ray pictures before and after irradiation were observed and discussed in clinical cases: the case of breast cancer in which 3,000 R/6 times/18 days of 5.5 MeV Liniac electron was irradiated to the chest wall, and the case of pulmonary cancer in which 5,000 rad/25 times/34 days of 6 MeV Liniac X-ray was irradiated in opposite 2 ports radiation beam treatment. The former revealed alveolar lesion and interlobular pleuritis at 4 month later, and remarkable lesion of pulmonary fibrosis was followed at 9 month after radiotherapy. The later developed radiation pneumonitis 1 month after radiotherapy, of which lesion extended to the upper part by 3 months later, and cancer recurred 6.5 month later.

  3. Renal calculus

    CERN Document Server

    Pyrah, Leslie N

    1979-01-01

    Stone in the urinary tract has fascinated the medical profession from the earliest times and has played an important part in the development of surgery. The earliest major planned operations were for the removal of vesical calculus; renal and ureteric calculi provided the first stimulus for the radiological investigation of the viscera, and the biochemical investigation of the causes of calculus formation has been the training ground for surgeons interested in metabolic disorders. It is therefore no surprise that stone has been the subject of a number of monographs by eminent urologists, but the rapid development of knowledge has made it possible for each one of these authors to produce something new. There is still a technical challenge to the surgeon in the removal of renal calculi, and on this topic we are always glad to have the advice of a master craftsman; but inevitably much of the interest centres on the elucidation of the causes of stone formation and its prevention. Professor Pyrah has had a long an...

  4. Ameliorative Effect of Different Concentration of Mushroom ...

    African Journals Online (AJOL)

    Prof. Ogunji

    ameliorative effect of mushroom in the post-experimental stage. Samples of liver and ... except in the liver which showed mild periportal chronic inflammatory cell. However, the .... alcohol for 12 hours and through absolute alcohol to remove ...

  5. Portulaca oleracea Linn seed extract ameliorates hydrogen ...

    African Journals Online (AJOL)

    Portulaca oleracea Linn seed extract ameliorates hydrogen ... induced cell death by inhibiting oxidative stress and ROS generation. Keywords: ... culture medium; therefore the stock solutions of ... acetic acid (1 %) and ethanol (50 %) to extract.

  6. Ameliorative effects of selenium and zinc

    African Journals Online (AJOL)

    Methidathion-induced hematological, biochemical and hepatohistological alterations in rat: Ameliorative effects of selenium and zinc. L Barkat, A Boumendjel, C Abdennour, MS Boulakoud, A El Feki, M Messarah ...

  7. Black ginseng extract ameliorates hypercholesterolemia in rats

    Directory of Open Access Journals (Sweden)

    Evelyn Saba

    2016-04-01

    Conclusion: Administration of BG extracts to Sprague Dawley rats fed with high-cholesterol diet ameliorated hypercholesterolemia, which was mediated via modulation of cholesterol-metabolizing marker genes. This data throw a light on BG's cardioprotective effects.

  8. Dietary Amelioration of Helicobacter Infection

    Science.gov (United States)

    Fahey, Jed W.; Stephenson, Katherine K.; Wallace, Alison J.

    2015-01-01

    We review herein the basis for using dietary components to treat and/or prevent Helicobacter pylori infection, with emphasis on: (a) work reported in the last decade, (b) dietary components for which there is mechanism-based plausibility, and (c) components for which clinical results on H. pylori amelioration are available. There is evidence that a diet-based treatment may reduce the levels and/or the virulence of H. pylori colonization without completely eradicating the organism in treated individuals. This concept was endorsed a decade ago by the participants in a small international consensus conference held in Honolulu, Hawaii, USA, and interest in such a diet-based approach has increased dramatically since then. This approach is attractive in terms of cost, treatment, tolerability and cultural acceptability. This review therefore highlights specific foods, food components, and food products, grouped as follows: bee products (e.g. honey and propolis), probiotics, dairy products, vegetables, fruits, oils, essential oils, and herbs, spices and other plants. A discussion of the small number of clinical studies that are available is supplemented by supportive in vitro and animal studies. This very large body of in vitro and pre-clinical evidence must now be followed up with rationally designed, unambiguous human trials. PMID:25799054

  9. Fructokinase activity mediates dehydration-induced renal injury.

    Science.gov (United States)

    Roncal Jimenez, Carlos A; Ishimoto, Takuji; Lanaspa, Miguel A; Rivard, Christopher J; Nakagawa, Takahiko; Ejaz, A Ahsan; Cicerchi, Christina; Inaba, Shinichiro; Le, MyPhuong; Miyazaki, Makoto; Glaser, Jason; Correa-Rotter, Ricardo; González, Marvin A; Aragón, Aurora; Wesseling, Catharina; Sánchez-Lozada, Laura G; Johnson, Richard J

    2014-08-01

    The epidemic of chronic kidney disease in Nicaragua (Mesoamerican nephropathy) has been linked with recurrent dehydration. Here we tested whether recurrent dehydration may cause renal injury by activation of the polyol pathway, resulting in the generation of endogenous fructose in the kidney that might subsequently induce renal injury via metabolism by fructokinase. Wild-type and fructokinase-deficient mice were subjected to recurrent heat-induced dehydration. One group of each genotype was provided water throughout the day and the other group was hydrated at night, after the dehydration. Both groups received the same total hydration in 24 h. Wild-type mice that received delayed hydration developed renal injury, with elevated serum creatinine, increased urinary NGAL, proximal tubular injury, and renal inflammation and fibrosis. This was associated with activation of the polyol pathway, with increased renal cortical sorbitol and fructose levels. Fructokinase-knockout mice with delayed hydration were protected from renal injury. Thus, recurrent dehydration can induce renal injury via a fructokinase-dependent mechanism, likely from the generation of endogenous fructose via the polyol pathway. Access to sufficient water during the dehydration period can protect mice from developing renal injury. These studies provide a potential mechanism for Mesoamerican nephropathy.

  10. Microencapsulation of Lefty-secreting engineered cells for pulmonary fibrosis therapy in mice.

    Science.gov (United States)

    Ma, Hongge; Qiao, Shupei; Wang, Zeli; Geng, Shuai; Zhao, Yufang; Hou, Xiaolu; Tian, Weiming; Chen, Xiongbiao; Yao, Lifen

    2017-05-01

    Idiopathic pulmonary fibrosis (IPF) is a progressive disease that causes unremitting deposition of extracellular matrix proteins, thus resulting in distortion of the pulmonary architecture and impaired gas exchange. Associated with high morbidity and mortality, IPF is generally refractory to current pharmacological therapies. Lefty A, a potent inhibitor of transforming growth factor-β signaling, has been shown to have promising antifibrotic ability in vitro for the treatment of renal fibrosis and other potential organ fibroses. Here, we determined whether Lefty A can attenuate bleomycin (BLM)-induced pulmonary fibrosis in vivo based on a novel therapeutic strategy where human embryonic kidney 293 (HEK293) cells are genetically engineered with the Lefty A-associated GFP gene. The engineered HEK293 cells were encapsulated in alginate microcapsules and then subcutaneously implanted in ICR mice that had 1 wk earlier been intratracheally administered BLM to induce pulmonary fibrosis. The severity of fibrosis in lung tissue was assessed using pathological morphology and collagen expression to examine the effect of Lefty A released from the microencapsulated cells. The engineered HEK293 cells with Lefty A significantly reduced the expression of connective tissue growth factor and collagen type I mRNA, lessened the morphological fibrotic effects induced by BLM, and increased the expression of matrix metalloproteinase-9. This illustrates that engineered HEK293 cells with Lefty A can attenuate pulmonary fibrosis in vivo, thus providing a novel method to treat human pulmonary fibrotic disease and other organ fibroses. Copyright © 2017 the American Physiological Society.

  11. Tiron ameliorates oxidative stress and inflammation in titanium dioxide nanoparticles induced nephrotoxicity of male rats.

    Science.gov (United States)

    Morgan, Ashraf; Galal, Mona K; Ogaly, Hanan A; Ibrahim, Marwa A; Abd-Elsalam, Reham M; Noshy, Peter

    2017-09-01

    Although the widespread use of titanium dioxide nanoparticles (TiO 2 NPs), few studies were conducted on its hazard influence on human health. Tiron a synthetic vitamin E analog was proven to be a mitochondrial targeting antioxidant. The current investigation was performed to assess the efficacy of tiron against TiO 2 NPs induced nephrotoxicity. Eighty adult male rats divided into four different groups were used: group I was the control, group II received TiO2 NPs (100mg\\Kg BW), group III received TiO2 NPs plus tiron (470mg\\kg BW), and group IV received tiron alone. Urea, creatinine and total protein concentrations were measured in serum to assess the renal function. Antioxidant status was estimated by determining the activities of glutathione peroxidase, superoxide dismutase, malondialdehyde (MDA) level and glutathione concentration in renal tissue. As well as Renal fibrosis was evaluated though measuring of transforming growth factor-β1 (TGFβ1) and matrix metalloproteinase 9 (MMP9) expression levels and histopathological examination. TiO 2 NPs treated rats showed marked elevation of renal indices, depletion of renal antioxidant enzymes with marked increase in MDA concentration as well as significant up-regulation in fibrotic biomarkers TGFβ1 and MMP9. Oral administration of tiron to TiO 2 NPs treated rats significantly attenuate the renal dysfunction through decreasing of renal indices, increasing of antioxidant enzymes activities, down-regulate the expression of fibrotic genes and improving the histopathological picture for renal tissue. In conclusion, tiron was proved to attenuate the nephrotoxicity induced by TiO 2 NPs through its radical scavenging and metal chelating potency. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  12. Naringin ameliorates gentamicin-induced nephrotoxicity and associated mitochondrial dysfunction, apoptosis and inflammation in rats: Possible mechanism of nephroprotection

    Energy Technology Data Exchange (ETDEWEB)

    Sahu, Bidya Dhar [Medicinal Chemistry and Pharmacology Division, Indian Institute of Chemical Technology (IICT), Hyderabad 500 007 (India); Tatireddy, Srujana [National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037 (India); Koneru, Meghana [Medicinal Chemistry and Pharmacology Division, Indian Institute of Chemical Technology (IICT), Hyderabad 500 007 (India); Borkar, Roshan M. [National Centre for Mass Spectrometry, Indian Institute of Chemical Technology (IICT), Hyderabad 500 007 (India); Kumar, Jerald Mahesh [CSIR-Centre for Cellular and Molecular Biology (CCMB), Hyderabad 500 007 (India); Kuncha, Madhusudana [Medicinal Chemistry and Pharmacology Division, Indian Institute of Chemical Technology (IICT), Hyderabad 500 007 (India); Srinivas, R. [National Centre for Mass Spectrometry, Indian Institute of Chemical Technology (IICT), Hyderabad 500 007 (India); Shyam Sunder, R. [Faculty of Pharmacy, Osmania University, Hyderabad 500 007 (India); Sistla, Ramakrishna, E-mail: sistla@iict.res.in [Medicinal Chemistry and Pharmacology Division, Indian Institute of Chemical Technology (IICT), Hyderabad 500 007 (India)

    2014-05-15

    Gentamicin-induced nephrotoxicity has been well documented, although its underlying mechanisms and preventive strategies remain to be investigated. The present study was designed to investigate the protective effect of naringin, a bioflavonoid, on gentamicin-induced nephrotoxicity and to elucidate the potential mechanism. Serum specific renal function parameters (blood urea nitrogen and creatinine) and histopathology of kidney tissues were evaluated to assess the gentamicin-induced nephrotoxicity. Renal oxidative stress (lipid peroxidation, protein carbonylation, enzymatic and non-enzymatic antioxidants), inflammatory (NF-kB [p65], TNF-α, IL-6 and MPO) and apoptotic (caspase 3, caspase 9, Bax, Bcl-2, p53 and DNA fragmentation) markers were also evaluated. Significant decrease in mitochondrial NADH dehydrogenase, succinate dehydrogenase, cytochrome c oxidase and mitochondrial redox activity indicated the gentamicin-induced mitochondrial dysfunction. Naringin (100 mg/kg) treatment along with gentamicin restored the mitochondrial function and increased the renal endogenous antioxidant status. Gentamicin induced increased renal inflammatory cytokines (TNF-α and IL-6), nuclear protein expression of NF-κB (p65) and NF-κB-DNA binding activity and myeloperoxidase (MPO) activity were significantly decreased upon naringin treatment. In addition, naringin treatment significantly decreased the amount of cleaved caspase 3, Bax, and p53 protein expression and increased the Bcl-2 protein expression. Naringin treatment also ameliorated the extent of histologic injury and reduced inflammatory infiltration in renal tubules. U-HPLS-MS data revealed that naringin co-administration along with gentamicin did not alter the renal uptake and/or accumulation of gentamicin in kidney tissues. These findings suggest that naringin treatment attenuates renal dysfunction and structural damage through the reduction of oxidative stress, mitochondrial dysfunction, inflammation and apoptosis in

  13. Exercise Ameliorates High Fat Diet Induced Cardiac Dysfunction by Increasing Interleukin 10

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    Varun eKesherwani

    2015-04-01

    Full Text Available Increasing evidence suggests that a sedentary lifestyle and a high fat diet (HFD leads to cardiomyopathy. Moderate exercise ameliorates cardiac dysfunction, however underlying molecular mechanisms are poorly understood. Increased inflammation due to induction of pro-inflammatory cytokine such as tumor necrosis factor-alpha (TNF-α and attenuation of anti-inflammatory cytokine such as interleukin10 (IL-10 contributes to cardiac dysfunction in obese and diabetics. We hypothesized that exercise training ameliorates HFD- induced cardiac dysfunction by mitigating obesity and inflammation through upregulation of IL-10 and downregulation of TNF-α. To test this hypothesis, eight week old, female C57BL/6J mice were fed with HFD and exercised (swimming 1hr/day for 5 days/week for eight weeks. The four treatment groups: normal diet (ND, HFD, HFD + exercise (HFD + Ex and ND + Ex were analyzed for mean body weight, blood glucose level, TNF-α, IL-10, cardiac fibrosis by Masson Trichrome, and cardiac dysfunction by echocardiography. Mean body weights were increased in HFD but comparatively less in HFD + Ex. The level of TNF-α was elevated and IL-10 was downregulated in HFD but ameliorated in HFD + Ex. Cardiac fibrosis increased in HFD and was attenuated by exercise in the HFD + Ex group. The percentage ejection fraction and fractional shortening were decreased in HFD but comparatively increased in HFD + Ex. There was no difference between ND and ND + Ex for the above parameters except an increase in IL-10 level following exercise. Based on these results, we conclude that exercise mitigates HFD- induced cardiomyopathy by decreasing obesity, inducing IL-10, and reducing TNF-α in mice.

