Fetal programming of chronic kidney disease: the role of maternal smoking, mitochondrial dysfunction, and epigenetic modfification.

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Stangenberg, Stephanie; Chen, Hui; Wong, Muh Geot; Pollock, Carol A; Saad, Sonia

2015-06-01

The role of an adverse in utero environment in the programming of chronic kidney disease in the adult offspring is increasingly recognized. The cellular and molecular mechanisms linking the in utero environment and future disease susceptibility remain unknown. Maternal smoking is a common modifiable adverse in utero exposure, potentially associated with both mitochondrial dysfunction and epigenetic modification in the offspring. While studies are emerging that point toward a key role of mitochondrial dysfunction in acute and chronic kidney disease, it may have its origin in early development, becoming clinically apparent when secondary insults occur. Aberrant epigenetic programming may add an additional layer of complexity to orchestrate fibrogenesis in the kidney and susceptibility to chronic kidney disease in later life. In this review, we explore the evidence for mitochondrial dysfunction and epigenetic modification through aberrant DNA methylation as key mechanistic aspects of fetal programming of chronic kidney disease and discuss their potential use in diagnostics and targets for therapy. Copyright © 2015 the American Physiological Society.

Warfarin accelerated vascular calcification and worsened cardiac dysfunction in remnant kidney mice

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Ming-Tsun Tsai

2018-04-01

Full Text Available Background: Vascular calcification is highly prevalent in end-stage renal disease (ESRD and is a significant risk factor for future cardiovascular events and death. Warfarin use results in dysfunction of matrix Gla protein, an inhibitor of vascular calcification. However, the effect of warfarin on vascular calcification in patients with ESRD is still not well characterized. Thus we investigated whether arterial calcification can be accelerated by warfarin treatment both in vitro and in vivo using a mouse remnant kidney model. Methods: Human aortic smooth muscle cells (HASMC were cultured in medium supplemented with warfarin and phosphate to investigate the potential role of this drug in osteoblast transdifferentiation. For in vivo study, adult male C57BL/6 mice underwent 5/6 nephrectomy were treated with active vitamin D3 plus warfarin to determine the extent of vascular calcification and parameters of cardiovascular function. Results: We found that the expressions of Runx2 and osteocalcin in HASMC were markedly enhanced in the culture medium containing warfarin and high phosphate concentration. Warfarin induced calcification of cultured HASMC in the presence of high phosphate levels, and this effect is inhibited by vitamin K2. Severe aortic calcification and reduced left ventricular ejection fractions were also noted in 5/6 nephrectomy mice treated with warfarin and active vitamin D3. Conclusion: Warfarin treatment contributes to the accelerated vascular calcification in animal models of advanced chronic kidney disease. Clinicians should therefore be aware of the profound risk of warfarin use on vascular calcification and cardiac dysfunction in patients with ESRD and atrial fibrillation. Keywords: Left ventricular dysfunction, Uremia, Vascular calcification, Warfarin

Echocardiographic study of cardiac dysfunction in patients of chronic kidney disease on hemodialysis

International Nuclear Information System (INIS)

Arshi, S.; Butt, G.U.D.; Mian, F.A.

2016-01-01

Objective: The objective of this study was to see echocardiographic findings of cardiac dysfunction in patients of chronic kidney disease (CKD) on hemodialysis. Study Design: Comparative cross sectional study. Place and Duration of Study: Department of nephrology, Pakistan Institute of Medical Sciences. Islamabad from September 2014 to February 2015. Patients and Methods: One hundred patients of either gender were included in this study. Fifty patients of chronic kidney disease stage V on hemodialysis were taken for echocardiography and fifty were normal. Echocardiography was done for cardiac dysfunction. Systolic function was measured by ejection fraction (EF) and fractional shortening (FS). Diastolic function was measured by E/A ratio. Results: Out of 100 patients included in the study, 50 patients were on hemodialysis and 50 were control. Left ventricular end systolic and end diastolic volumes were higher in patients on hemodialysis than controls as well as left atrial enlargement and inter ventricular septum which was statistically significant. Ejection fraction, although normal and fractional shortening decreased in patients on hemodialysis (p<0.05). Diastolic dysfunction was present in 36 patients on hemodialysis, while absent in the control group. Conclusion: Patients with chronic kidney disease on hemodialysis have higher prevalence of cardiac dysfunction. (author)

Naringin ameliorates gentamicin-induced nephrotoxicity and associated mitochondrial dysfunction, apoptosis and inflammation in rats: Possible mechanism of nephroprotection

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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

Estrogen-related receptor α is essential for maintaining mitochondrial integrity in cisplatin-induced acute kidney injury.

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Tsushida, Keigo; Tanabe, Katsuyuki; Masuda, Kana; Tanimura, Satoshi; Miyake, Hiromasa; Arata, Yuka; Sugiyama, Hitoshi; Wada, Jun

2018-04-15

Acute kidney injury (AKI) has been associated with not only higher in-hospital mortality but also the subsequent development of chronic kidney disease (CKD). Recent evidence has suggested the involvement of mitochondrial dysfunction and impaired dynamics in the pathogenesis of AKI. Estrogen-related receptor α (ERRα) is an orphan nuclear receptor that acts as a transcription factor to regulate the transcription of genes required for mitochondrial biogenesis and oxidative phosphorylation. In the present study, we examined the effects of ERRα deficiency on the progression of AKI induced by cisplatin. Male C57BL/6 J wild-type and ERRα -/- mice received a single intraperitoneal injection of 20 mg/kg cisplatin. Seventy-two hours after the injection, kidney function and morphology were evaluated. ERRα expression was observed in renal tubules, and cisplatin inhibited its translocation into nuclei. ERRα deficiency exacerbated cisplatin-induced renal dysfunction and tubular injury, as well as oxidative stress and apoptosis. ERRα -/- mice kidneys revealed lower mitochondrial DNA content and swollen mitochondria with reduced cristae. In addition, these mice had lower expression of the mitochondrial fusion protein mitofusin-2. The cisplatin-induced decrease in mitochondrial DNA and altered mitochondrial structure were more severe in ERRα -/- mice. In cultured mouse proximal tubular epithelial cells, the ERRα inverse agonist XCT-790 significantly inhibited mitofusin-2 expression and induced mitochondrial fragmentation. Taken together, our findings suggest the involvement of ERRα in the progression of cisplatin-induced AKI probably through impaired mitochondrial dynamics. Copyright © 2018 Elsevier Inc. All rights reserved.