  14. Nephrogenic systemic fibrosis: Review of 408 biopsy-confirmed cases

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    Zhitong Zou

    2011-01-01

    Full Text Available Nephrogenic systemic fibrosis (NSF has now been virtually eliminated by the discovery of its association with gadolinium-based contrast agents (GBCAs and the consequent reduced use of GBCA-enhanced magnetic resonance imaging (MRI in severe renal failure patients. This review of 408 biopsy-confirmed cases shows how to minimize NSF risk when performing GBCA-enhanced MRI or magnetic resonance angiography. The absence of any NSF cases in patients less than 8 years old or greater than 87 years old suggests that infants and elderly patients are already protected. Limiting GBCA dose to a maximum of 0.1 mMol/kg, dialyzing dialysis patients quickly following GBCA administration, delaying administration of GBCA in acute renal failure until after renal function returns or dialysis is initiated, and avoiding nonionic linear GBCA in renal failure patients, especially when there are pro-inflammatory conditions, appear to have reduced NSF risk to the point where safe GBCA-enhanced MRI is possible in most patients.

  15. The Mitochondrial Cardiolipin Remodeling Enzyme Lysocardiolipin Acyltransferase Is a Novel Target in Pulmonary Fibrosis

    Science.gov (United States)

    Huang, Long Shuang; Mathew, Biji; Zhao, Yutong; Noth, Imre; Reddy, Sekhar P.; Harijith, Anantha; Usatyuk, Peter V.; Berdyshev, Evgeny V.; Kaminski, Naftali; Zhou, Tong; Zhang, Wei; Zhang, Yanmin; Rehman, Jalees; Kotha, Sainath R.; Gurney, Travis O.; Parinandi, Narasimham L.; Lussier, Yves A.; Garcia, Joe G. N.

    2014-01-01

    Rationale: Lysocardiolipin acyltransferase (LYCAT), a cardiolipin-remodeling enzyme regulating the 18:2 linoleic acid pattern of mammalian mitochondrial cardiolipin, is necessary for maintaining normal mitochondrial function and vascular development. We hypothesized that modulation of LYCAT expression in lung epithelium regulates development of pulmonary fibrosis. Objectives: To define a role for LYCAT in human and murine models of pulmonary fibrosis. Methods: We analyzed the correlation of LYCAT expression in peripheral blood mononuclear cells (PBMCs) with the outcomes of pulmonary functions and overall survival, and used the murine models to establish the role of LYCAT in fibrogenesis. We studied the LYCAT action on cardiolipin remodeling, mitochondrial reactive oxygen species generation, and apoptosis of alveolar epithelial cells under bleomycin challenge. Measurements and Main Results: LYCAT expression was significantly altered in PBMCs and lung tissues from patients with idiopathic pulmonary fibrosis (IPF), which was confirmed in two preclinical murine models of IPF, bleomycin- and radiation-induced pulmonary fibrosis. LYCAT mRNA expression in PBMCs directly and significantly correlated with carbon monoxide diffusion capacity, pulmonary function outcomes, and overall survival. In both bleomycin- and radiation-induced pulmonary fibrosis murine models, hLYCAT overexpression reduced several indices of lung fibrosis, whereas down-regulation of native LYCAT expression by siRNA accentuated fibrogenesis. In vitro studies demonstrated that LYCAT modulated bleomycin-induced cardiolipin remodeling, mitochondrial membrane potential, reactive oxygen species generation, and apoptosis of alveolar epithelial cells, potential mechanisms of LYCAT-mediated lung protection. Conclusions: This study is the first to identify modulation of LYCAT expression in fibrotic lungs and offers a novel therapeutic approach for ameliorating lung inflammation and pulmonary fibrosis. PMID

  16. Therapeutic targets in liver fibrosis.

    Science.gov (United States)

    Fallowfield, Jonathan A

    2011-05-01

    Detailed analysis of the cellular and molecular mechanisms that mediate liver fibrosis has provided a framework for therapeutic approaches to prevent, slow down, or even reverse fibrosis and cirrhosis. A pivotal event in the development of liver fibrosis is the activation of quiescent hepatic stellate cells (HSCs) to scar-forming myofibroblast-like cells. Consequently, HSCs and the factors that regulate HSC activation, proliferation, and function represent important antifibrotic targets. Drugs currently licensed in the US and Europe for other indications target HSC-related components of the fibrotic cascade. Their deployment in the near future looks likely. Ultimately, treatment strategies for liver fibrosis may vary on an individual basis according to etiology, risk of fibrosis progression, and the prevailing pathogenic milieu, meaning that a multiagent approach could be required. The field continues to develop rapidly and starts to identify exciting potential targets in proof-of-concept preclinical studies. Despite this, no antifibrotics are currently licensed for use in humans. With epidemiological predictions for the future prevalence of viral, obesity-related, and alcohol-related cirrhosis painting an increasingly gloomy picture, and a shortfall in donors for liver transplantation, the clinical urgency for new therapies is high. There is growing interest from stakeholders keen to exploit the market potential for antifibrotics. However, the design of future trials for agents in the developmental pipeline will depend on strategies that enable equal patient stratification, techniques to reliably monitor changes in fibrosis over time, and the definition of clinically meaningful end points.

  17. Enhancement of CD147 on M1 macrophages induces differentiation of Th17 cells in the lung interstitial fibrosis.

    Science.gov (United States)

    Geng, Jie-jie; Zhang, Kui; Chen, Li-na; Miao, Jin-lin; Yao, Meng; Ren, Ying; Fu, Zhi-guang; Chen, Zhi-nan; Zhu, Ping

    2014-09-01

    Lung interstitial fibrosis is a chronic lung disease, and few effective therapies are available to halt or reverse the progression of the disease. In murine and human lung fibrosis, the expression of CD147 is increased. However, the role of CD147 in lung fibrosis has not been identified, and it remains to be determined whether lung fibrosis would be improved by decreasing the expression of CD147. A murine bleomycin-induced lung interstitial fibrosis model was used in the experiments, and HAb18 mAbs and CsA were administered during the induction of lung fibrosis. In our study, we found that the HAb18 mAbs markedly reduced the collagen score and down-regulated M1 macrophages and Th17 cells. In vitro, flow cytometry analysis showed that M1 macrophages induced higher Th17 differentiation than M2 macrophages. After treatment with HAb18 mAbs or after reducing the expression of CD147 by lentivirus interference in M1 macrophages, the level of Th17 cells were significantly inhibited. In conclusion, HAb18 mAbs or CsA treatment ameliorates lung interstitial fibrosis. CD147 promoted M1 macrophage and induced the differentiation of Th17 cells in lung interstitial fibrosis, perhaps by regulating some cytokines such as IL-6, IL-1β, IL-12 and IL-23. These results indicated that CD147 may play an important role in the development of lung interstitial fibrosis. Copyright © 2014 Elsevier B.V. All rights reserved.

  18. TRANSPLANTE RENAL

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    Soraia Geraldo Rozza Lopes

    2014-01-01

    Full Text Available El objetivo del estudio fue comprender el significado de espera del trasplante renal para las mujeres en hemodiálisis. Se trata de un estudio cualitativo-interpretativo, realizado con 12 mujeres en hemodiálisis en Florianópolis. Los datos fueron recolectados a través de entrevistas en profundidad en el domicilio. Fue utilizado el software Etnografh 6.0 para la pre-codificación y posterior al análisis interpretativo emergieron dos categorías: “las sombras del momento actual”, que mostró que las dificultades iniciales de la enfermedad están presentes, pero las mujeres pueden hacer frente mejor a la enfermedad y el tratamiento. La segunda categoría, “la luz del trasplante renal”, muestra la esperanza impulsada por la entrada en la lista de espera para un trasplante.

  19. Mechanisms underlying the ameliorative property of lisinopril in progressive mesangioproliferative nephritis.

    Science.gov (United States)

    Shinosaki, Toshihiro; Miyai, Ikuko; Nomura, Yasuharu; Kobayashi, Tatsuo; Sunagawa, Norio; Kurihara, Hidetake

    2002-08-01

    The present study was performed to clarify the mechanism underlying the beneficial effects of lisinopril on chronic glomerulonephritis. Chronic glomerulonephritis was induced by a single injection of E30 monoclonal antibody (E30) recognizing Thy-1.1 antigen to unilaterally nephrectomized rats. E30 injection resulted in persistent massive proteinuria with a decrease in anionic charge sites on the glomerular basement membrane (GBM) at 8 weeks. Also, renal tissue from rats treated with E30 showed typical glomerulosclerosis and tubulointerstitial fibrosis. Lisinopril exerted a potent antiproteinuric effect and suppressed the progression of both glomerulosclerosis and tubulointerstitial fibrosis. Lisinopril recovered the reduced number of anionic charge sites on GBM, accounting for the positive action against massive proteinuria. Immunostaining for desmin revealed that lisinopril treatment prevented the injury of glomerular epithelial cells (GECs) occurring in the chronic nephritic stage. Also, the level of gene expression of transforming growth factor-beta (TGF-beta) and plasminogen activator inhibitor-1 (PAI-1) in the renal cortex were reduced, suggesting that lisinopril improved extracellular matrix (ECM) metabolism. These results indicated that proteinuria in Thy-1.1 antibody-induced chronic nephritis is associated with a decrease in anionic charge sites on GBM, and that the antiproteinuric effect of lisinopril is attributable to protection against GEC damage. Suppression of TGF-beta and PAI-1 expression contributed to the preventive effect of lisinopril on ECM deposition in renal tissue. Copyright 2002 S. Karger AG, Basel

  20. Role of pressure in angiotensin II-induced renal injury: chronic servo-control of renal perfusion pressure in rats.

    Science.gov (United States)

    Mori, Takefumi; Cowley, Allen W

    2004-04-01

    Renal perfusion pressure was servo-controlled chronically in rats to quantify the relative contribution of elevated arterial pressure versus angiotensin II (Ang II) on the induction of renal injury in Ang II-induced hypertension. Sprague-Dawley rats fed a 4% salt diet were administered Ang II for 14 days (25 ng/kg per minute IV; saline only for sham rats), and the renal perfusion pressure to the left kidney was continuously servo-controlled to maintain a normal pressure in that kidney throughout the period of hypertension. An aortic occluder was implanted around the aorta between the two renal arteries and carotid and femoral arterial pressure were measured continuously throughout the experiment to determine uncontrolled and controlled renal perfusion pressure, respectively. Renal perfusion pressure of uncontrolled, controlled, and sham kidneys over the period of Ang II or saline infusion averaged 152.6+/-7.0, 117.4+/-3.5, and 110.7+/-2.2 mm Hg, respectively. The high-pressure uncontrolled kidneys exhibited tubular necrosis and interstitial fibrosis, especially prominent in the outer medullary region. Regional glomerular sclerosis and interlobular artery injury were also pronounced. Controlled kidneys were significantly protected from interlobular artery injury, juxtamedullary glomeruli injury, tubular necrosis, and interstitial fibrosis as determined by comparing the level of injury. Glomerular injury was not prevented in the outer cortex. Transforming growth factor (TGF)-beta and active NF-kappaB proteins determined by immunohistochemistry were colocalized in the uncontrolled kidney in regions of interstitial fibrosis. We conclude that the preferential juxtamedullary injury found in Ang II hypertension is largely induced by pressure and is probably mediated through the TGF-beta and NF-kappaB pathway.

  1. Seguimiento del perfil proteico urinario en el trasplante renal

    OpenAIRE

    Facio, María Laura; Madalena, Leticia; Bacqué, María del Carmen; Idiarte, Laura; Pandolfo, Marcela; Angerosa, Margarita; Alejandre, Mariel; Fraind, Susana; Bresciani, Pablo; Pizzolato, Marco

    2010-01-01

    La nefropatía crónica del trasplante (NCT) se caracteriza por fibrosis intersticial y atrofia tubular, pero su etiología es diversa. El objetivo del trabajo fue evaluar el seguimiento cualitativo de proteínas urinarias en pacientes con más de seis años de trasplante renal y compararlo con parámetros de laboratorio y con biopsia renal. Se evaluaron 17 pacientes durante un año, a través de creatinina sérica, proteinuria y fraccionamiento proteico por electroforesis en geles de poliacrilamida (S...

  2. Two Case Reports and Actual Treatment Approachs of Retroperitoneal Fibrosis

    Directory of Open Access Journals (Sweden)

    Eymen Gazel

    2013-06-01

    Full Text Available Retroperitoneal fibrosis (RPF is a rare disease of unclear etiology, which is characterized by a chronic non specific inflammation of the retroperitoneum. This inflammation of the retroperitoneum may entrap and obstruct retroperitoneal structures, particularly the ureters. Patients with RPF show non specific clinical symptoms, including poorly localized back pain, general malaise, weight loss, anemia, features of renal failure and occasionally, mild fever. The early symptoms are non specific and an accurate diagnosis is often achieved only subsequent to urological obstruction or the occurrence of renal failure. Although a number of scientific journals devoted to RPF are present in the litera¬ture, there is no accepted diagnostic or therapeutic strategy for this disease. However, there are several therapeutic strate¬gies which have been proven to be effective. Hereby, we reported two cases of retroperitoneal fibrosis which had similar symptoms and findings but different responses to medical treatment .We aimed to discuss challanges of RPF%u2019s diagnosis and the treatment protocol.

  3. Idiopathic pulmonary fibrosis

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    Noble Paul W

    2008-03-01

    Full Text Available Abstract Idiopathic pulmonary fibrosis (IPF is a non-neoplastic pulmonary disease that is characterized by the formation of scar tissue within the lungs in the absence of any known provocation. IPF is a rare disease which affects approximately 5 million persons worldwide. The prevalence is estimated to be slightly greater in men (20.2/100,000 than in women (13.2/100,000. The mean age at presentation is 66 years. IPF initially manifests with symptoms of exercise-induced breathless and dry coughing. Auscultation of the lungs reveals early inspiratory crackles, predominantly located in the lower posterior lung zones upon physical exam. Clubbing is found in approximately 50% of IPF patients. Cor pulmonale develops in association with end-stage disease. In that case, classic signs of right heart failure may be present. Etiology remains incompletely understood. Some environmental factors may be associated with IPF (cigarette smoking, exposure to silica and livestock. IPF is recognized on high-resolution computed tomography by peripheral, subpleural lower lobe reticular opacities in association with subpleural honeycomb changes. IPF is associated with a pathological lesion known as usual interstitial pneumonia (UIP. The UIP pattern consists of normal lung alternating with patches of dense fibrosis, taking the form of collagen sheets. The diagnosis of IPF requires correlation of the clinical setting with radiographic images and a lung biopsy. In the absence of lung biopsy, the diagnosis of IPF can be made by defined clinical criteria that were published in guidelines endorsed by several professional societies. Differential diagnosis includes other idiopathic interstitial pneumonia, connective tissue diseases (systemic sclerosis, polymyositis, rheumatoid arthritis, forme fruste of autoimmune disorders, chronic hypersensitivity pneumonitis and other environmental (sometimes occupational exposures. IPF is typically progressive and leads to significant

  4. Lysyl oxidase‑like 2 is expressed in kidney tissue and is associated with the progression of tubulointerstitial fibrosis.