Zymosan-induced immune challenge modifies the stress response of hypoxic air-breathing fish (Anabas testudineus Bloch): Evidence for reversed patterns of cortisol and thyroid hormone interaction, differential ion transporter functions and non-specific immune response.

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Simi, S; Peter, Valsa S; Peter, M C Subhash

2017-09-15

Fishes have evolved physiological mechanisms to exhibit stress response, where hormonal signals interact with an array of ion transporters and regulate homeostasis. As major ion transport regulators in fish, cortisol and thyroid hormones have been shown to interact and fine-tune the stress response. Likewise, in fishes many interactions have been identified between stress and immune components, but the physiological basis of such interaction has not yet delineated particularly in air-breathing fish. We, therefore, investigated the responses of thyroid hormones and cortisol, ion transporter functions and non-specific immune response of an obligate air-breathing fish Anabas testudineus Bloch to zymosan treatment or hypoxia stress or both, to understand how immune challenge modifies the pattern of stress response in this fish. Induction of experimental peritonitis in these fish by zymosan treatment (200ngg -1 ) for 24h produced rise in respiratory burst and lysozomal activities in head kidney phagocytes. In contrast, hypoxia stress for 30min in immune-challenged fish reversed these non-specific responses of head kidney phagocytes. The decline in plasma cortisol in zymosan-treated fish and its further suppression by hypoxia stress indicate that immune challenge suppresses the cortisol-driven stress response of this fish. Likewise, the decline in plasma T 3 and T 4 after zymosan-treatment and the rise in plasma T 4 after hypoxia stress in immune-challenged fish indicate a critical role for thyroid hormone in immune-stress response due to its differential sensitivity to both immune and stress challenges. Further, analysis of the activity pattern of ion-dependent ATPases viz. Na + /K + -ATPase, H + /K + -ATPase and Na + /NH 4 + -ATPase indicates a functional interaction of ion transport system with the immune response as evident in its differential and spatial modifications after hypoxia stress in immune-challenged fish. The immune-challenge that produced differential

Mequindox-Induced Kidney Toxicity Is Associated With Oxidative Stress and Apoptosis in the Mouse

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Qianying Liu

2018-05-01

Full Text Available Mequindox (MEQ, belonging to quinoxaline-di-N-oxides (QdNOs, is a synthetic antimicrobial agent widely used in China. Previous studies found that the kidney was one of the main toxic target organs of the QdNOs. However, the mechanisms underlying the kidney toxicity caused by QdNOs in vivo still remains unclear. The present study aimed to explore the molecular mechanism of kidney toxicity in mice after chronic exposure to MEQ. MEQ led to the oxidative stress, apoptosis, and mitochondrial damage in the kidney of mice. Meanwhile, MEQ upregulated Bax/Bcl-2 ratio, disrupted mitochondrial permeability transition pores, caused cytochrome c release, and a cascade activation of caspase, eventually induced apoptosis. The oxidative stress mediated by MEQ might led to mitochondria damage and apoptosis in a mitochondrial-dependent apoptotic pathway. Furthermore, upregulation of the Nrf2-Keap1 signaling pathway was also observed. Our findings revealed that the oxidative stress, mitochondrial dysfunction, and the Nrf2-Keap1 signaling pathway were associated with the kidney apoptosis induced by MEQ in vivo.

Duration of streptozotocin-induced diabetes differentially affects p38-mitogen-activated protein kinase (MAPK phosphorylation in renal and vascular dysfunction

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Gupta Akanksha

2005-03-01

Full Text Available Abstract Background In the present study we tested the hypothesis that progression of streptozotocin (STZ-induced diabetes (14-days to 28-days would produce renal and vascular dysfunction that correlate with altered p38- mitogen-activated protein kinase (p38-MAPK phosphorylation in kidneys and thoracic aorta. Methods Male Sprague Dawley rats (350–400 g were randomized into three groups: sham (N = 6, 14-days diabetic (N = 6 and 28-days diabetic rats (N = 6. Diabetes was induced using a single tail vein injection of STZ (60 mg/kg, I.V. on the first day. Rats were monitored for 28 days and food, water intake and plasma glucose levels were noted. At both 14-days and 28-days post diabetes blood samples were collected and kidney cortex, medulla and aorta were harvested from each rat. Results The diabetic rats lost body weight at both 14-days (-10% and 28-days (-13% more significantly as compared to sham (+10% group. Glucose levels were significantly elevated in the diabetic rats at both 14-days and 28-days post-STZ administration. Renal dysfunction as evidenced by renal hypertrophy, increased plasma creatinine concentration and reduced renal blood flow was observed in 14-days and 28-days diabetes. Vascular dysfunction as evidenced by decreased carotid blood flow was observed in 14-days and 28-days diabetes. We observed an up-regulation of inducible nitric oxide synthase (iNOS, prepro endothelin-1 (preproET-1 and phosphorylated p38-MAPK in thoracic aorta and kidney cortex but not in kidney medulla in 28-days diabetes group. Conclusion The study provides evidence that diabetes produces vascular and renal dysfunction with a profound effect on signaling mechanisms at later stage of diabetes.

Endothelial progenitor cell dysfunction in patients with progressive chronic kidney disease

NARCIS (Netherlands)

Krenning, Guido; Dankers, Patricia Y. W.; Drouven, Johannes W.; Waanders, Femke; Franssen, Casper F. M.; van Luyn, Marja J. A.; Harmsen, Martin C.; Popa, Eliane R.

Krenning G, Dankers PY, Drouven JW, Waanders F, Franssen CF, van Luyn MJ, Harmsen MC, Popa ER. Endothelial progenitor cell dysfunction in patients with progressive chronic kidney disease. Am J Physiol Renal Physiol 296: F1314-F1322, 2009. First published April 1, 2009; doi:

Renal dysfunction induced by long-term exposure to depleted uranium in rats

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Zhu, Guoying; Xiang, Xiqiao; Chen, Xiao; Wang, Lihua; Hu, Heping; Weng, Shifang [Fudan University, Institute of Radiation Medicine, Shanghai (China)

2009-01-15

Depleted uranium (DU) is a kind of radioactive heavy metal which can enter into the body via inhalation (aerosols), ingestion (drinking and eating) and wounds (embedded), and causes chemical and/or radiation-induced toxicities. In this study, male Sprague Dawley rats were surgically implanted in gastrocnemius muscle with DU fragments at three dose levels (low-dose, medium-dose and high-dose), with biologically inert tantalum (Ta) fragments served as controls. At 1 day, 7 days, and 3, 6, and 12 months after implantation, the rats were euthanized and tissue samples were collected, and uranium levels were measured in a variety of tissues by inductively coupled plasma-mass spectrometry (ICP-MS) to analyze the dynamic changes and distribution of uranium in rats. Thereafter, at 3, 6 and 12 months after implantation, the rats were euthanized after the collection of 24 h urine, blood and kidney samples were collected for analysis of DU-induced renal histopathologic changes and renal dysfunction. It was observed that DU concentrations in all the DU implanted groups were higher than that in Ta control group, and DU concentrations in the kidney increased with the implanted times, peaked at the 90 days after implantation, with a high correlation to the implanted DU doses, and then began to decrease gradually and slowly, and the DU concentrations in kidney still maintained at a relatively high level even at the 360 days after implantation. Otherwise, chronic DU contamination could induce the pathological changes of renal glomeruli, tubules and mesenchyme, such as interstitial fibrosis, enlarged interstice of renal tubular epithelial cells, tumefactions and necrosis of epithelial cells, shrinkage and disappearance of cavity of Bowman's capsule. By TEM, it was shown that the basement membrane of glomerulus was incrassated, mitochondrial of kidney proximal tubule had visible tumefaction and became bigger, and the mitochondrial cristae became shorter and disorderly in

Renal dysfunction induced by long-term exposure to depleted uranium in rats

International Nuclear Information System (INIS)

Zhu, Guoying; Xiang, Xiqiao; Chen, Xiao; Wang, Lihua; Hu, Heping; Weng, Shifang

2009-01-01

Depleted uranium (DU) is a kind of radioactive heavy metal which can enter into the body via inhalation (aerosols), ingestion (drinking and eating) and wounds (embedded), and causes chemical and/or radiation-induced toxicities. In this study, male Sprague Dawley rats were surgically implanted in gastrocnemius muscle with DU fragments at three dose levels (low-dose, medium-dose and high-dose), with biologically inert tantalum (Ta) fragments served as controls. At 1 day, 7 days, and 3, 6, and 12 months after implantation, the rats were euthanized and tissue samples were collected, and uranium levels were measured in a variety of tissues by inductively coupled plasma-mass spectrometry (ICP-MS) to analyze the dynamic changes and distribution of uranium in rats. Thereafter, at 3, 6 and 12 months after implantation, the rats were euthanized after the collection of 24 h urine, blood and kidney samples were collected for analysis of DU-induced renal histopathologic changes and renal dysfunction. It was observed that DU concentrations in all the DU implanted groups were higher than that in Ta control group, and DU concentrations in the kidney increased with the implanted times, peaked at the 90 days after implantation, with a high correlation to the implanted DU doses, and then began to decrease gradually and slowly, and the DU concentrations in kidney still maintained at a relatively high level even at the 360 days after implantation. Otherwise, chronic DU contamination could induce the pathological changes of renal glomeruli, tubules and mesenchyme, such as interstitial fibrosis, enlarged interstice of renal tubular epithelial cells, tumefactions and necrosis of epithelial cells, shrinkage and disappearance of cavity of Bowman's capsule. By TEM, it was shown that the basement membrane of glomerulus was incrassated, mitochondrial of kidney proximal tubule had visible tumefaction and became bigger, and the mitochondrial cristae became shorter and disorderly in alignment

Optical cryoimaging for assessment of radiation-induced injury to rat kidney metabolic state

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Mehrvar, Shima; Funding la Cour, Mette; Medhora, Meetha; Camara, Amadou K. S.; Ranji, Mahsa

2018-02-01

Objective: This study utilizes fluorescence cryoimaging to quantitatively assess the effect of a high dose of irradiation on rat renal metabolism through redox state. Introduction: Exposure to high doses of irradiation could lead to death, in part, due to renal dysfunction. The kidney is one of the most sensitive organs that exhibit delayed injuries in survivors of acute radiation syndrome. In this study, optical cryoimaging was utilized to examine the potential for renal mitochondrial dysfunction after partial-body irradiation (PBI) and the mitigating effect of lisinopril-treatment, an angiotensin converting enzyme inhibitor that is FDA-approved for other indications. Materials and methods: Rats were exposed to a single dose of 13 Gy leg-out partial body irradiation (PBI, by X-rays). Rats (n = 5/group) received no further treatment, or lisinopril started one week after irradiation and continued at 24 mg/m2 /day. The non-irradiated siblings were used as controls. After 150 days, the rats were sacrificed, and their kidneys harvested and snap frozen in liquid nitrogen for later cryoimaging. The 3D images of metabolic indices (NADH and FAD) were captured, and the redox ratio i.e. NADH/FAD was calculated. The mitochondrial redox state of three groups of rat kidneys were quantified by calculating the volumetric mean of redox ratio images (RR). Results: 3D cryoimaging revealed that in PBI only kidneys, the metabolic marker (RR) decreased significantly by 78% compared to non-irradiated controls. Treatment with lisinopril significantly improved the RR by 93% in groups exposed to PBI. Conclusion: This study aimed at quantifying the level of the mitochondrial redox state of irradiated rat kidneys compared to non-irradiated kidneys (controls) and the efficacy of lisinopril to preserve kidney metabolism after irradiation. PBI oxidized the metabolic state of kidneys and lisinopril mitigated the radiation-induced injury on renal mitochondria.

Association Between Inflammatory Markers and Progression to Kidney Dysfunction: Examining Different Assessment Windows in Patients With Type 1 Diabetes.