    Science.gov (United States)

    Choi, Sung-Eun; Jeon, Nara; Choi, Hoon Young; Shin, Jae Il; Jeong, Hyeon Joo; Lim, Beom Jin

    2017-09-01

    Tubulointerstitial fibrosis is a common end point of chronic kidney diseases, and preventing its progression is key to avoiding renal failure. Transforming growth factor‑β (TGF‑β) and associated molecules promote tubulointerstitial fibrosis; however, effective therapies targeting these molecules have yet to be developed. Lysyl oxidase‑like 2 (LOXL2), which is involved in invasive growth and metastasis of malignant neoplasms, has recently been reported to serve a key role in hepatic and pulmonary fibrosis. However, little is currently known regarding LOXL2 expression in the kidney and its involvement in tubulointerstitial fibrosis. The present study evaluated LOXL2 expression in human and mouse kidney tissues, as well as in cultured renal cells. LOXL2 protein expression was detected in glomerular capillary loops and tubular epithelial cells in human and mouse kidneys. Glomerular LOXL2 was localized to the cytoplasm of podocytes, as determined by double immunofluorescence microscopy using a podocyte marker (synaptopodin). This result was supported by western blot analysis, which demonstrated that LOXL2 protein expression is present in cultured human podocytes and HK‑2 human proximal tubular cells. In addition, the mRNA and protein expression levels of LOXL2 were higher in a mouse model of tubulointerstitial fibrosis compared with in control mice. In addition, immunohistochemistry results demonstrated that LOXL2 is present in the fibrous interstitium and infiltrating mononuclear cells in a mouse model of tubulointerstitial fibrosis. The present study demonstrated that LOXL2 is expressed in compartments of renal tissue, where it appears to contribute to the progression of tubulointerstitial fibrosis.

  5. Breakdown in Breathing: The Complexities of Cystic Fibrosis

    Science.gov (United States)

    ... Healthier Lungs in Kids Wise Choices Living with Cystic Fibrosis In between checkups, practice good self-care and ... Links What Is Cystic Fibrosis? Learning About Cystic Fibrosis NIH Cystic Fibrosis Fact Sheet Genetic and Rare Diseases Information ...

  6. Increased circulating miR-21 levels are associated with kidney fibrosis.

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    François Glowacki

    Full Text Available MicroRNAs (miRNAs are a class of noncoding RNA acting at a post-transcriptional level to control the expression of large sets of target mRNAs. While there is evidence that miRNAs deregulation plays a causative role in various complex disorders, their role in fibrotic kidney diseases is largely unexplored. Here, we found a strong up-regulation of miR-21 in the kidneys of mice with unilateral ureteral obstruction and also in the kidneys of patients with severe kidney fibrosis. In addition, mouse primary fibroblasts derived from fibrotic kidneys exhibited higher miR-21 expression level compared to those derived from normal kidneys. Expression of miR-21 in normal primary kidney fibroblasts was induced upon TGFβ exposure, a key growth factor involved in fibrogenesis. Finally, ectopic expression of miR-21 in primary kidney fibroblasts was sufficient to promote myofibroblast differentiation. As circulating miRNAs have been suggested as promising non-invasive biomarkers, we further assess whether circulating miR-21 levels are associated with renal fibrosis using sera from 42 renal transplant recipients, categorized according to their renal fibrosis severity, evaluated on allograft biopsies (Interstitial Fibrosis/Tubular Atrophy (IF/TA. Circulating miR-21 levels are significantly increased in patients with severe IF/TA grade (IF/TA grade 3: 3.0±1.0 vs lower grade of fibrosis: 1.5±1.2; p = 0.001. By contrast, circulating miR-21 levels were not correlated with other renal histological lesions. In a multivariate linear regression model including IF/TA grade and estimated GFR, independent associations were found between circulating miR-21 levels and IF/TA score (ß = 0.307, p = 0.03, and between miR-21 levels and aMDRD (ß = -0.398, p = 0.006. Altogether, these data suggest miR-21 has a key pathogenic role in kidney fibrosis and may represent a novel, predictive and reliable blood marker of kidney fibrosis.

  7. Effect of Cuscuta chinensis on renal function in ischemia/reperfusion-induced acute renal failure rats.

    Science.gov (United States)

    Shin, Sun; Lee, Yun Jung; Kim, Eun Ju; Lee, An Sook; Kang, Dae Gill; Lee, Ho Sub

    2011-01-01

    The kidneys play a central role in regulating water, ion composition and excretion of metabolic waste products in the urine. Cuscuta chinensis has been known as an important traditional Oriental medicine for the treatment of liver and kidney disorders. Thus, we studied whether an aqueous extract of Cuscuta chinensis (ACC) seeds has an effect on renal function parameters in ischemia/reperfusion-induced acute renal failure (ARF) rats. Administration of 250 mg/kg/day ACC showed that renal functional parameters including urinary excretion rate, osmolality, Na(+), K(+), Cl(-), creatinine clearance, solute-free water reabsorption were significantly recovered in ischemia/reperfusion-induced ARF. Periodic acid Schiff staining showed that administration of ACC improved tubular damage in ischemia/reperfusion-induced ARF. In immunoblot and immunohistological examinations, ischemia/reperfusion-induced ARF decreased the expressions of water channel AQP 2, 3 and sodium potassium pump Na,K-ATPase in the renal medulla. However, administration of ACC markedly incremented AQP 2, 3 and Na,K-ATPase expressions. Therefore, these data indicate that administration of ACC ameliorates regulation of the urine concentration and renal functions in rats with ischemia/reperfusion-induced ARF.

  8. BILATERAL DUPLICATION OF RENAL ARTERIES

    OpenAIRE

    Prajkta A Thete; Mehera Bhoir; M.V.Ambiye

    2014-01-01

    Routine dissection of a male cadaver revealed the presence of bilateral double renal arteries. On the right side the accessory renal artery originated from the abdominal aorta just above the main renal artery. On the left side the accessory renal artery originated from the abdominal aorta about 1 cm above the main renal artery. Knowledge of the variations of renal vascular anatomy has importance in exploration and treatment of renal trauma, renal transplantation, renal artery embolization, su...

  9. Diffusion-Weighted Magnetic Resonance Imaging in Renal Lesion Characterization

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    Elif Karadeli

    2012-03-01

    Conclusion: The technique has the advantage that it is non-invasive without need for gadolinium administration, takes about 2 minute. This method provides qualitative and quantitative infomation on tissue characterization. DA-MRI and ADC values are important for characterization of renal lesions. Especially, utility of diffusion-weighted magnetic resonance imaging in the patients with risk for nephrogenic systemic fibrosis (NSF could be beneficial. [Cukurova Med J 2012; 37(1: 27-36

  10. Angiotensin II induces kidney inflammatory injury and fibrosis through binding to myeloid differentiation protein-2 (MD2).

    Science.gov (United States)

    Xu, Zheng; Li, Weixin; Han, Jibo; Zou, Chunpeng; Huang, Weijian; Yu, Weihui; Shan, Xiaoou; Lum, Hazel; Li, Xiaokun; Liang, Guang

    2017-03-21

    Growing evidence indicates that angiotensin II (Ang II), a potent biologically active product of RAS, is a key regulator of renal inflammation and fibrosis. In this study, we tested the hypothesis that Ang II induces renal inflammatory injury and fibrosis through interaction with myeloid differentiation protein-2 (MD2), the accessory protein of toll-like receptor 4 (TLR4) of the immune system. Results indicated that in MD2 -/- mice, the Ang II-induced renal fibrosis, inflammation and kidney dysfunction were significantly reduced compared to control Ang II-infused wild-type mice. Similarly, in the presence of small molecule MD2 specific inhibitor L6H21 or siRNA-MD2, the Ang II-induced increases of pro-fibrotic and pro-inflammatory molecules were prevented in tubular NRK-52E cells. MD2 blockade also inhibited activation of NF-κB and ERK. Moreover, MD2 blockade prevented the Ang II-stimulated formation of the MD2/TLR4/MyD88 signaling complex, as well as the increased surface binding of Ang II in NRK-52E cells. In addition, Ang II directly bound recombinant MD2 protein, rather than TLR4 protein. We conclude that MD2 is a significant contributor in the Ang II-induced kidney inflammatory injury in chronic renal diseases. Furthermore, MD2 inhibition could be a new and important therapeutic strategy for preventing progression of chronic renal diseases.

  11. Distribution and components of interstitial inflammation and fibrosis in IgG4-related kidney disease: analysis of autopsy specimens.

    Science.gov (United States)

    Hara, Satoshi; Kawano, Mitsuhiro; Mizushima, Ichiro; Harada, Kenichi; Takata, Takuma; Saeki, Takako; Ubara, Yoshifumi; Sato, Yasuharu; Nagata, Michio

    2016-09-01

    IgG4-related kidney disease (IgG4-RKD) occasionally progresses to chronic renal failure and is pathologically characterized by IgG4-positive lymphoplasmacyte-rich tubulointerstitial nephritis with storiform fibrosis (bird's-eye pattern fibrosis). Although radiology reveals a heterogeneous distribution of affected areas in this disease, their true distribution within the whole kidney is still unknown because of difficulty in estimating this from needle biopsy samples. Using 5 autopsy specimens, the present study histologically characterized the distribution and components of interstitial inflammation and fibrosis in IgG4-RKD. Interstitial lymphoplasmacytic infiltration or fibrosis was observed in a variety of anatomical locations such as intracapsular, subcapsular, cortical, perivascular, and perineural regions heterogeneously in a patchy distribution. They tended to be more markedly accumulated around medium- and small-sized vessels. Storiform fibrosis was limited to the cortex. Immunostaining revealed nonfibrillar collagens (collagen IV and VI) and fibronectin predominance in the cortical lesion, including storiform fibrosis. In contrast, fibril-forming collagens (collagen I and III), collagen VI, and fibronectin were the main components in the perivascular lesion. In addition, α-smooth muscle actin-positive myofibroblasts were prominently accumulated in the early lesion and decreased with progression, suggesting that myofibroblasts produce extracellular matrices forming a peculiar fibrosis. In conclusion, perivascular inflammation or fibrosis of medium- and small-sized vessels is a newly identified pathologic feature of IgG4-RKD. Because storiform fibrosis contains mainly nonfibrillar collagens, "interstitial fibrosclerosis" would be a suitable term to reflect this. The relation between the location and components of fibrosis determined in whole kidney samples provides new clues to the pathophysiology underlying IgG4-RKD. Copyright © 2016 The Authors. Published

  12. Hypothyroidism presenting as reversible renal impairment: an interesting case report.

    Science.gov (United States)

    Vikrant, Sanjay; Chander, Subhash; Kumar, Satish; Gupta, Dalip

    2013-10-01

    We describe an interesting case of reversible renal impairment secondary to hypothyroidism. A 57-years-old man was referred from peripheral institution for evaluation of elevated serum creatinine. He had vague complaints of weakness, lethargy and muscle ache but no urinary symptoms. He was found to have hypothyroidism, and thyroid hormone replacement therapy (THRT) was started which resulted in reversal of the renal dysfunction. There was marked improvement in estimated glomerular filtration rate. 99mTc DTPA renal scans done before and after THRT suggested hypothyroidism responsible for this reversible renal impairment. Several studies have described the pathophysiology of diminished renal function in hypothyroidism. Few studies or case reports have shown total amelioration of renal impairment as seen in our patient. The etiology is presumed to be multifactorial, in which hemodynamic effects and a direct effect of thyroid hormone on the kidney play an important role. We suggest that patients with renal impairment of unknown cause have thyroid function tests undertaken as part of routine investigation.

  13. Nlrp3 prevents early renal interstitial edema and vascular permeability in unilateral ureteral obstruction.

    Directory of Open Access Journals (Sweden)

    Wilco P Pulskens

    Full Text Available Progressive renal disease is characterized by tubulo-interstitial injury with ongoing inflammation and fibrosis. The Nlrp3 inflammasome contributes to these pathophysiological processes through its canonical effects in cytokine maturation. Nlrp3 may additionally exert inflammasome-independent effects following tissue injury. Hence, in this study we investigated potential non-canonical effects of Nlrp3 following progressive renal injury by subjecting WT and Nlrp3-deficient (-/- mice to unilateral ureter obstruction (UUO. Our results revealed a progressive increase of renal Nlrp3 mRNA in WT mice following UUO. The absence of Nlrp3 resulted in enhanced tubular injury and dilatation and an elevated expression of injury biomarker NGAL after UUO. Moreover, interstitial edema was significantly elevated in Nlrp3-/- mice. This could be explained by increased intratubular pressure and an enhanced tubular and vascular permeability. In accordance, renal vascular leakage was elevated in Nlrp3-/- mice that associated with reduced mRNA expression of intercellular junction components. The decreased epithelial barrier function in Nlrp3-/- mice was not associated with increased apoptosis and/or proliferation of renal epithelial cells. Nlrp3 deficiency did not affect renal fibrosis or inflammation. Together, our data reveal a novel non-canonical effect of Nlrp3 in preserving renal integrity and protection against early tubular injury and interstitial edema following progressive renal injury.

  14. Acitretin treatment in (pre)malignant skin disorders of renal transplant recipients: Histologic and immunohistochemical effects.

    NARCIS (Netherlands)

    Smit, J.V.; Sevaux, R.G.L. de; Blokx, W.A.M.; Kerkhof, P.C.M. van de; Hoitsma, A.J.; Jong, E.M.G.J. de

    2004-01-01

    BACKGROUND: The incidence of (pre)malignant skin lesions after renal transplantation is high. Acitretin treatment appears to decrease the number of new squamous cell carcinomas and ameliorates the aspect and reduces the number of actinic keratoses. However, no histologic and immunohistochemical

  15. Fibrosis imaging : Current concepts and future directions

    NARCIS (Netherlands)

    Baues, Maike; Dasgupta, Anshuman; Ehling, Josef; Prakash, Jai; Boor, Peter; Tacke, Frank; Kiessling, Fabian; Lammers, Twan

    2017-01-01

    Fibrosis plays an important role in many different pathologies. It results from tissue injury, chronic inflammation, autoimmune reactions and genetic alterations, and it is characterized by the excessive deposition of extracellular matrix components. Biopsies are routinely employed for fibrosis

  16. Pathological assessment of liver fibrosis regression

    Directory of Open Access Journals (Sweden)

    WANG Bingqiong

    2017-03-01

    Full Text Available Hepatic fibrosis is the common pathological outcome of chronic hepatic diseases. An accurate assessment of fibrosis degree provides an important reference for a definite diagnosis of diseases, treatment decision-making, treatment outcome monitoring, and prognostic evaluation. At present, many clinical studies have proven that regression of hepatic fibrosis and early-stage liver cirrhosis can be achieved by effective treatment, and a correct evaluation of fibrosis regression has become a hot topic in clinical research. Liver biopsy has long been regarded as the gold standard for the assessment of hepatic fibrosis, and thus it plays an important role in the evaluation of fibrosis regression. This article reviews the clinical application of current pathological staging systems in the evaluation of fibrosis regression from the perspectives of semi-quantitative scoring system, quantitative approach, and qualitative approach, in order to propose a better pathological evaluation system for the assessment of fibrosis regression.

  17. Computed tomography of cystic pancreatic fibrosis

    International Nuclear Information System (INIS)

    Brachlow, M.; Zaunbauer, W.; Haertel, M.

    1984-01-01

    The computer tomographic appearances of atrophic and lipomatous degeneration of the pancreas in cystic pancreatic fibrosis are described. CT exploration of the pancreas in recommended, particularly in differential diagnostic aspects of cystic fibrosis. (orig.) [de

  18. Rapid decline in 51Cr-EDTA measured renal function during the first weeks following lung transplantation

    DEFF Research Database (Denmark)

    Hornum, M.; Iversen, M.; Steffensen, I.

    2009-01-01

    We previously described a 54% decline in renal function at 6 months after lung transplantation (LTx). We hypothesized that this decline is a very early event following LTx. Thirty-one consecutive patients (16 females/15 males), mean age 49 (+/-13) years, with emphysema, cystic fibrosis/bronchiect......We previously described a 54% decline in renal function at 6 months after lung transplantation (LTx). We hypothesized that this decline is a very early event following LTx. Thirty-one consecutive patients (16 females/15 males), mean age 49 (+/-13) years, with emphysema, cystic fibrosis....../bronchiectasis or idiopathic pulmonary fibrosis were included in an analysis of renal function before and after LTx. The glomerular filtration rate (GFR) was measured using the (51)Cr-ethylenediaminetetra acetic acid plasma clearance single injection technique (mGFR) at baseline before transplantation and at 1, 2, 3 and 12...

  19. Evaluation of phytochemicals, antioxidant activity and amelioration of pulmonary fibrosis with Phyllanthus emblica leaves.

    Science.gov (United States)

    Tahir, Irsa; Khan, Muhammad Rashid; Shah, Naseer Ali; Aftab, Maryam

    2016-10-24

    In the present study the antioxidant potential of a methanol extract of Phyllanthus emblica leaves (PELE) was determined by in vitro methods as well as by an in vivo animal model, along with HPLC-DAD screening for phyto-constituents. The in vitro antioxidant potential of PELE was assessed by scavenging of DPPH, nitric oxide and anti-lipid peroxidation assays. For in vivo evaluation, a 60-day experimental plan was followed in which Sprague Dawley rats were administered with 1 mL/kg of CCl 4 (CCl 4 : DMSO + Olive oil; 30 % v/v) alone or with different doses of PELE (200, 400 mg/kg p.o.). Silymarin (100 mg/kg) as standard drug was also administered to CCl 4 treated rats. HPLC-DAD analysis was performed to quantify polyphenolic phytochemicals. PELE exhibited an appreciable in vitro antioxidant activity and scavenged the DPPH radical (IC 50  = 39.73 ± 2.12 μg/mL) and nitric oxide (IC 50  = 39.14 ± 2.31 μg/mL) while for anti-lipid peroxidation moderate antioxidant activity was noticed. Reduced levels of antioxidant enzyme activities viz., superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and reduced glutathione (GSH) whereas enhanced levels of total extractable proteins, lipid peroxides (TBARS), nitrite and H 2 O 2 were induced by CCl 4 administration in lungs of rat. Co-administration of PELE to rats exhibited a dose dependent decline in the oxidative injuries induced in these parameters. Histopathological damages such as disrupted alveoli, infiltration of macrophages and modified architecture of Clara cells was reversed to the normal state with co-administration of PELE. HPLC-DAD analysis indicated the presence of gallic acid, rutin, kaempferol and caffeic acid in the PELE. The findings of this study demonstrate that presence of polyphenolics and other active constituents in PELE might play a significant role in repairing the pulmonary damages instigated with CCl 4 .

  20. Protective roles of pulmonary rehabilitation mixture in experimental pulmonary fibrosis in vitro and in vivo

    International Nuclear Information System (INIS)

    Zhang, L.; Ji, Y.X.; Jiang, W.L.; Lv, C.J.

    2015-01-01

    Abnormal high mobility group protein B1 (HMGB1) activation is involved in the pathogenesis of pulmonary fibrosis. Pulmonary rehabilitation mixture (PRM), which combines extracts from eight traditional Chinese medicines, has very good lung protection in clinical use. However, it is not known if PRM has anti-fibrotic activity. In this study, we investigated the effects of PRM on transforming growth factor-β1 (TGF-β1)-mediated and bleomycin (BLM)-induced pulmonary fibrosis in vitro and in vivo. The effects of PRM on TGF-β1-mediated epithelial-mesenchymal transition (EMT) in A549 cells, on the proliferation of human lung fibroblasts (HLF-1) in vitro, and on BLM-induced pulmonary fibrosis in vivo were investigated. PRM treatment resulted in a reduction of EMT in A549 cells that was associated with attenuating an increase of vimentin and a decrease of E-cadherin. PRM inhibited the proliferation of HLF-1 at an IC 50 of 0.51 µg/mL. PRM ameliorated BLM-induced pulmonary fibrosis in rats, with reduction of histopathological scores and collagen deposition, and a decrease in α-smooth muscle actin (α-SMA) and HMGB1 expression. An increase in receptor for advanced glycation end-product (RAGE) expression was found in BLM-instilled lungs. PRM significantly decreased EMT and prevented pulmonary fibrosis through decreasing HMGB1 and regulating RAGE in vitro and in vivo. PRM inhibited TGF-β1-induced EMT via decreased HMGB1 and vimentin and increased RAGE and E-cadherin levels. In summary, PRM prevented experimental pulmonary fibrosis by modulating the HMGB1/RAGE pathway

  1. Protective roles of pulmonary rehabilitation mixture in experimental pulmonary fibrosis in vitro and in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, L.; Ji, Y.X.; Jiang, W.L.; Lv, C.J. [School of Pharmaceutical Sciences, Binzhou Medical University, Yantai (China)

    2015-05-08

    Abnormal high mobility group protein B1 (HMGB1) activation is involved in the pathogenesis of pulmonary fibrosis. Pulmonary rehabilitation mixture (PRM), which combines extracts from eight traditional Chinese medicines, has very good lung protection in clinical use. However, it is not known if PRM has anti-fibrotic activity. In this study, we investigated the effects of PRM on transforming growth factor-β1 (TGF-β1)-mediated and bleomycin (BLM)-induced pulmonary fibrosis in vitro and in vivo. The effects of PRM on TGF-β1-mediated epithelial-mesenchymal transition (EMT) in A549 cells, on the proliferation of human lung fibroblasts (HLF-1) in vitro, and on BLM-induced pulmonary fibrosis in vivo were investigated. PRM treatment resulted in a reduction of EMT in A549 cells that was associated with attenuating an increase of vimentin and a decrease of E-cadherin. PRM inhibited the proliferation of HLF-1 at an IC{sub 50} of 0.51 µg/mL. PRM ameliorated BLM-induced pulmonary fibrosis in rats, with reduction of histopathological scores and collagen deposition, and a decrease in α-smooth muscle actin (α-SMA) and HMGB1 expression. An increase in receptor for advanced glycation end-product (RAGE) expression was found in BLM-instilled lungs. PRM significantly decreased EMT and prevented pulmonary fibrosis through decreasing HMGB1 and regulating RAGE in vitro and in vivo. PRM inhibited TGF-β1-induced EMT via decreased HMGB1 and vimentin and increased RAGE and E-cadherin levels. In summary, PRM prevented experimental pulmonary fibrosis by modulating the HMGB1/RAGE pathway.

  2. Radionuclide evaluation of renal transplants

    International Nuclear Information System (INIS)

    Yang Hong; Zhao Deshan

    2000-01-01

    Radionuclide renal imaging and plasma clearance methods can quickly quantitate renal blood flow and function in renal transplants. They can diagnose acute tubular necrosis and rejection, renal scar, surgical complications such as urine leaks, obstruction and renal artery stenosis after renal transplants. At the same time they can assess the therapy effect of renal transplant complications and can also predict renal transplant survival from early post-operative function studies

  3. Myeloid-Derived Suppressor Cells Ameliorate Cyclosporine A-Induced Hypertension in Mice.

    Science.gov (United States)

    Chiasson, Valorie L; Bounds, Kelsey R; Chatterjee, Piyali; Manandhar, Lochana; Pakanati, Abhinandan R; Hernandez, Marcos; Aziz, Bilal; Mitchell, Brett M

    2018-01-01

    The calcineurin inhibitor cyclosporine A (CsA) suppresses the immune system but promotes hypertension, vascular dysfunction, and renal damage. CsA decreases regulatory T cells and this contributes to the development of hypertension. However, CsA's effects on another important regulatory immune cell subset, myeloid-derived suppressor cells (MDSCs), is unknown. We hypothesized that augmenting MDSCs would ameliorate the CsA-induced hypertension and vascular and renal injury and dysfunction and that CsA reduces MDSCs in mice. Daily interleukin-33 treatment, which increased MDSC levels, completely prevented CsA-induced hypertension and vascular and renal toxicity. Adoptive transfer of MDSCs from control mice into CsA-treated mice after hypertension was established dose-dependently reduced blood pressure and vascular and glomerular injury. CsA treatment of aortas and kidneys isolated from control mice for 24 hours decreased relaxation responses and increased inflammation, respectively, and these effects were prevented by the presence of MDSCs. MDSCs also prevented the CsA-induced increase in fibronectin in microvascular and glomerular endothelial cells. Last, CsA dose-dependently reduced the number of MDSCs by inhibiting calcineurin and preventing cell proliferation, as other direct calcineurin signaling pathway inhibitors had the same dose-dependent effect. These data suggest that augmenting MDSCs can reduce the cardiovascular and renal toxicity and hypertension caused by CsA. © 2017 American Heart Association, Inc.

  4. Distal renal tubular acidosis

    Science.gov (United States)

    ... this disorder. Alternative Names Renal tubular acidosis - distal; Renal tubular acidosis type I; Type I RTA; RTA - distal; Classical RTA Images Kidney anatomy Kidney - blood and urine flow References Bose A, Monk RD, Bushinsky DA. Kidney ...

  5. Renal microvascular disease determines the responses to revascularization in experimental renovascular disease.

    Science.gov (United States)

    Chade, Alejandro R; Kelsen, Silvia

    2010-08-01

    Percutaneous transluminal renal angioplasty (PTRA) is the most frequent therapeutic approach to resolving renal artery stenosis (RAS). However, renal function recovers in only 30% of the cases. The causes of these poor outcomes are still unknown. We hypothesized that preserving the renal microcirculation distal to RAS will improve the responses to PTRA. RAS was induced in 28 pigs. In 14, vascular endothelial growth factor (VEGF)-165 0.05 microg/kg was infused intrarenally (RAS+VEGF). Single-kidney function was assessed in all pigs in vivo using ultrafast CT after 6 weeks. Observation of half of the RAS and RAS+VEGF pigs was completed. The other half underwent PTRA and repeated VEGF, and CT studies were repeated 4 weeks later. Pigs were then euthanized, the stenotic kidney removed, renal microvascular (MV) architecture reconstructed ex vivo using 3D micro-CT, and renal fibrosis quantified. The degree of RAS and hypertension were similar in RAS and RAS+VEGF. Renal function and MV density were decreased in RAS but improved in RAS+VEGF. PTRA largely resolved RAS, but the improvements of hypertension and renal function were greater in RAS+VEGF+PTRA than in RAS+PTRA, accompanied by a 34% increase in MV density and decreased fibrosis. Preservation of the MV architecture and function in the stenotic kidney improved the responses to PTRA, indicating that renal MV integrity plays a role in determining the responses to PTRA. This study indicates that damage and early loss of renal MV is an important determinant of the progression of renal injury in RAS and instigates often irreversible damage.

  6. Ameliorative effect of Lentinus squarrosulus mycomeat against ...

    African Journals Online (AJOL)

    Ameliorative effect of Lentinus squarrosulus mycomeat against Pseudomonas aeruginosa infection using albino rat as animal model. ... Morphological appearance and behavior of the rats were used as the assessment method for adverse reactions. After a period of 26 days, the rats were sacrificed with the liver, spleen and ...

  7. Radiation pericarditis and myocardial fibrosis

    Energy Technology Data Exchange (ETDEWEB)

    Westerhof, P W; van der Putte, S C.J.

    1976-06-01

    The case of a 45-yr-old man with constrictive pericarditis due to radiation for Hodgkin's disease is described. After pericardiectomy the clinical condition did not improve. At necropsy an extensive fibrosis of the myocardium especially located in the anterior part of the heart was found. The clinical consequences of this finding with respect to surgical treatment are briefly discussed.

  8. Hepatic fibrosis: Concept to treatment.

    Science.gov (United States)

    Trautwein, Christian; Friedman, Scott L; Schuppan, Detlef; Pinzani, Massimo

    2015-04-01

    Understanding the molecular mechanisms underlying liver fibrogenesis is fundamentally relevant to developing new treatments that are independent of the underlying etiology. The increasing success of antiviral treatments in blocking or reversing the fibrogenic progression of chronic liver disease has unearthed vital information about the natural history of fibrosis regression, and has established important principles and targets for antifibrotic drugs. Although antifibrotic activity has been demonstrated for many compounds in vitro and in animal models, none has been thoroughly validated in the clinic or commercialized as a therapy for fibrosis. In addition, it is likely that combination therapies that affect two or more key pathogenic targets and/or pathways will be needed. To accelerate the preclinical development of these combination therapies, reliable single target validation is necessary, followed by the rational selection and systematic testing of combination approaches. Improved noninvasive tools for the assessment of fibrosis content, fibrogenesis and fibrolysis must accompany in vivo validation in experimental fibrosis models, and especially in clinical trials. The rapidly changing landscape of clinical trial design for liver disease is recognized by regulatory agencies in the United States (FDA) and Western Europe (EMA), who are working together with the broad range of stakeholders to standardize approaches to testing antifibrotic drugs in cohorts of patients with chronic liver diseases. Copyright © 2015. Published by Elsevier B.V.

  9. [Genetic counseling in cystic fibrosis].

    Science.gov (United States)

    Julia, S; Bieth, E

    2000-08-01

    Genetic counseling is an important part of health care in patients with cystic fibrosis or respiratory diseases associated with the CFTR (cystic fibrosis transmembrane conductance regulator) gene, including certain types of allergic bronchopulmonary aspergilloses or bronchial diseases (diffuse bronchiectasia). The basic goal is to provide patients with information on the transmission of cystic fibrosis and to asses the risk of recurrence. This risk is determined from molecular biology analyses examining the CFTR gene. Genotyping is the only means of screening for the heterozygous state, frequent in the French population (about 1/30). Because of the large number of mutated alleles not covered entirely by the genetic tests, there remains a question of probability expressed as a residual risk of a heterozygous state. A prenatal genotype diagnosis should be proposed to heterozygous couples who have a 25% risk of having a diseased child. Technically, this is almost always possible and the results are highly reliable. Nevertheless, there remains the risks related to sample taking and the ethical issue about which the patients must be informed. Management of these at risk couples who desire a child must be based on a multidisciplinary approach, particularly important when one of the parents has overt cystic fibrosis.