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Baker, Nathaniel L; Hunt, Kelly J; Stevens, Danielle R; Jarai, Gabor; Rosen, Glenn D; Klein, Richard L; Virella, Gabriel; Lopes-Virella, Maria F

2018-01-01

To determine whether biomarkers of inflammation and endothelial dysfunction are associated with the development of kidney dysfunction and the time frame of their association. Biomarkers were measured at four time points during 28 years of treatment and follow-up in patients with type 1 diabetes in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort. In addition to traditional biomarkers of inflammation (C-reactive protein and fibrinogen), we measured interleukin-6 (IL-6) and soluble tumor necrosis factor receptors 1 and 2 (sTNFR-1/2), markers of endothelial dysfunction (soluble intracellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin [sE-selectin]), and fibrinolysis (total and active plasminogen activator inhibitor-1 [PAI-1]). Renal outcomes were defined as progression to incident chronic kidney disease (stage 3 or more severe) or macroalbuminuria (albumin excretion rate ≥300 mg/24 h). Prospective multivariate event-time analyses were used to determine the association of each biomarker with each subsequent event within prespecified intervals (3-year and 10-year windows). Multivariate event-time models indicated that several markers of inflammation (sTNFR-1/2), endothelial dysfunction (sE-selectin), and clotting/fibrinolysis (fibrinogen and PAI-1) are significantly associated with subsequent development of kidney dysfunction. Although some markers showed variations in the associations between the follow-up windows examined, the results indicate that biomarkers (sTNFR-1/2, sE-selectin, PAI-1, and fibrinogen) are associated with progression to chronic kidney disease in both the 3-year and the 10-year windows. Plasma markers of inflammation, endothelial dysfunction, and clotting/fibrinolysis are associated with progression to kidney dysfunction in type 1 diabetes during both short-term and long-term follow-up. © 2017 by the American Diabetes Association.

Regeneration of the liver at different periods of mononuclear infiltration induced by zymosan granules

International Nuclear Information System (INIS)

Shcherbakov, V.I.; Komlyagina, T.G.; Mayanskii, D.N.

1985-01-01

The aim of this investigation was to discover how the liver,with areas of mononuclear infiltration, developing in response to activation of Kupffer cells (KC) by zymosan granules (ZG), regenerates. In the experiments, an intraperitoneal injection of 1 microCi of 3 H-thymidine/g body weight was given to the mice 1 h before sacrifice. Proliferation of hepatocytes and regeneration of the liver were intensified most when partial resection of the liver (PRL) was performed at the peak of mononuclear infiltration of the liver, namely five days after injection of ZG. The data indicate that not only activated KC, but also areas of mononuclear infiltration potentiate hepatocyte regeneration

[Cyclic vomiting with ketosis as a cause of acute kidney dysfunction: own clinical experience].

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Ostrowska-Nawarycz, L; Rapacka, E; Baszczyński, J; Górski, P; Czajka, J; Makowski, M; Kudzin, A

2000-04-01

The aim of the study was to evaluate renal activity during cyclic vomiting with ketosis. The clinical material was obtained from 50 cases of children hospitalized in Department of Pediatrics Military Medical University within 1993-1999 what makes about 1% of all patients. The examined group consisted of 26 boys (52%) and 24 girls (48%). Three of the children were repeatedly hospitalized (3 to 8 times) because of acetonemic vomiting. The special attention during the laboratory studies was paid to evaluation of renal activity. Vomiting with ketosis were associated with temporary kidneys acute dysfunction in 46% of cases. In 98% of cases the parenteral hydration was necessary. Ketonemic vomiting with kidneys dysfunction was observed mainly with the children in pre-school age.

Lycopene Usage as a Treatment for Kidney Dysfunctions Induced by Adriamycin in Rats

International Nuclear Information System (INIS)

Mekawy, H.M.S.

2012-01-01

Adriamycin is chemically synthesized antibiotic anthracycline and due to the successful action of it as a chemotherapy agent, several strategies have been tried to prevent or attenuate the side effects of adriamycin. Lycopene, a carotenoid naturally occurring in tomatoes, has attracted considerable attention as an antioxidant. Rats were divided into 4 groups; control group, ravaged and injected with vehicles, lycopene group, received lycopene (5 mg/kg body weight/day by gavages) and injected intra peritoneum (ip) with 0.5 ml of vehicle for 7 weeks. Adriamycin group injected with adriamycin (4 doses of ip 4 mg/kg body weight at 3, 4, 5 and 6 weeks) or adriamycin and lycopene group received both lycopen and adriamycin dosage. In adriamycin groups, plasma creatinine, urea and malondialdeyde (MDA) levels were increased significantly, total proteins level was decreased and serum nitric oxide (NO) level was increased significantly. Moreover, blood level of reduced glutathione (GSH) and levels of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSHPx) were reduced significantly. Furthermore, renal MDA and NO concentrations were increased significantly and levels of GSH, SOD, CAT and GSHPx were reduced significantly. Protracted treatment of adriamycin-treated rats with lycopene resulted in a significant modulation in all plasma, serum, blood and renal tested parameters. These results have suggested that lycopene modulated the kidney damage induced by the adriamycin nephrotoxicant in male rats. The mechanisms of lycopene overcome against adriamycin-induced toxicity were proved to be due to inhibition of lipid per oxidation (LP) and GSH depletion. The present study demonstrated a beneficial effect of lycopene treatment against adriamycin-induced kidney disorders by reversing the oxidative stress

CD44-deficiency attenuates the immunologic responses to LPS and delays the onset of endotoxic shock-induced renal inflammation and dysfunction.

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Elena Rampanelli

Full Text Available Acute kidney injury (AKI is a common complication during systemic inflammatory response syndrome (SIRS, a potentially deadly clinical condition characterized by whole-body inflammatory state and organ dysfunction. CD44 is a ubiquitously expressed cell-surface transmembrane receptor with multiple functions in inflammatory processes, including sterile renal inflammation. The present study aimed to assess the role of CD44 in endotoxic shock-induced kidney inflammation and dysfunction by using CD44 KO and WT mice exposed intraperitoneally to LPS for 2, 4, and 24 hours . Upon LPS administration, CD44 expression in WT kidneys was augmented at all time-points. At 2 and 4 hours, CD44 KO animals showed a preserved renal function in comparison to WT mice. In absence of CD44, the pro-inflammatory cytokine levels in plasma and kidneys were lower, while renal expression of the anti-inflammatory cytokine IL-10 was higher. The cytokine levels were associated with decreased leukocyte influx and endothelial activation in CD44 KO kidneys. Furthermore, in vitro assays demonstrated a role of CD44 in enhancing macrophage cytokine responses to LPS and leukocyte migration. In conclusion, our study demonstrates that lack of CD44 impairs the early pro-inflammatory cytokine response to LPS, diminishes leukocyte migration/chemotaxis and endothelial activation, hence, delays endotoxic shock-induced AKI.

Salt and nitric oxide synthase inhibition-induced hypertension: kidney dysfunction and brain anti-oxidant capacity.