  10. Cardio-renal syndrome

    OpenAIRE

    Gnanaraj, Joseph; Radhakrishnan, Jai

    2016-01-01

    Cardio-renal syndrome is a commonly encountered problem in clinical practice. Its pathogenesis is not fully understood. The purpose of this article is to highlight the interaction between the cardiovascular system and the renal system and how their interaction results in the complex syndrome of cardio-renal dysfunction. Additionally, we outline the available therapeutic strategies to manage this complex syndrome.

  11. Renal inflammatory myofibroblastic tumor

    DEFF Research Database (Denmark)

    Heerwagen, S T; Jensen, C; Bagi, P

    2007-01-01

    Renal inflammatory myofibroblastic tumor (IMT) is a rare soft-tissue tumor of controversial etiology with a potential for local recurrence after incomplete surgical resection. The radiological findings in renal IMT are not well described. We report two cases in adults with a renal mass treated...

  12. Nephrogenic systemic fibrosis after application of gadolinium-based contrast agents - a status paper

    International Nuclear Information System (INIS)

    Heinrich, M.; Uder, M.

    2007-01-01

    Recently the association of a rare disease named ''nephrogenic systemic fibrosis'' (NSF) with the administration of gadolinium-containing contrast media, especially gadodiamide (Omniscan, GE-Healthcare), was described. NSF is a scleroderma-like disease characterised by widespread tissue fibrosis. Until now, NSF cases were observed only in patients with kidney disease. Almost all patients were suffering from chronic renal insufficiency, 90 % of them required renal replacement therapy. The true incidence of the disease is unknown. First retrospective analyses of selected collectives of patients with end-stage renal disease showed 2 - 5 % cases of NSF after administration of Gadolinium-containing contrast agents with an odds ratio of 20 - 50 in comparison to non-exposed controls. NSF is a serious adverse reaction, which may result in severe disabilities and even death. Therefore all radiologists applying gadolinium-based contrast agents should be informed about this disease and the recent recommendations for its prevention. On the basis of the published data, Omniscan should not be used in patients with severe renal impairment (GFR 2 ) and those who have had or are undergoing liver transplantation. In neonates and infants up to 1 year of age, Omniscan should only be used after careful consideration. Also the other gadolinium-based contrast agents should be used in high-risk patients only after careful consideration using the lowest dose possible

  13. Preservation of renal function by intensive glycemic control

    Directory of Open Access Journals (Sweden)

    Naoya Toriu

    2018-01-01

    Full Text Available We report the case of a 67-year-old Japanese woman with type 1 diabetes mellitus. At 47 years of age, her hemoglobin A1c (HbA1c was 10.0%, and she had overt nephropathy. The first renal biopsy yielded a diagnosis of diabetic nephropathy. Intensive glycemic control was initiated and her HbA1c improved to 6.0%. Renal dysfunction showed no progression for 15 years. At 62 years of age, a second renal biopsy was performed. Glomerular lesions did not show progression but tubulointerstitial fibrosis and vascular lesions showed progression compared with the first biopsy. Intensive glycemic control can prevent the progression of glomerular lesions, but might not be effective for interstitial and vascular lesions.

  14. Metabolomic Analysis of N-acetylcysteine Protection of Injury from Gadolinium-DTPA Contrast Agent in Rats with Chronic Renal Failure.

    Science.gov (United States)

    Wan, Chuanling; Xue, Rong; Zhan, Youyang; Wu, Yijie; Li, Xiaojing; Pei, Fengkui

    2017-09-01

    Gadolinium-based contrast agents (GBCAs) are frequently used to enhance the diagnostic efficacy of magnetic resonance imaging. On the other hand, the association between GBCA administration in patients with advanced renal disease and nephrogenic systemic fibrosis (NSF) was also noted. NSF is a systemic disorder characterized by widespread tissue fibrosis that may lead to death. N-acetylcysteine (NAC) protects rats from injury induced by gadolinium-based contrast agents, but the underlying mechanisms remain unclear. In this study, a nuclear magnetic resonance-based metabolomic approach was used to systematically investigate the protective effects of NAC on Gd-DTPA-induced injury. Thirty-two male Sprague-Dawley rats were given adenine (200 mg·kg -1 body weight) by oral gavage once a day for 3 weeks to induce chronic renal failure (CRF). NAC (600 mg/L in drinking water for 9 days) pretreatment was initiated 2 days before Gd-DTPA injection (a single tail vein injection, 2 mmol/kg body weight). Serum and liver samples were collected on day 7 after Gd-DTPA injection. By study design, the serum and hepatic metabolic changes of rats were measured in four groups of eight each: CRF, CRF-Gd, CRF-Gd-NAC, and CRF-NAC. Gd-DTPA administration to rats with CRF resulted in disturbances of several metabolic pathways, including glucose, lipid, glutamate, choline, gut microbiota, one-carbon, and purine metabolism. NAC pretreatment reversed the abundance changes of high-density lipoprotein, low-density lipoprotein, very low-density lipoprotein, glutamate, glutamine, oxidized glutathione, choline, phosphocholine, glycerophosphocholine, trimethylamine, and trimethylamine-N-oxide induced by Gd-DTPA. It is noteworthy, however, that the ameliorating effects of NAC on the disturbance of glutamate, choline, and gut microbiota metabolism may be specific to Gd-DTPA. In all, these findings could be potentially useful to decipher the underlying mechanisms of NAC protective effects from the

  15. Traumatic renal infarction

    International Nuclear Information System (INIS)

    Yashiro, Naobumi; Ohtomo, Kuni; Kokubo, Takashi; Itai, Yuji; Iio, Masahiro

    1986-01-01

    Four cases of traumatic renal artery occlusion were described and illustrated. In two cases, direct blows to the abdomen compressed the renal artery against the vertebral column. Clinically, they were severely injured with macroscopic hematuria. Aortograms showed abrupt truncation of renal arteries. In the other two, rapid deceleration caused sudden displacement of the kidney producing an intimal tear with resultant thrombosis. Although they showed little injury without macrohematuria, aortograms revealed tapered occlusion of renal arteries. One of them developed hypertension. ''Rim sign'' of post-contrast CT and hypertension resulted from traumatic renal artery occlusion were reviewed. (author)

  16. Brazilian red propolis attenuates hypertension and renal damage in 5/6 renal ablation model.

    Directory of Open Access Journals (Sweden)

    Flávio Teles

    Full Text Available The pathogenic role of inflammation and oxidative stress in chronic kidney disease (CKD is well known. Anti-inflammatories and antioxidant drugs has demonstrated significant renoprotection in experimental nephropathies. Moreover, the inclusion of natural antioxidants derived from food and herbal extracts (such as polyphenols, curcumin and lycopene as an adjuvant therapy for slowing CKD progression has been largely tested. Brazilian propolis is a honeybee product, whose anti-inflammatory, antimicrobial and antioxidant effects have been widely shown in models of sepsis, cancer, skin irritation and liver fibrosis. Furthermore, previous studies demonstrated that this compound promotes vasodilation and reduces hypertension. However, potential renoprotective effects of propolis in CKD have never been investigated. The aim of this study was to evaluate the effects of a subtype of Brazilian propolis, the Red Propolis (RP, in the 5/6 renal ablation model (Nx. Adult male Wistar rats underwent Nx and were divided into untreated (Nx and RP-treated (Nx+RP groups, after 30 days of surgery; when rats already exhibited marked hypertension and proteinuria. Animals were observed for 90 days from the surgery day, when Nx+RP group showed significant reduction of hypertension, proteinuria, serum creatinine retention, glomerulosclerosis, renal macrophage infiltration and oxidative stress, compared to age-matched untreated Nx rats, which worsened progressively over time. In conclusion, RP treatment attenuated hypertension and structural renal damage in Nx model. Reduction of renal inflammation and oxidative stress could be a plausible mechanism to explain this renoprotection.

  17. Inhibition of Protease-activated Receptor 1 Ameliorates Intestinal Radiation Mucositis in a Preclinical Rat Model

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Junru; Kulkarni, Ashwini [Division of Radiation Health, University of Arkansas for Medical Sciences, Little Rock, Arkansas (United States); Chintala, Madhu [Schering-Plough Research Institute, Kenilworth, New Jersey (United States); Fink, Louis M. [Nevada Cancer Institute, Las Vegas, Nevada (United States); Hauer-Jensen, Martin, E-mail: mhjensen@life.uams.edu [Division of Radiation Health, University of Arkansas for Medical Sciences, Little Rock, Arkansas (United States); Surgery Service, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas (United States)

    2013-01-01

    Purpose: To determine, using a specific small-molecule inhibitor of protease-activated receptor 1 (PAR1) signaling, whether the beneficial effect of thrombin inhibition on radiation enteropathy development is due to inhibition of blood clotting or to cellular (PAR1-mediated) thrombin effects. Methods and Materials: Rats underwent fractionated X-irradiation (5 Gy Multiplication-Sign 9) of a 4-cm small-bowel segment. Early radiation toxicity was evaluated in rats receiving PAR1 inhibitor (SCH602539, 0, 10, or 15 mg/kg/d) from 1 day before to 2 weeks after the end of irradiation. The effect of PAR1 inhibition on development of chronic intestinal radiation fibrosis was evaluated in animals receiving SCH602539 (0, 15, or 30 mg/kg/d) until 2 weeks after irradiation, or continuously until termination of the experiment 26 weeks after irradiation. Results: Blockade of PAR1 ameliorated early intestinal toxicity, with reduced overall intestinal radiation injury (P=.002), number of myeloperoxidase-positive (P=.03) and proliferating cell nuclear antigen-positive (P=.04) cells, and collagen III accumulation (P=.005). In contrast, there was no difference in delayed radiation enteropathy in either the 2- or 26-week administration groups. Conclusion: Pharmacological blockade of PAR1 seems to reduce early radiation mucositis but does not affect the level of delayed intestinal radiation fibrosis. Early radiation enteropathy is related to activation of cellular thrombin receptors, whereas platelet activation or fibrin formation may play a greater role in the development of delayed toxicity. Because of the favorable side-effect profile, PAR1 blockade should be further explored as a method to ameliorate acute intestinal radiation toxicity in patients undergoing radiotherapy for cancer and to protect first responders and rescue personnel in radiologic/nuclear emergencies.

  18. Expression of GSK-3β in renal allograft tissue and its significance in pathogenesis of chronic allograft dysfunction

    Directory of Open Access Journals (Sweden)

    Yan Qiang

    2012-01-01

    Full Text Available Abstract Objective To explore the expression of Glycogen synthase kinase 3 beta (GSK-3β in renal allograft tissue and its significance in the pathogenesis of chronic allograft dysfunction. Methods Renal allograft biopsy was performed in all of the renal allograft recipients with proteinuria or increased serum creatinine level who came into our hospital from January 2007 to December 2009. Among them 28 cases was diagnosed as chronic allograft dysfunction based on pahtological observation, including 21 males with a mean age of 45 ± 10 years old and 7 females with a mean age of 42 ± 9 years old. The time from kidney transplantation to biopsy were 1-9 (3.5 years. Their serum creatinine level were 206 ± 122 umol/L. Immunohistochemical assay and computer-assisted genuine color image analysis system (imagepro-plus 6.0 were used to detect the expression of GSK-3β in the renal allografts of 28 cases of recipients with chronic allograft dysfunction. Mean area and mean integrated optical density of GSK-3β expression were calculated. The relationship between expression level of GSK-3β and either the grade of inflammatory cell infiltration or interstitial fibrosis/tubular atrophy in renal allograft was analyzed. Five specimens of healthy renal tissue were used as controls. Results The expression level of the GSK-3β was significantly increased in the renal allograft tissue of recipients with chronic allograft dysfunction, compared to normal renal tissues, and GSK-3β expression became stronger along with the increasing of the grade of either inflammatory cell infiltration or interstitial fibrosis/tubular atrophy in renal allograft tissue. Conclusion There might be a positive correlation between either inflammatory cell infiltration or interstitial fibrosis/tubular atrophy and high GSK-3β expression in renal allograft tissue. Virtual slides The virtual slide(s for this article can be found here: http

  19. Retroperitoneal fibrosis: the clinical and radiological manifestation

    International Nuclear Information System (INIS)

    Pan Weidong; Zhao Rongguo; Qin Mingwei; Xue Huadan; Liang Jixiang

    2005-01-01

    Objective: To analyze the clinical and radiological features of retroperitoneal fibrosis (RPF), and to deepen the understanding of this unusual disease and improve the diagnostic level at the early stage. Methods: Fourteen cases (10 males and 4 females, mean age 45.8 years) of pathologically diagnosed RPF from January 1990 to June 2004 were summarized. The clinical and radiological performance of the cases were analyzed. All patients received non-contrast CT scanning, 10 of them underwent enhanced CT scanning as well. 8 patients received MRI, 10 patients received IVP examination, and 11 received B-ultrasound. Results: (1) The very first symptoms usually included back pain, bellyache (10 cases), or urinary tract obstruction (3 cases), with increase of ESR, IgG, CRP value and abnormal renal function. (2) The result of radiological examination showed that 11 lesions of the 14 cases located at retroperitoneum. Ten cases were mass type and 4 cases were diffuse type. Non-contrast CT scanning revealed soft tissue mass at retroperitoneum with in homogenous or homogenous density. After contrast medium injection the lesions were enhanced with different extent. MRI results showed that the lesions presented low signal in T 1 WI, while in T 2 WI the signals had no obvious coherence but were different from one case to another. Conclusion: Radiological examination is one of the important methods for diagnosis of RPF. Based on the different characteristics of RPF in CT and MRI, together with the clinical findings, we will get valuable references for staging and follow-up of RPF. (authors)

  20. Ameliorative effects of arctiin from Arctium lappa on experimental glomerulonephritis in rats.

    Science.gov (United States)

    Wu, Jian-Guo; Wu, Jin-Zhong; Sun, Lian-Na; Han, Ting; Du, Jian; Ye, Qi; Zhang, Hong; Zhang, Yu-Guang

    2009-11-01

    Membranous glomerulonephritis (MGN) remains the most common cause of adult-onset nephrotic syndrome in the world and up to 40% of untreated patients will progress to end-stage renal disease. Although the treatment of MGN with immunosuppressants or steroid hormones can attenuate the deterioration of renal function, numerous treatment-related complications have also been established. In this study, the ameliorative effects of arctiin, a natural compound isolated from the fruits of Arctium lappa, on rat glomerulonephritis induced by cationic bovine serum albumin (cBSA) were determined. After oral administration of arctiin (30, 60, 120 mg/kgd) for three weeks, the levels of serum creatinine (Scr) and blood urea nitrogen (BUN) and 24-h urine protein content markedly decreased, while endogenous creatinine clearance rate (ECcr) significantly increased. The parameters of renal lesion, hypercellularity, infiltration of polymorphonuclear leukocyte (PMN), fibrinoid necrosis, focal and segmental proliferation and interstitial infiltration, were reversed. In addition, we observed that arctiin evidently reduced the levels of malondialdehyde (MDA) and pro-inflammatory cytokines including interleukin-6 (IL-6) and tumor necrosis factor (TNF-alpha), suppressed nuclear factor-kappaB p65 (NF-kappaB) DNA binding activity, and enhanced superoxide dismutase (SOD) activity. These findings suggest that the ameliorative effects of arctiin on glomerulonephritis is carried out mainly by suppression of NF-kappaB activation and nuclear translocation and the decreases in the levels of these pro-inflammatory cytokines, while SOD is involved in the inhibitory pathway of NF-kappaB activation. Arctiin has favorable potency for the development of an inhibitory agent of NF-kappaB and further application to clinical treatment of glomerulonephritis, though clinical studies are required.