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Oktar, Süleyman; Ilhan, Selçuk; Meydan, Sedat; Aydin, Mehmet; Yönden, Zafer; Gökçe, Ahmet

2010-01-01

The specific aim of this study was to examine the effects of salt-loading on kidney function and brain antioxidant capacity. Wistar rats were divided into four groups: Control rats were given normal drinking water and no drug treatment for 2 weeks. LNNA group: rats were given normal drinking water and the nitric oxide (NO) inhibitor NG-nitro-L-arginine (L-NNA), 3 mg/kg/day. LNNA + Salt group: rats were given drinking water containing salt 2% and 3 mg/kg L-NNA. Salt group: rats were given drinking water containing salt 2% and no drug treatment. Basal blood pressure and the levels of serum BUN, creatinine, uric acid, cortisol, electrolyte, serum antioxidant capacity, and oxidative stress were measured. NO, superoxide dismutase (SOD), and catalase (CAT) levels were measured in the hypothalamus, brainstem, and cerebellum. Salt overload increased the blood pressure of the LNNA + Salt group. Salt-loading enhanced BUN, creatinine, sodium retention. High salt produced an increase in uric acid levels and a decrease in cortisol levels in serum. Additionally, the oxidative stress index in serum increased in the LNNA + Salt group. Salt-loading enhanced brain NO levels, but not SOD and CAT activity. L-NNA increased brain SOD activity, but not CAT and NO levels. In conclusion, salt-loading causes hypertension, kidney dysfunction, and enhances oxidative stress in salt-sensitive rats.

Inhibition of HDAC6 protects against rhabdomyolysis-induced acute kidney injury.

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Shi, Yingfeng; Xu, Liuqing; Tang, Jinhua; Fang, Lu; Ma, Shuchen; Ma, Xiaoyan; Nie, Jing; Pi, Xiaoling; Qiu, Andong; Zhuang, Shougang; Liu, Na

2017-03-01

Histone deacetylase 6 (HDAC6) inhibition has been reported to protect against ischemic stroke and prolong survival after sepsis in animal models. However, it remains unknown whether HDAC6 inhibition offers a renoprotective effect after acute kidney injury (AKI). In this study, we examined the effect of tubastatin A (TA), a highly selective inhibitor of HDAC6, on AKI in a murine model of glycerol (GL) injection-induced rhabdomyolysis. Following GL injection, the mice developed severe acute tubular injury as indicated by renal dysfunction; expression of neutrophil gelatinase-associated lipocalin (NGAL), an injury marker of renal tubules; and an increase of TdT-mediated dUTP nick-end labeling (TUNEL)-positive tubular cells. These changes were companied by increased HDAC6 expression in the cytoplasm of renal tubular cells. Administration of TA significantly reduced serum creatinine and blood urea nitrogen levels as well as attenuated renal tubular damage in injured kidneys. HDAC6 inhibition also resulted in decreased expression of NGAL, reduced apoptotic cell, and inactivated caspase-3 in the kidney after acute injury. Moreover, injury to the kidney increased phosphorylation of nuclear factor (NF)-κB and expression of multiple cytokines/chemokines including tumor necrotic factor-α and interleukin-6 and monocyte chemoattractant protein-1, as well as macrophage infiltration. Treatment with TA attenuated all those responses. Finally, HDAC6 inhibition reduced the level of oxidative stress by suppressing malondialdehyde (MDA) and preserving expression of superoxide dismutase (SOD) in the injured kidney. Collectively, these data indicate that HDAC6 contributes to the pathogenesis of rhabdomyolysis-induced AKI and suggest that HDAC6 inhibitors have therapeutic potential for AKI treatment. Copyright © 2017 the American Physiological Society.

The Protective Effect of Omega-3 Against Thioacetamide Induced Lipid and Renal Dysfunction in Male Rats

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Davood Moghadamnia

2016-10-01

Full Text Available Background Thioacetamide causes lipid and kidney dysfunction.Omega-3 unsaturated fatty acids prevent the progression of renal diseases. Objectives This study aimed to assess the protective effects of omega-3 fish oil supplement on thioacetamide induced lipid and kidney dysfunction in male rats. Methods In this experimental study, 42 male rats were divided into 6 groups of 7: control group sham group which received 0.4 mL olive oil as a solvent, Thioacetamide group receiving thioacetamide at a dose of 150 mg/kg once as intraperitoneal injection, Experimental groups of 1, 2 and 3 which received omega-3 fish oil supplement at the doses of 100, 200, 300 mg/kg orally for 3 months respectively and then they received thioacetamide at the dose of 150 mg/kg intraperitoneally for once. The levels of serum creatinine, BUN, total cholesterol, LDL, HDL, FBS, triglyceride, sodium and potassium were measured. The pathological changes of tissue samples of the kidneys were studied after hematoxylin-eosin staining. The data were analyzed by SPSS-18 software and using one way ANOVA and Tukey as post hoc test. Significant level was considered to be P < 0.05. Results The mean serum levels of potassium in the second experimental group significantly decreased (5.26 ± 0.02 compared to the group receiving thioacetamide (6.50 ± 0. The mean serum sodium in all experimental groups decreased significantly compared to the group receiving thioacetamide. The mean serum levels of total cholesterol in experimental group 3 (66.80 ± 1.46 significantly decreased compared to the group receiving thioacetamide (84 ± 0.57. No significant changes were observed in the mean serum levels of FBS, BUN, HDL, LDL, triglycerides and creatinine in all experimental groups compared to the group receiving thioacetamide. All the experimental groups improved renal histological changes induced by thioacetamide and these protective effects were dose-dependent (P ≤ 0.05. Conclusions The results of

Suramin protects from cisplatin-induced acute kidney injury

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Dupre, Tess V.; Doll, Mark A.; Shah, Parag P.; Sharp, Cierra N.; Kiefer, Alex; Scherzer, Michael T.; Saurabh, Kumar; Saforo, Doug; Siow, Deanna; Casson, Lavona; Arteel, Gavin E.; Jenson, Alfred Bennett; Megyesi, Judit; Schnellmann, Rick G.; Beverly, Levi J.