  1. Celecoxib and octreotide synergistically ameliorate portal hypertension via inhibition of angiogenesis in cirrhotic rats.

    Science.gov (United States)

    Gao, Jin-Hang; Wen, Shi-Lei; Feng, Shi; Yang, Wen-Juan; Lu, Yao-Yao; Tong, Huan; Liu, Rui; Tang, Shi-Hang; Huang, Zhi-Yin; Tang, Ying-Mei; Yang, Jin-Hui; Xie, Hui-Qi; Tang, Cheng-Wei

    2016-10-01

    Abnormal angiogenesis is critical for portal hypertension in cirrhosis. Except for etiological treatment, no efficient medication or regime has been explored to treat the early stage of cirrhosis when angiogenesis is initiated or overwhelming. In this study, we explored an anti-angiogenesis effort through non-cytotoxic drugs octreotide and celecoxib to treat early stage of cirrhotic portal hypertension in an animal model. Peritoneal injection of thioacetamide (TAA) was employed to induce liver cirrhosis in rats. A combination treatment of celecoxib and octreotide was found to relieve liver fibrosis, portal venous pressure, micro-hepatic arterioportal fistulas, intrahepatic and splanchnic angiogenesis. Celecoxib and octreotide exerted their anti-angiogenesis effect via an axis of cyclooxygenase-2/prostaglandin E2/EP-2/somatostatin receptor-2, which consequently down-regulated phosphorylation of extracellular signal-regulated kinase (p-ERK)-hypoxia-inducible factor-1α (HIF-1α)-vascular endothelial growth factor (VEGF) integrated signaling pathways. In conclusions, combination of celecoxib and octreotide synergistically ameliorated liver fibrosis and portal hypertension of the cirrhotic rats induced by TAA via the inhibition of intrahepatic and extrahepatic angiogenesis. The potential mechanisms behind the regimen may due to the inactivation of p-ERK-HIF-1α-VEGF signaling pathway.

  2. Epidemiology of idiopathic pulmonary fibrosis

    Directory of Open Access Journals (Sweden)

    Ley B

    2013-11-01

    Full Text Available Brett Ley, Harold R Collard Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of California San Francisco, San Francisco, California, USA Abstract: Idiopathic pulmonary fibrosis is a chronic fibrotic lung disease of unknown cause that occurs in adults and has a poor prognosis. Its epidemiology has been difficult to study because of its rarity and evolution in diagnostic and coding practices. Though uncommon, it is likely underappreciated both in terms of its occurrence (ie, incidence, prevalence and public health impact (ie, health care costs and resource utilization. Incidence and mortality appear to be on the rise, and prevalence is expected to increase with the aging population. Potential risk factors include occupational and environmental exposures, tobacco smoking, gastroesophageal reflux, and genetic factors. An accurate understanding of its epidemiology is important, especially as novel therapies are emerging. Keywords: idiopathic pulmonary fibrosis, epidemiology, incidence, prevalence, mortality, risk factors

  3. MRI in mucoviscidosis (cystic fibrosis)

    International Nuclear Information System (INIS)

    Eichinger, M.; Puderbach, M.; Kauczor, H.-U.; Heussel, C.-P.

    2006-01-01

    Cystic fibrosis (CF) is a multi-systemic disease with major impact on the lungs. Pulmonary manifestation is crucial for the prognosis and life expectancy of patients. Imaging modalities and lung function tests reflect the pulmonary status in these patients. The standard imaging modality for diagnosis and follow-up of pulmonary changes is chest x-ray. The gold standard for the detection of parenchymal lung changes remains high resolution computed tomography (HRCT), but this is not used routinely for CF-patients due to radiation exposure. Magnetic resonance imaging (MRI) used to be of no importance in monitoring cystic fibrosis lung disease, as shown in studies from the 1980s and early 1990s. The continuing improvement of MRI techniques, however, has allowed for an adequate application of this non-radiation method in diagnosing the major pulmonary findings in CF, in addition to the assessment of lung function. (orig.) [de

  4. [Historical compilation of cystic fibrosis].

    Science.gov (United States)

    Navarro, Salvador

    2016-01-01

    Cystic fibrosis is the most common life-shortening recessively inherited disorder in the Caucasian population. The genetic mutation that most frequently provokes cystic fibrosis (ΔF508) appeared at least 53,000years ago. For many centuries, the disease was thought to be related to witchcraft and the "evil eye" and it was only in 1938 that Dorothy H. Andersen characterized this disorder and suspected its genetic origin. The present article reviews the pathological discoveries and diagnostic and therapeutic advances made in the last 75 years. The review ends with some considerations for the future. Copyright © 2015 Elsevier España, S.L.U. and AEEH y AEG. All rights reserved.

  5. Fibrosis endomiocárdica

    Directory of Open Access Journals (Sweden)

    María Juliana Rodríguez-González

    2017-07-01

    Una de las formas más comunes de miocardiopatía restrictiva es la fibrosis endomiocárdica la cual es endémica en algunas zonas tropicales especialmente en África (países de bajos ingresos, pero en nuestro medio hay pocos reportes de aparición. Su etiología es desconocida, aunque existen diversos mecanismos que han sido involucrados en su fisiopatología. Su diagnóstico se basa en estudios imagenológicos (ecocardiograma transtorácico y resonancia magnética nuclear cardíaca. El pronóstico es muy pobre, y usualmente se diagnostica en etapas muy avanzadas de la enfermedad. Se describe el caso de una paciente femenina, adulta media, que debutó con cardiopatía restrictiva, cuyo diagnóstico final fue fibrosis endomiocárdica.

  6. Recommendations for quality improvement in genetic testing for cystic fibrosis European Concerted Action on Cystic Fibrosis

    NARCIS (Netherlands)

    Dequeker, E; Cuppens, H; Dodge, J; Estivill, [No Value; Goossens, M; Pignatti, PF; Scheffer, H; Schwartz, M; Schwarz, M; Tummler, B; Cassiman, JJ

    These recommendations for quality improvement of cystic fibrosis genetic diagnostic testing provide general guidelines for the molecular genetic testing of cystic fibrosis in patients/individuals. General strategies for testing as well as guidelines for laboratory procedures, internal and external

  7. sup(99m)Tc-DMSA renal scintigraphy in renal failure due to various renal diseases

    Energy Technology Data Exchange (ETDEWEB)

    Hosokawa, S; Daijo, K; Okabe, T; Kawamura, J; Hara, A [Kyoto Univ. (Japan). Hospital

    1979-08-01

    Renal contours in renal failure were studied by means of sup(99m)Tc-dimercaptosuccinic acid (DMSA) renoscintigraphy. Renal cortical images were obtained even in renal failure cases. Causes of renal failure were chronic glomerulonephritis in 7, bilateral renal tuberculosis in 2, chronic pyelonephritis in 3, bilateral renal calculi in 3, diabetic nephropathy in 2, polycystic kidney disease in 2 and stomach cancer in 1.

  8. sup(99m)Tc-DMSA renal scintigraphy in renal failure due to various renal diseases

    International Nuclear Information System (INIS)

    Hosokawa, Shin-ichi; Daijo, Kazuyuki; Okabe, Tatsushiro; Kawamura, Juichi; Hara, Akira

    1979-01-01

    Renal contours in renal failure were studied by means of sup(99m)Tc-dimercaptosuccinic acid (DMSA) renoscintigraphy. Renal cortical images were obtained even in renal failure cases. Causes of renal failure were chronic glomerulonephritis in 7, bilateral renal tuberculosis in 2, chronic pyelonephritis in 3, bilateral renal calculi in 3, diabetic nephropathy in 2, polycystic kidney disease in 2 and stomach cancer in 1. (author)

  9. Cytokine accumulation in osteitis fibrosa of renal osteodystrophy

    Directory of Open Access Journals (Sweden)

    Duarte M.E.L.

    2002-01-01

    Full Text Available Bone marrow fibrosis occurs in association with a number of pathological states. Despite the extensive fibrosis that sometimes characterizes renal osteodystrophy, little is known about the factors that contribute to marrow accumulation of fibrous tissue. Because circulating cytokines are elevated in uremia, possibly in response to elevated parathyroid hormone levels, we have examined bone biopsies from 21 patients with end-stage renal disease and secondary hyperparathyroidism. Bone sections were stained with antibodies to human interleukin-1alpha (IL-1alpha, IL-6, IL-11, tumor necrosis factor-alpha (TNF-alpha and transforming growth factor-ß (TGF-ß using an undecalcified plastic embedding method. Intense staining for IL-1alpha, IL-6, TNF-alpha and TGF-ß was evident within the fibrotic tissue of the bone marrow while minimal IL-11 was detected. The extent of cytokine deposition corresponded to the severity of fibrosis, suggesting their possible involvement in the local regulation of the fibrotic response. Because immunoreactive TGF-ß and IL-6 were also detected in osteoblasts and osteocytes, we conclude that selective cytokine accumulation may have a role in modulating bone and marrow cell function in parathyroid-mediated uremic bone disease.

  10. Lactate in cystic fibrosis sputum

    DEFF Research Database (Denmark)

    Bensel, Tobias; Stotz, Martin; Borneff-Lipp, Marianne

    2011-01-01

    Antibiotic therapy is thought to improve lung function in patients with cystic fibrosis (CF) by decreasing neutrophil-derived inflammation. We investigated the origin and clinical significance of lactate in the chronically inflamed CF lung. Methods Lactate was measured in sputa of 18 exacerbated...... and 25 stable CF patients via spectrophotometry and gaschromatography. Lung function was assessed via spirometry. Seven patients with chronic obstructive pulmonary disease (COPD) and three patients with acute lung inflammation served as control groups. Neutrophil and bacterial lactate production...

  11. Anorexia nervosa in cystic fibrosis.

    Science.gov (United States)

    Linkson, Lynette; Macedo, Patricia; Perrin, Felicity M R; Elston, Caroline M

    2018-03-01

    This article explores the challenges associated with diagnosing and managing eating disorders such as anorexia nervosa amongst adolescents and adults with cystic fibrosis. It reviews the known risk factors, generic verses disease specific eating disorder risk screening tools and considers the ethical dilemmas associated with critically low body mass indices. A case review is included to illustrate the complexities of managing both conditions in the context of declining respiratory function. Copyright © 2017. Published by Elsevier Ltd.

  12. Idiopathic pulmonary fibrosis: treatment update.

    LENUS (Irish Health Repository)

    O'Connell, Oisin J

    2011-11-01

    Idiopathic pulmonary fibrosis (IPF) is the most common of the idiopathic interstitial pneumonias. Despite multiple recent clinical trials, there is no strong evidence supporting a survival advantage for any agent in the management of patients with IPF. The limited effectiveness of current treatment regimes has led to a search for novel therapies including antifibrotic strategies. This article reviews the evidence supporting the treatments currently used in the management of IPF.

  13. [Effect of edaravone on oxidative stress and myocardial fibrosis induced by isoproterenol in rats].

    Science.gov (United States)

    Wang, Shixiang; Lu, Zhifeng; Xu, Wei; Chen, Youquan; Chen, Ximing

    2015-11-01

    To investigate the effect of edaravone on oxidative stress and myocardial fibrosis induced by isoproterenol in rats. Fifty male SD rats were randomly divided into 5 groups, including a control group, a myocardial fibrosis model (established by injections of isopropyl adrenaline for 10 days) group, and 3 edaravone groups with edaravone treatment at low, medium, or high doses for 14 days. After the treatments, the rats were examined for the degree of myocardial fibrosis, left ventricular mass index (LVMI), collagen volume fraction (CVF), and myocardial contents of collagen I (Col I), collage III (Col III), hydroxyproline (Hyp), superoxide dismutase (SOD), malondialdehyde (MDA), and nitric oxide (NO); The expression of transforming growth factor-β1 (TGF-β1) in the myocardial tissues was examined by immunofluorescence assay and Western blotting. Compared with the control rats, the rat models of myocardial fibrosis showed significantly increased CVF and LVMI (P=0.000), which were lowered by edaravone treatments in a dose-dependent manner (Pedaravone; the contents of MDA was higher (P=0.000) and SOD and NO were lower in the model group (P=0.000), and edaravone treatments obviously increased SOD and NO contents (Pedaravone treatments (P=0.000). The myocardial content of MDA was positively correlated while SOD and NO were negatively with LVMI, CVF, Col I, Col III and Hyp; TGF-β1 was positively correlated with LVMI, CVF, Col I, Col III, Hyp and MDA but negatively with SOD and NO. Edaravone can relieve oxidative stress and inhibit TGF-β1 activation to ameliorate myocardial fibrosis in rats.

  14. Endogenous annexin A1 counter-regulates bleomycin-induced lung fibrosis

    Directory of Open Access Journals (Sweden)

    Flower Roderick J

    2011-10-01

    Full Text Available Abstract Background The balancing functions of pro/anti-inflammatory mediators of the complex innate responses have been investigated in a variety of experimental inflammatory settings. Annexin-A1 (AnxA1 is one mediator of endogenous anti-inflammation, affording regulation of leukocyte trafficking and activation in many contexts, yet its role in lung pathologies has been scarcely investigated, despite being highly expressed in lung cells. Here we have applied the bleomycin lung fibrosis model to AnxA1 null mice over a 21-day time-course, to monitor potential impact of this mediator on the control of the inflammatory and fibrotic phases. Results Analyses in wild-type mice revealed strict spatial and temporal regulation of the Anxa1 gene, e.g. up-regulation in epithelial cells and infiltrated granulocytes at day 7, followed by augmented protein levels in alveolar macrophages by day 21. Absence of AnxA1 caused increases in: i the degree of inflammation at day 7; and ii indexes of fibrosis (assessed by deposition of hydroxyproline in the lung at day 7 and 21. These alterations in AnxA1 null mice were paralleled by augmented TGF-β1, IFN-γ and TNF-α generation compared to wild-type mice. Finally, treatment of wild type animals with an AnxA1 peptido-mimetic, given prophylactically (from day 0 to 21 or therapeutically (from day 14 onward, ameliorated both signs of inflammation and fibrosis. Conclusion Collectively these data reveal a pathophysiological relevance for endogenous AnxA1 in lung inflammation and, more importantly, fibrosis, and may open new insights for the pharmacological treatment of lung fibrosis.