2015-01-01

Cisplatin, a commonly used cancer chemotherapeutic, has a dose-limiting side effect of nephrotoxicity. Approximately 30% of patients administered cisplatin suffer from kidney injury, and there are limited treatment options for the treatment of cisplatin-induced kidney injury. Suramin, which is Federal Drug Administration-approved for the treatment of trypanosomiasis, improves kidney function after various forms of kidney injury in rodent models. We hypothesized that suramin would attenuate cisplatin-induced kidney injury. Suramin treatment before cisplatin administration reduced cisplatin-induced decreases in kidney function and injury. Furthermore, suramin attenuated cisplatin-induced expression of inflammatory cytokines and chemokines, endoplasmic reticulum stress, and apoptosis in the kidney cortex. Treatment of mice with suramin 24 h after cisplatin also improved kidney function, suggesting that the mechanism of protection is not by inhibition of tubular cisplatin uptake or its metabolism to nephrotoxic species. If suramin is to be used in the context of cancer, then it cannot prevent cisplatin-induced cytotoxicity of cancer cells. Suramin did not alter the dose-response curve of cisplatin in lung adenocarcinoma cells in vitro. In addition, suramin pretreatment of mice harboring lung adenocarcinomas did not alter the initial cytotoxic effects of cisplatin (DNA damage and apoptosis) on tumor cells. These results provide evidence that suramin has potential as a renoprotective agent for the treatment/prevention of cisplatin-induced acute kidney injury and justify future long-term preclinical studies using cotreatment of suramin and cisplatin in mouse models of cancer. PMID:26661653

Activation-Inactivation Cycling of Rab35 and ARF6 Is Required for Phagocytosis of Zymosan in RAW264 Macrophages

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Youhei Egami

2015-01-01

Full Text Available Phagocytosis of zymosan by phagocytes is a widely used model of microbial recognition by the innate immune system. Live-cell imaging showed that fluorescent protein-fused Rab35 accumulated in the membranes of phagocytic cups and then dissociated from the membranes of newly formed phagosomes. By our novel pull-down assay for Rab35 activity, we found that Rab35 is deactivated immediately after zymosan internalization into the cells. Phagosome formation was inhibited in cells expressing the GDP- or GTP-locked Rab35 mutant. Moreover, the simultaneous expression of ACAP2—a Rab35 effector protein—with GTP-locked Rab35 or the expression of plasma membrane-targeted ACAP2 showed a marked inhibitory effect on phagocytosis through ARF6 inactivation by the GAP activity of ACAP2. ARF6, a substrate for ACAP2, was also localized on the phagocytic cups and dissociated from the membranes of internalized phagosomes. In support of the microscopic observations, ARF6-GTP pull-down experiments showed that ARF6 is transiently activated during phagosome formation. Furthermore, the expression of GDP- or GTP-locked ARF6 mutants also suppresses the uptake of zymosan. These data suggest that the activation-inactivation cycles of Rab35 and ARF6 are required for the uptake of zymosan and that ACAP2 is an important component that links Rab35/ARF6 signaling during phagocytosis of zymosan.

Myeloid Heme Oxygenase-1 Regulates the Acute Inflammatory Response to Zymosan in the Mouse Air Pouch

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Rita Brines

2018-01-01

Full Text Available Heme oxygenase-1 (HO-1 is induced by many stimuli to modulate the activation and function of different cell types during innate immune responses. Although HO-1 has shown anti-inflammatory effects in different systems, there are few data on the contribution of myeloid HO-1 and its role in inflammatory processes is not well understood. To address this point, we have used HO-1M-KO mice with myeloid-restricted deletion of HO-1 to specifically investigate its influence on the acute inflammatory response to zymosan in vivo. In the mouse air pouch model, we have shown an exacerbated inflammation in HO-1M-KO mice with increased neutrophil infiltration accompanied by high levels of inflammatory mediators such as interleukin-1β, tumor necrosis factor-α, and prostaglandin E2. The expression of the degradative enzyme matrix metalloproteinase-3 (MMP-3 was also enhanced. In addition, we observed higher levels of serum MMP-3 in HO-1M-KO mice compared with control mice, suggesting the presence of systemic inflammation. Altogether, these findings demonstrate that myeloid HO-1 plays an anti-inflammatory role in the acute response to zymosan in vivo and suggest the interest of this target to regulate inflammatory processes.

Mitigation of diazinon-induced cardiovascular and renal dysfunction by gallic acid

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Ajibade, Temitayo Olabisi; Omobowale, Temidayo Olutayo; Asenuga, Ebunoluwa Racheal; Afolabi, Jeremiah Moyinoluwa; Adedapo, Adeolu Alex

2016-01-01

Studies of the link between environmental pollutants and cardiovascular dysfunction, neglected for decades, have recently provided new insights into the pathology and consequences of these killers. In this study, rats were divided into four groups, each containing 10 rats. The rats in group one served as controls and were administered normal saline, whereas the rats in group two were orally gavaged with 3 mg/kg of diazinon (DZN) alone for twenty one consecutive days. The rats in groups 3 and 4 were administered respective 60 mg/kg and 120 mg/kg gallic acid (GA) in addition to DZN for twenty one consecutive days. Exposure of rats to diazinon significantly (pgallic acid in diazinon-induced anemia and associated cardiovascular dysfunction in rats. Treatment with gallic acid reversed the oxidative stress markers studied, increased the antioxidant defence system and reduced deleterious effects on hematological parameters in rats. Pathologic findings of the heart and kidney were also found to be lessened. PMID:28652848

Effects of in vitro lactoferricin and lactoferrin on the head kidney cells of European sea bass (Dicentrarchus labrax, L.).

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Henry, Morgane A; Alexis, Maria N

2009-08-15

Antimicrobial, anti-inflammatory and immunomodulating properties of lactoferrin have been demonstrated in mammals and in fish. However, in vivo, lactoferrin is digested by gastric pepsin treatment into the N-terminal derived peptide named lactoferricin. This has been so far overlooked in fish in vitro studies. The aim of the present study was to assess in vitro the effects of both lactoferricin and lactoferrin on the head kidney cells of European sea bass (Dicentrarchus labrax, L.) in order to determine their potential as dietary additives and to get some insight into their mode of action. In vitro lactoferricin decreased significantly the chemiluminescent response of head kidney cells but did not affect the zymosan-triggered chemiluminescence activity. On the other hand, a high concentration of lactoferrin directly stimulated chemiluminescence but reduced the zymosan-triggered chemiluminescence. The bactericidal activity of head kidney cells was also significantly diminished by pre-incubation with lactoferrin in a dose-dependent manner. Although no significant effect of lactoferricin or lactoferrin was evidenced on head kidney cellular viability, absent or negative effect on the priming of respiratory burst activity suggested that care should be taken when using lactoferrin in the diet of sea bass and high doses should be avoided. Hypotheses about the mechanisms of action of lactoferricin and lactoferrin are presented.

A Review: Radiographic Iodinated Contrast Media-Induced Thyroid Dysfunction

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Leung, Angela M.; Braverman, Lewis E.; Brent, Gregory A.; Pearce, Elizabeth N.

2015-01-01

Context: Thyroid hormone production is dependent on adequate iodine intake. Excess iodine is generally well-tolerated, but thyroid dysfunction can occur in susceptible individuals after excess iodine exposure. Radiological iodinated contrast media represent an increasingly common source of excess iodine. Objective: This review will discuss the thyroidal response after acute exposure to excess iodine; contrast iodine-induced thyroid dysfunction; risks of iodine-induced thyroid dysfunction in vulnerable populations, such as the fetus, neonate, and patients with impaired renal function; and recommendations for the assessment and treatment of contrast iodine-induced thyroid dysfunction. Methods: Data for this review were identified by searching PubMed, Google Scholar, and references from relevant articles from 1948 to 2014. Conclusions: With the increase in the use of computed tomography scans in the United States, there is increasing risk of contrast-induced thyroid dysfunction. Patients at risk of developing iodine-induced thyroid dysfunction should be closely monitored after receiving iodinated contrast media and should be treated as needed. PMID:25375985

Honey feeding protects kidney against cisplatin nephrotoxicity through suppression of inflammation.

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Hamad, Rania; Jayakumar, Calpurnia; Ranganathan, Punithavathi; Mohamed, Riyaz; El-Hamamy, Mahmoud M I; Dessouki, Amina A; Ibrahim, Abdelazim; Ramesh, Ganesan

2015-08-01

Cisplatin is a highly effective chemotherapeutic drug used to treat a wide variety of solid tumors. However, its use was limited due its dose-limiting toxicity to the kidney. Currently, there are no therapies available to treat or prevent cisplatin nephrotoxicity. Honey is a naturally occurring complex liquid and widely used in traditional Ayurvedic medicine to treat many illnesses. However, its effect on cisplatin nephrotoxicity is unknown. To determine the role of honey in cisplatin nephrotoxicity, animals were pretreated orally for a week and then cisplatin was administered. Honey feeding was continued for another 3 days. Our results show that animals with cisplatin-induced kidney dysfunction, as determined by increased serum creatinine, which received honey feeding had less kidney dysfunction. Improved kidney function was associated with better preservation of kidney morphology in honey-treated group as compared to the cisplatin alone-treated group. Interestingly, honey feeding significantly reduced cisplatin-induced tubular epithelial cell death, immune infiltration into the kidney as well as cytokine and chemokine expression and excretion as compared to cisplatin treated animals. Western blot analysis shows that cisplatin-induced increase in phosphorylation of NFkB was completely suppressed with honey feeding. In conclusion, honey feeding protects the kidney against cisplatin nephrotoxicity through suppression of inflammation and NFkB activation. © 2015 Wiley Publishing Asia Pty Ltd.

Cadmium induced oxidative stress in kidney epithelia cells

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Bjerregaard, Henning F.

2007-01-01

Cadmium (Cd) is an important industrial and environmental pollutant. In humans exposed to Cd via oral and/or pulmonary routes, the kidney is by far the primary organ affected adversely by Cd. It have been estimated that 7% of the human population may develop renal dysfunction from Cd exposure...... of generation of ROS in this pathway remains unclear.     The aim of the present study was to monitor, in real time, the rates of ROS generation to be able to directly determine their production dynamics in living cells in response to drugs. Initial studies were planed in to use 2,7-dichlorofluorescein...... production from mitochondria due to an increase in the intracellular calcium concentration. Visual inspection of cultured cells showed that the Cd induced destruction of the cell membrane after three hours was abolished when cells were pretreated with N-acetylcysteine or CCCP, indicating that ROS generation...

Upregulation of microRNA 142-3p in the peripheral blood and urinary cells of kidney transplant recipients with post-transplant graft dysfunction.

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Domenico, T D; Joelsons, G; Montenegro, R M; Manfro, R C

2017-04-03

We analyzed microRNA (miR)-142-3p expression in leucocytes of the peripheral blood and urinary sediment cell samples obtained from kidney transplant recipients who developed graft dysfunction. Forty-one kidney transplant recipients with kidney graft dysfunction and 8 stable patients were included in the study. The groups were divided according to histological analysis into acute rejection group (n=23), acute tubular necrosis group (n=18) and stable patients group used as a control for gene expression (n=8). Percutaneous biopsies were performed and peripheral blood samples and urine samples were obtained. miR-142-3p was analyzed by real-time polymerase chain reaction. The group of patients with acute tubular necrosis presented significantly higher expressions in peripheral blood (Ptransplantation and may potentially be used as a non-invasive biomarker for renal graft dysfunction.

Blood transfusion improves renal oxygenation and renal function in sepsis-induced acute kidney injury in rats.

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Zafrani, Lara; Ergin, Bulent; Kapucu, Aysegul; Ince, Can

2016-12-20

The effects of blood transfusion on renal microcirculation during sepsis are unknown. This study aimed to investigate the effect of blood transfusion on renal microvascular oxygenation and renal function during sepsis-induced acute kidney injury. Twenty-seven Wistar albino rats were randomized into four groups: a sham group (n = 6), a lipopolysaccharide (LPS) group (n = 7), a LPS group that received fluid resuscitation (n = 7), and a LPS group that received blood transfusion (n = 7). The mean arterial blood pressure, renal blood flow, and renal microvascular oxygenation within the kidney cortex were recorded. Acute kidney injury was assessed using the serum creatinine levels, metabolic cost, and histopathological lesions. Nitrosative stress (expression of endothelial (eNOS) and inducible nitric oxide synthase (iNOS)) within the kidney was assessed by immunohistochemistry. Hemoglobin levels, pH, serum lactate levels, and liver enzymes were measured. Fluid resuscitation and blood transfusion both significantly improved the mean arterial pressure and renal blood flow after LPS infusion. Renal microvascular oxygenation, serum creatinine levels, and tubular damage significantly improved in the LPS group that received blood transfusion compared to the group that received fluids. Moreover, the renal expression of eNOS was markedly suppressed under endotoxin challenge. Blood transfusion, but not fluid resuscitation, was able to restore the renal expression of eNOS. However, there were no significant differences in lactic acidosis or liver function between the two groups. Blood transfusion significantly improved renal function in endotoxemic rats. The specific beneficial effect of blood transfusion on the kidney could have been mediated in part by the improvements in renal microvascular oxygenation and sepsis-induced endothelial dysfunction via the restoration of eNOS expression within the kidney.