  15. Role of glutathione biosynthesis in endothelial dysfunction and fibrosis

    Directory of Open Access Journals (Sweden)

    Cristina Espinosa-Díez

    2018-04-01

    Full Text Available Glutathione (GSH biosynthesis is essential for cellular redox homeostasis and antioxidant defense. The rate-limiting step requires glutamate-cysteine ligase (GCL, which is composed of the catalytic (GCLc and the modulatory (GCLm subunits. To evaluate the contribution of GCLc to endothelial function we generated an endothelial-specific Gclc haplo-insufficient mouse model (Gclc e/+ mice. In murine lung endothelial cells (MLEC derived from these mice we observed a 50% reduction in GCLc levels compared to lung fibroblasts from the same mice. MLEC obtained from haplo-insufficient mice showed significant reduction in GSH levels as well as increased basal and stimulated ROS levels, reduced phosphorylation of eNOS (Ser 1177 and increased eNOS S-glutathionylation, compared to MLEC from wild type (WT mice. Studies in mesenteric arteries demonstrated impaired endothelium-dependent vasodilation in Gclc(e/+ male mice, which was corrected by pre-incubation with GSH-ethyl-ester and BH4. To study the contribution of endothelial GSH synthesis to renal fibrosis we employed the unilateral ureteral obstruction model in WT and Gclc(e/+ mice. We observed that obstructed kidneys from Gclc(e/+ mice exhibited increased deposition of fibrotic markers and reduced Nrf2 levels. We conclude that the preservation of endothelial GSH biosynthesis is not only critical for endothelial function but also in anti-fibrotic responses. Keywords: Glutamate-cysteine ligase, ROS, Glutathione, Endothelial dysfunction, Kidney Fibrosis

  16. Pathogenic mechanism in lung fibrosis

    International Nuclear Information System (INIS)

    Witschi, H.; Haschek, W.M.; Meyer, K.R.; Ullrich, R.L.; Dalbey, W.E.

    1979-01-01

    The purpose of the study was to examine whether an interaction between two agents causing alveolar epithelial damage would produce lung fibrosis. In mouse lung, intraperitoneal injection of the antioxidant butylated hydroxytoluene causes diffuse alveolar type I cell necrosis, followed by proliferation of type II alveolar cells. In animals exposed to 70% O 2 or 100-200 rad x rays during the phase of type II cell proliferation following BHT, diffuse interstitial lung fibrosis developed within 2 weeks. Quantitative analysis of the lungs for hydroxyproline showed that the interaction between BHT and O 2 or x rays was synergistic. If exposure to O 2 or x rays was delayed until epithelial recovery was complete, no fibrosis was seen. Abnormally high levels of lung collagen persisted up to 6 months after one single treatment with BHT and 100 rad x rays. A commonly seen form of chronic lung damage may thus be caused by an acute interaction between a bloodborne agent which damages the alveolar cell and a toxic inhalant or x rays, provided a critically ordered sequence of exposure is observed

  17. Oral submucous fibrosis: an update

    Directory of Open Access Journals (Sweden)

    Wollina U

    2015-04-01

    Full Text Available Uwe Wollina,1 Shyam B Verma,2 Fareedi Mukram Ali,3 Kishor Patil4 1Department of Dermatology and Allergology, Academic Teaching Hospital Dresden-Friedrichstadt, Dresden, Germany; 2Nirvana Skin Clinic, Vadodara, Gujarat, India; 3Departments of Oral and Maxillofacial Surgery, SMBT Dental College, Sangamner, Maharashtra, India; 4Departments of Oral Pathology and Microbiology, SMBT Dental College, Sangamner, Maharashtra, India Abstract: Oral submucous fibrosis (OSF is a premalignant condition caused by betel chewing. It is very common in Southeast Asia but has started to spread to Europe and North America. OSF can lead to squamous cell carcinoma, a risk that is further increased by concomitant tobacco consumption. OSF is a diagnosis based on clinical symptoms and confirmation by histopathology. Hypovascularity leading to blanching of the oral mucosa, staining of teeth and gingiva, and trismus are major symptoms. Major constituents of betel quid are arecoline from betel nuts and copper, which are responsible for fibroblast dysfunction and fibrosis. A variety of extracellular and intracellular signaling pathways might be involved. Treatment of OSF is difficult, as not many large, randomized controlled trials have been conducted. The principal actions of drug therapy include antifibrotic, anti-inflammatory, and antioxygen radical mechanisms. Potential new drugs are on the horizon. Surgery may be necessary in advanced cases of trismus. Prevention is most important, as no healing can be achieved with available treatments. Keywords: betel nut, betel quid, oral disease, squamous cell carcinoma, tobacco, fibrosis

  18. Cystic Fibrosis-Related Diabetes

    Directory of Open Access Journals (Sweden)

    Kayani Kayani

    2018-02-01

    Full Text Available Cystic fibrosis (CF is the most common autosomal recessive disorder in Caucasian populations. Individuals with CF have seen significant increases in life expectancy in the last 60 years. As a result, previously rare complications are now coming to light. The most common of these is cystic fibrosis-related diabetes (CFRD, which affects 40–50% of CF adults. CFRD significantly impacts the pulmonary function and longevity of CF patients, yet a lack of consensus on the best methods to diagnose and treat CFRD remains. We begin by reviewing our understanding of the pathogenesis of CFRD, as emerging evidence shows the cystic fibrosis transmembrane conductance regulator (CFTR also has important roles in the release of insulin and glucagon and in the protection of β cells from oxidative stress. We then discuss how current recommended methods of CFRD diagnosis are not appropriate, as continuous glucose monitoring becomes more effective, practical, and cost-effective. Finally, we evaluate emerging treatments which have narrowed the mortality gap within the CF patient group. In the future, pharmacological potentiators and correctors directly targeting CFTR show huge promise for both CFRD and the wider CF patient groups.

  19. Low-intensity pulsed ultrasound enhances angiogenesis and ameliorates contractile dysfunction of pressure-overloaded heart in mice.

    Directory of Open Access Journals (Sweden)

    Tsuyoshi Ogata

    Full Text Available Chronic left ventricular (LV pressure overload causes relative ischemia with resultant LV dysfunction. We have recently demonstrated that low-intensity pulsed ultrasound (LIPUS improves myocardial ischemia in a pig model of chronic myocardial ischemia through enhanced myocardial angiogenesis. In the present study, we thus examined whether LIPUS also ameliorates contractile dysfunction in LV pressure-overloaded hearts.Chronic LV pressure overload was induced with transverse aortic constriction (TAC in mice. LIPUS was applied to the whole heart three times in the first week after TAC and was repeated once a week for 7 weeks thereafter (n = 22. Animals in the control groups received the sham treatment without LIPUS (n = 23. At 8 weeks after TAC, LV fractional shortening was depressed in the TAC-Control group, which was significantly ameliorated in the TAC-LIPUS group (30.4±0.5 vs. 36.2±3.8%, P<0.05. Capillary density was higher and perivascular fibrosis was less in the LV in the TAC-LIPUS group than in the TAC-Control group. Myocardial relative ischemia evaluated with hypoxyprobe was noted in the TAC-Control group, which was significantly attenuated in the TAC-LIPUS group. In the TAC-LIPUS group, as compared with the control group, mRNA expressions of BNP and collagen III were significantly lower (both P<0.05 and protein expressions of VEGF and eNOS were significantly up-regulated associated with Akt activation (all P<0.05. No adverse effect related to the LIPUS therapy was noted.These results indicate that the LIPUS therapy ameliorates contractile dysfunction in chronically pressure-overloaded hearts through enhanced myocardial angiogenesis and attenuated perivascular fibrosis. Thus, the LIPUS therapy may be a promising, non-invasive treatment for cardiac dysfunction due to chronic pressure overload.

  20. Vitamin E supplementation in people with cystic fibrosis.

    Science.gov (United States)

    Okebukola, Peter O; Kansra, Sonal; Barrett, Joanne

    2017-03-06

    People with cystic fibrosis are at an increased risk of fat-soluble vitamin deficiency including vitamin E. Vitamin E deficiency can cause a host of conditions such as haemolytic anaemia, cerebellar ataxia and cognitive difficulties. Vitamin E supplementation is widely recommended in cystic fibrosis and aims to ameliorate this deficiency. This is an updated version of the review. To determine the effects of any level of vitamin E supplementation on the frequency of vitamin E deficiency disorders in people with cystic fibrosis. We searched the Cochrane Group's Cystic Fibrosis Trials Register and also searched international trial registers for any ongoing clinical trials that were not identified during our register search.Date of last search of the Register: 10 October 2016. Date of last search of international trial registers: 15 February 2017. Randomised controlled trials and quasi-randomised controlled trials comparing any preparation of vitamin E supplementation to placebo or no supplement, regardless of dosage or duration. Two authors extracted outcome data from each study (published information) and assessed the risk of bias of each included study. Four studies with a total of 141 participants were included in the review, two of these were in children (aged six months to 14.5 years), and the other two did not specify participants' age. All studies used different formulations and doses of vitamin E for various durations of treatment (10 days to six months). Two studies compared the supplementation of fat-soluble as well as water-soluble formulations to no supplementation in different arms of the same study. A third study compared a water-soluble formulation to a placebo; and in the fourth study a fat-soluble formulation of vitamin E was assessed against placebo.At one month, three months and six months, water-soluble vitamin E significantly improved serum vitamin E levels compared with control: at one month, two studies, mean difference 17.66 (95% confidence

  1. Imaging of renal osteodystrophy

    Energy Technology Data Exchange (ETDEWEB)

    Jevtic, V. E-mail: vladimir.jevtic@mf.uni-lj.si

    2003-05-01

    Chronic renal insufficiency, hemodialysis, peritoneal dialysis, renal transplantation and administration of different medications provoke complex biochemical disturbances of the calcium-phosphate metabolism with wide spectrum of bone and soft tissue abnormalities termed renal osteodystrophy. Clinically most important manifestation of renal bone disease includes secondary hyperparathyroidism, osteomalacia/rickets, osteoporosis, adynamic bone disease and soft tissue calcification. As a complication of long-term hemodialysis and renal transplantation amyloid deposition, destructive spondyloarthropathy, osteonecrosis, and musculoskeletal infections may occur. Due to more sophisticated diagnostic methods and more efficient treatment classical radiographic features of secondary hyperparathyroidism and osteomalacia/rickets are now less frequently seen. Radiological investigations play an important role in early diagnosis and follow-up of the renal bone disease. Although numerous new imaging modalities have been introduced in clinical practice (scintigraphy, CT, MRI, quantitative imaging), plain film radiography, especially fine quality hand radiograph, still represents most widely used examination.

  2. Imaging of renal osteodystrophy

    International Nuclear Information System (INIS)

    Jevtic, V.

    2003-01-01

    Chronic renal insufficiency, hemodialysis, peritoneal dialysis, renal transplantation and administration of different medications provoke complex biochemical disturbances of the calcium-phosphate metabolism with wide spectrum of bone and soft tissue abnormalities termed renal osteodystrophy. Clinically most important manifestation of renal bone disease includes secondary hyperparathyroidism, osteomalacia/rickets, osteoporosis, adynamic bone disease and soft tissue calcification. As a complication of long-term hemodialysis and renal transplantation amyloid deposition, destructive spondyloarthropathy, osteonecrosis, and musculoskeletal infections may occur. Due to more sophisticated diagnostic methods and more efficient treatment classical radiographic features of secondary hyperparathyroidism and osteomalacia/rickets are now less frequently seen. Radiological investigations play an important role in early diagnosis and follow-up of the renal bone disease. Although numerous new imaging modalities have been introduced in clinical practice (scintigraphy, CT, MRI, quantitative imaging), plain film radiography, especially fine quality hand radiograph, still represents most widely used examination

  3. Otorhinolaryngologic manifestations of cystic fibrosis: literature review

    Directory of Open Access Journals (Sweden)

    Carvalho, Carolina Pimenta

    2008-12-01

    Full Text Available Introduction: Cystic Fibrosis is the most common recessive autosomic genetic disease among Caucasians. It's caused by mutations in the gene that decodes regulatory protein for transmembrane conductance, resulting in defective transport of chlorine. Objective: Review the literature about Cystic Fibrosis, with emphasis on otorhinolaryngologic manifestations. Method: The online Pub Med databases were researched and we applied the following search terms Fibrosis Cystic and Sinusitis, and Mucoviscidosis and Sinusitis. Conclusions: Although it is not the main cause of death, the otorhinolaryngologic manifestations of the Cystic Fibrosis bring important morbidity to these patients.

  4. Mitochondrial catalase overexpressed transgenic mice are protected against lung fibrosis in part via preventing alveolar epithelial cell mitochondrial DNA damage.

    Science.gov (United States)

    Kim, Seok-Jo; Cheresh, Paul; Jablonski, Renea P; Morales-Nebreda, Luisa; Cheng, Yuan; Hogan, Erin; Yeldandi, Anjana; Chi, Monica; Piseaux, Raul; Ridge, Karen; Michael Hart, C; Chandel, Navdeep; Scott Budinger, G R; Kamp, David W

    2016-12-01

    Alveolar epithelial cell (AEC) injury and mitochondrial dysfunction are important in the development of lung fibrosis. Our group has shown that in the asbestos exposed lung, the generation of mitochondrial reactive oxygen species (ROS) in AEC mediate mitochondrial DNA (mtDNA) damage and apoptosis which are necessary for lung fibrosis. These data suggest that mitochondrial-targeted antioxidants should ameliorate asbestos-induced lung. To determine whether transgenic mice that express mitochondrial-targeted catalase (MCAT) have reduced lung fibrosis following exposure to asbestos or bleomycin and, if so, whether this occurs in association with reduced AEC mtDNA damage and apoptosis. Crocidolite asbestos (100µg/50µL), TiO 2 (negative control), bleomycin (0.025 units/50µL), or PBS was instilled intratracheally in 8-10 week-old wild-type (WT - C57Bl/6J) or MCAT mice. The lungs were harvested at 21d. Lung fibrosis was quantified by collagen levels (Sircol) and lung fibrosis scores. AEC apoptosis was assessed by cleaved caspase-3 (CC-3)/Surfactant protein C (SFTPC) immunohistochemistry (IHC) and semi-quantitative analysis. AEC (primary AT2 cells from WT and MCAT mice and MLE-12 cells) mtDNA damage was assessed by a quantitative PCR-based assay, apoptosis was assessed by DNA fragmentation, and ROS production was assessed by a Mito-Sox assay. Compared to WT, crocidolite-exposed MCAT mice exhibit reduced pulmonary fibrosis as measured by lung collagen levels and lung fibrosis score. The protective effects in MCAT mice were accompanied by reduced AEC mtDNA damage and apoptosis. Similar findings were noted following bleomycin exposure. Euk-134, a mitochondrial SOD/catalase mimetic, attenuated MLE-12 cell DNA damage and apoptosis. Finally, compared to WT, asbestos-induced MCAT AT2 cell ROS production was reduced. Our finding that MCAT mice have reduced pulmonary fibrosis, AEC mtDNA damage and apoptosis following exposure to asbestos or bleomycin suggests an important role

  5. Clinical observation of calcium dobesilate in the treatment of chronic renal allograft dysfunction

    Institute of Scientific and Technical Information of China (English)

    Zheng Xue-yang; Han Shu; Zhou Mei-sheng; Fu Shang-xi; Wang Li-ming

    2014-01-01

    Abstract BACKGROUND: Calcium dobesilate (calcium dihydroxy-2, 5-benzenesulfonate) has been widely used to treat chronic venous insufficiency and diabetic retinopathy, especialy many clinical studies showed that calcium dobesilate as vasoprotective compound ameliorates renal lesions in diabetic nephropathy. However, there are few literatures reported calcium dobesilate in the treatment of chronic renal alograft dysfunction after renal transplantation. OBJECTIVE:To observe the efficacy and safety of calcium dobesilate on chronic renal dysfunction after renal transplantation. METHODS:A total of 152 patients with chronic renal alograft dysfunction after renal transplantation were enroled from the Military Institute of Organ Transplantation, Changzheng Hospital, Second Military Medical University of Chinese PLA. They were randomly divided into the treatment group (n=78) and the control group (n=74). Patients in the treatment group received 500 mg of calcium dobesilate three times daily for eight weeks. Al patients were treated with calcineurin inhibitor-based triple immunosuppressive protocols and comprehensive therapies. RESULTS AND CONCLUSION: For patients receiving calcium dobesilate, serum creatinine, blood urea nitrogen and uric acid decreased significantly at two weeks after treatment and maintained a stable level (P 0.05). Administration of calcium dobesilate did not change the general condition of patients with renal insufficiency, nor did it affect blood concentrations of the immunosuppressive agents. Calcium dobesilate may help to delay the progress of graft injury in patients with chronic renal graft dysfunction by conjugating with creatinine, ameliorating the impaired microcirculation and its antioxidant property. The decline in serum creatinine aleviates patients’ anxiety and concern arising from the elevation of creatinine. However, the negative interference with serum creatinine caused by calcium dobesilate should be cautious in order to avoid

  6. Attenuation of hyperlipidemia- and diabetes-induced early-stage apoptosis and late-stage renal dysfunction via administration of fibroblast growth factor-21 is associated with suppression of renal inflammation.

    Directory of Open Access Journals (Sweden)

    Chi Zhang

    Full Text Available BACKGROUND: Lipotoxicity is a key feature of the pathogenesis of diabetic kidney disease, and is attributed to excessive lipid accumulation (hyperlipidemia. Increasing evidence suggests that fibroblast growth factor (FGF21 has a crucial role in lipid metabolism under diabetic conditions. OBJECTIVE: The present study investigated whether FGF21 can prevent hyperlipidemia- or diabetes-induced renal damage, and if so, the possible mechanism. METHODS: Mice were injected with free fatty acids (FFAs, 10 mg/10 g body weight or streptozotocin (150 mg/kg to establish a lipotoxic model or type 1 diabetic model, respectively. Simultaneously the mice were treated with FGF21 (100 µg/kg for 10 or 80 days. The kidney weight-to-tibia length ratio and renal function were assessed. Systematic and renal lipid levels were detected by ELISA and Oil Red O staining. Renal apoptosis was examined by TUNEL assay. Inflammation, oxidative stress, and fibrosis were assessed by Western blot. RESULTS: Acute FFA administration and chronic diabetes were associated with lower kidney-to-tibia length ratio, higher lipid levels, severe renal apoptosis and renal dysfunction. Obvious inflammation, oxidative stress and fibrosis also observed in the kidney of both mice models. Deletion of the fgf21 gene further enhanced the above pathological changes, which were significantly prevented by administration of exogenous FGF21. CONCLUSION: These results suggest that FFA administration and diabetes induced renal damage, which was further enhanced in FGF21 knock-out mice. Administration of FGF21 significantly prevented both FFA- and diabetes-induced renal damage partially by decreasing renal lipid accumulation and suppressing inflammation, oxidative stress, and fibrosis.

  7. Renal artery stenosis

    International Nuclear Information System (INIS)

    Desberg, A.; Paushter, D.M.; Lammert, G.K.; Hale, J.; Troy, R.; Novic, A.; Nally, J. Jr.

    1989-01-01

    Renal artery disease is a potentially correctable cause of hypertension. Previous studies have suggested the utility of duplex sonography in accurately detecting and grading the severity of renal artery stenosis. The purpose of this paper is to evaluate color flow Doppler for this use. Forty-three kidneys were examined by color-flow Doppler and conventional duplex sampling in patients with suspected renovascular hypertension or those undergoing aortography for unrelated reasons. Doppler tracings were obtained from the renal arteries and aorta with calculation of the renal aortic ratio (RAR) and resistive index (RI). Results of Doppler sampling with color flow guidance were compared with aortograms in a blinded fashion

  8. Incidental renal neoplasms

    DEFF Research Database (Denmark)

    Rabjerg, Maj; Mikkelsen, Minne Nedergaard; Walter, Steen

    2014-01-01

    On the basis of associations between tumor size, pathological stage, histological subtype and tumor grade in incidentally detected renal cell carcinoma vs symptomatic renal cell carcinoma, we discussed the need for a screening program of renal cell carcinoma in Denmark. We analyzed a consecutive...... series of 204 patients with renal tumors in 2011 and 2012. The tumors were classified according to detection mode: symptomatic and incidental and compared to pathological parameters. Eighty-nine patients (44%) were symptomatic, 113 (55%) were incidental. Information was not available in two patients...

  9. Close to Transplant Renal Artery Stenosis and Percutaneous Transluminal Treatment

    Directory of Open Access Journals (Sweden)

    Leonardou Polytimi

    2011-01-01

    Full Text Available Purpose. To evaluate the efficacy of percutaneous transluminal angioplasty (PTA in the management of arterial stenosis located close to the allograft anastomosis (close-TRAS. Materials and Methods. 31 patients with renal transplants were admitted to our institution because of persistent hypertension and impairment of transplant renal function and underwent angiography for vascular investigation. 27 were diagnosed suffering from transplant renal artery stenosis (TRAS, whereas 4 had severe iliac artery stenosis proximal to the transplant anastomosis (Prox-TRAS. 3 cases of TRAS coexisted with segmental renal arterial stenosis, whereas 3 other cases of TRAS were caused by kinking and focal stenosis in the middle of the transplanted renal artery. Results. Angioplasty and stenting were successfully applied to all patients with iliac artery stenosis as well as to those with TRAS and segmental artery stenosis. Two of three patients with kinking were well treated with angioplasty and stenting, whereas one treated only with angioplasty necessitated surgery. No major procedure-related complications appeared, and the result was decrease of the serum creatinine level and of the blood pressure. Conclusions. PTA is the appropriate initial treatment of TRAS and close-TRAS, with low morbidity and mortality rates, achieving improvement of graft function and amelioration of hypertension.

  10. Renal cell carcinoma in patient with crossed fused renal ectopia

    Directory of Open Access Journals (Sweden)

    Ozgur Cakmak

    2016-01-01

    Full Text Available Primary renal cell carcinomas have rarely been reported in patients with crossed fused renal ectopia. We presented a patient with right to left crossed fused kidney harbouring renal tumor. The most frequent tumor encountered in crossed fused renal ectopia is renal cell carcinoma. In this case, partial nephrectomy was performed which pave way to preservation of the uninvolved both renal units. Due to unpredictable anatomy, careful preoperative planning and meticulous delineation of renal vasculature is essential for preservation of the uninvolved renal units.

  11. Stages of Renal Cell Cancer

    Science.gov (United States)

    ... Tumors Treatment Genetics of Kidney Cancer Research Renal Cell Cancer Treatment (PDQ®)–Patient Version General Information About Renal Cell Cancer Go to Health Professional Version Key Points Renal ...

  12. Bilateral papillary renal cell carcinoma

    International Nuclear Information System (INIS)

    Gossios, K.; Vazakas, P.; Argyropoulou, M.; Stefanaki, S.; Stavropoulos, N.E.

    2001-01-01

    Papillary renal cell carcinoma is a subgroup of malignant renal epithelial neoplasms. We report the clinical and imaging findings of a case with multifocal and bilateral renal cell carcinoma which are nonspecific. (orig.)

  13. Ciclosporin Does Not Influence Bone Marrow-Derived Cell Differentiation to Myofibroblasts Early after Renal Ischemia/Reperfusion

    NARCIS (Netherlands)

    Broekema, Martine; Harmsen, Martin C.; Koerts, Jasper A.; van Kooten, Theo G.; Uges, Donald R. A.; Petersen, Arjen H.; van Luyn, Marja J. A.; Navis, Gerjan; Popa, Eliane R.

    2009-01-01

    Background: Ischemia/reperfusion injury (IRI) is a risk factor for the development of interstitial fibrosis. Previously we had shown that after renal IRI, bone marrow-derived cells (BMDC) can differentiate to interstitial myofibroblasts. Here we hypothesized that the immunosuppressant ciclosporin A

  14. The Sociology and Entrenchment. A Cystic Fibrosis Test for Everyone?

    DEFF Research Database (Denmark)

    Koch, Lene; Stemerding, Dirk

    1994-01-01

    Socialmedicine, genetic screening, cystic fibrosis, ethics, political regulation, sociology of technology......Socialmedicine, genetic screening, cystic fibrosis, ethics, political regulation, sociology of technology...

  15. DA-1229, a dipeptidyl peptidase IV inhibitor, protects against renal injury by preventing podocyte damage in an animal model of progressive renal injury.

    Science.gov (United States)

    Eun Lee, Jee; Kim, Jung Eun; Lee, Mi Hwa; Song, Hye Kyoung; Ghee, Jung Yeon; Kang, Young Sun; Min, Hye Sook; Kim, Hyun Wook; Cha, Jin Joo; Han, Jee Young; Han, Sang Youb; Cha, Dae Ryong

    2016-05-01

    Although dipeptidyl peptidase IV (DPPIV) inhibitors are known to have renoprotective effects, the mechanism underlying these effects has remained elusive. Here we investigated the effects of DA-1229, a novel DPPIV inhibitor, in two animal models of renal injury including db/db mice and the adriamycin nephropathy rodent model of chronic renal disease characterized by podocyte injury. For both models, DA-1229 was administered at 300 mg/kg/day. DPPIV activity in the kidney was significantly higher in diabetic mice compared with their nondiabetic controls. Although DA-1229 did not affect glycemic control or insulin resistance, DA-1229 did improve lipid profiles, albuminuria and renal fibrosis. Moreover, DA-1229 treatment resulted in decreased urinary excretion of nephrin, decreased circulating and kidney DPPIV activity, and decreased macrophage infiltration in the kidney. In adriamycin-treated mice, DPPIV activity in the kidney and urinary nephrin loss were both increased, whereas glucagon-like peptide-1 concentrations were unchanged. Moreover, DA-1229 treatment significantly improved proteinuria, renal fibrosis and inflammation associated with decreased urinary nephrin loss, and kidney DPP4 activity. In cultured podocytes, DA-1229 restored the high glucose/angiotensin II-induced increase of DPPIV activity and preserved the nephrin levels in podocytes. These findings suggest that activation of DPPIV in the kidney has a role in the progression of renal disease, and that DA-1229 may exert its renoprotective effects by preventing podocyte injury.

  16. Calcium Stone Growth in Urine from Cystic Fibrosis Patients and Healthy Controls

    Science.gov (United States)

    McSorley, Anita; Jones, Andrew M.; Webb, A. Kevin; Rao, P. Nagaraj; Kavanagh, John P.

    2007-04-01

    Cystic fibrosis patients have an increased risk of renal stone disease. There is some evidence that this may be related to a different excretory pattern of stone risk factors, but an alternative hypothesis, that the urine of cystic fibrosis patients is deficient in urinary inhibitors of crystallization and stone formation has not been tested. Here we have grown calcium stones, in vitro, in the presence of urine from healthy controls and compared this with growth in the presence of urine from cystic fibrosis patients. A stone farm was used to grow twelve calcium stones simultaneously, firstly in artificial urine for about 200 hours and then in 90% whole human urine for another 500 hours. Six of the stones received urine from healthy controls and six received urine from adult cystic fibrosis patients. There were no significant differences in stone mass at any of the key time points or in the overall growth pattern (p>0.05) between stones destined for, or treated with, urine from CF patients and the controls. Human urine greatly inhibited stone growth in vitro but there was no difference in the growth rate in urine from healthy controls and CF patients. This refutes the hypothesis that a tendency for a higher prevalence of urinary stones in CF patients is related to a deficiency in inhibitory activity.

  17. Fetal polycystic renal disease: prenatal sonographic findings with pathologic correlation

    International Nuclear Information System (INIS)

    Jun, Soon Ae; Park, Yong Hyun; Cha, Sun Hee; Kay, Jung Woong; Cho, Joo Yeon; Cha, Kwang Yul; Cha, Kyung Sub; Chi, Je G.

    1990-01-01

    Polycystic renal disease are congenital disorders, most of which are fatal in the postnatal period. A series of ten cases of polycystic renal disease diagnosed prenatally by ultrasonography is presented. Diagnostic criteria of ultrasonography for cystic renal disease are; 1. enlarge kidney (4 cases) 2. echogenic density of kidney (3 cases) 3. 0.4 - 0.9cm sized multiple cysts within the renal cortex (3 cases) 4. decreased amount of amniotic fluid (4 cases) 5. hydronephrosis (4 cases) 6. distended bladder (2 cases) 7. absence of bladder (2 cases) Eight of ten cases were confirmed by autopsy. Seven cases had other associated congenital anomalies, i.e. pulmonary hypoplasia (5), hepatic fibrosis (3), congenital heart disease (3), tracheoesophageal fistula with imperforate anus (1), caudal regression syndrome (1), Meckel-Gruber syndrome (1) and ambiguous genitalia (2). Additional cytogenetic study of the fetus and the careful family history taking followed by prenatal diagnosis of cystic renal disease. Precise prenatal diagnosis may allow patients the option of elective abortion or may prevent unnecessary obstetric intervention

  18. Differential expression of proteoglycans in tissue remodeling and lymphangiogenesis after experimental renal transplantation in rats.

    Directory of Open Access Journals (Sweden)

    Heleen Rienstra

    Full Text Available BACKGROUND: Chronic transplant dysfunction explains the majority of late renal allograft loss and is accompanied by extensive tissue remodeling leading to transplant vasculopathy, glomerulosclerosis and interstitial fibrosis. Matrix proteoglycans mediate cell-cell and cell-matrix intera