Kidney-on-a-Chip: a New Technology for Predicting Drug Efficacy, Interactions, and Drug-induced Nephrotoxicity.

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Lee, Jeonghwan; Kim, Sejoong

2018-03-08

The kidneys play a pivotal role in most drug-removal processes and are important when evaluating drug safety. Kidney dysfunction resulting from various drugs is an important issue in clinical practice and during the drug development process. Traditional in vivo animal experiments are limited with respect to evaluating drug efficacy and nephrotoxicity due to discrepancies in drug pharmacokinetics and pharmacodynamics between humans and animals, and static cell culture experiments cannot fully reflect the actual microphysiological environment in humans. A kidney-on-a-chip is a microfluidic device that allows the culture of living renal cells in 3-dimensional channels and mimics the human microphysiological environment, thus simulating the actual drug filtering, absorption, and secretion process.. In this review, we discuss recent developments in microfluidic culturing technique and describe current and future kidney-on-a-chip applications. We focus on pharmacological interactions and drug-induced nephrotoxicity, and additionally discuss the development of multi-organ chips and their possible applications. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Prenatal iron deficiency causes sex-dependent mitochondrial dysfunction and oxidative stress in fetal rat kidneys and liver.

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Woodman, Andrew G; Mah, Richard; Keddie, Danae; Noble, Ronan M N; Panahi, Sareh; Gragasin, Ferrante S; Lemieux, Hélène; Bourque, Stephane L

2018-06-01

Prenatal iron deficiency alters fetal developmental trajectories, which results in persistent changes in organ function. Here, we studied the effects of prenatal iron deficiency on fetal kidney and liver mitochondrial function. Pregnant Sprague-Dawley rats were fed partially or fully iron-restricted diets to induce a state of moderate or severe iron deficiency alongside iron-replete control rats. We assessed mitochondrial function via high-resolution respirometry and reactive oxygen species generation via fluorescence microscopy on gestational d 21. Hemoglobin levels were reduced in dams in the moderate (-31%) and severe groups (-54%) compared with controls, which was accompanied by 55% reductions in fetal hemoglobin levels in both moderate and severe groups versus controls. Male iron-deficient kidneys exhibited globally reduced mitochondrial content and respiration, as well as increased cytosolic superoxide and decreased NO. Female iron-deficient kidneys exhibited complex II down-regulation and increased mitochondrial oxidative stress. Male iron-deficient livers exhibited reduced complex IV respiration and increased cytosolic superoxide, whereas female liver tissues exhibited no alteration in oxidant levels or mitochondrial function. These findings indicate that prenatal iron deficiency causes changes in mitochondrial content and function as well as oxidant status in a sex- and organ-dependent manner, which may be an important mechanism that underlies the programming of cardiovascular disease.-Woodman, A. G., Mah, R., Keddie, D., Noble, R. M. N., Panahi, S., Gragasin, F. S., Lemieux, H., Bourque, S. L. Prenatal iron deficiency causes sex-dependent mitochondrial dysfunction and oxidative stress in fetal rat kidneys and liver.

Renal dysfunction and chronic kidney disease in ischemic stroke and transient ischemic attack: A population-based study.

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Hayden, Derek; McCarthy, Christine; Akijian, Layan; Callaly, Elizabeth; Ní Chróinín, Danielle; Horgan, Gillian; Kyne, Lorraine; Duggan, Joseph; Dolan, Eamon; O' Rourke, Killian; Williams, David; Murphy, Sean; O'Meara, Yvonne; Kelly, Peter J

2017-10-01

Background and purpose The prevalence of chronic kidney disease (estimated glomerular filtration rate (eGFR) chronic kidney disease (CKD)) in ischemic stroke and transient ischemic attack (TIA) is unknown, as estimates have been based on single-point estimates of renal function. Studies investigating the effect of renal dysfunction (eGFR < 60 mL/min per 1.73 m 2 , renal dysfunction) on post-stroke outcomes are limited to hospitalized cohorts and have provided conflicting results. Methods We investigated rates, determinants and outcomes of renal dysfunction in ischemic stroke and TIA in the North Dublin Population Stroke Study. We also investigate the persistence of renal dysfunction in 90-day survivors to determine the prevalence of CKD. Ascertainment included hot and cold pursuit using multiple overlapping sources. Survival analysis was performed using Kaplan-Meier survival curves and Cox proportional hazards modeling. Results In 547 patients (ischemic stroke in 76.4%, TIA in 23.6%), the mean eGFR at presentation was 63.7 mL/min/1.73 m 2 (SD 22.1). Renal dysfunction was observed in 44.6% (244/547). Among 90-day survivors, 31.2% (139/446) met criteria for CKD. After adjusting for age and stroke severity, eGFR < 45 mL/min/1.73 m 2 (hazard ratio 2.53, p = 0.01) independently predicted 28-day fatality but not at two years. Poor post-stroke functional outcome (Modified Rankin Scale 3-5) at two years was more common in those with renal dysfunction (52.5% vs. 20.6%, p < 0.001). After adjusting for age, stroke severity and pre-stroke disability, renal dysfunction (OR 2.17, p = 0.04) predicted poor functional outcome. Conclusion Renal dysfunction and CKD are common in ischemic stroke and TIA. Renal dysfunction is associated with considerable post-stroke morbidity and mortality. Further studies are needed to investigate if modifiable mechanisms underlie these associations.

High-fat diet induces an initial adaptation of mitochondrial bioenergetics in the kidney despite evident oxidative stress and mitochondrial ROS production

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Ruggiero, Christine; Ehrenshaft, Marilyn; Cleland, Ellen

2011-01-01

Obesity and metabolic syndrome are associated with an increased risk for several diabetic complications, including diabetic nephropathy and chronic kidney diseases. Oxidative stress and mitochondrial dysfunction are often proposed mechanisms in various organs in obesity models, but limited data are available on the kidney. Here, we fed a lard-based high-fat diet to mice to investigate structural changes, cellular and subcellular oxidative stress and redox status, and mitochondrial biogenesis and function in the kidney. The diet induced characteristic changes, including glomerular hypertrophy, fibrosis, and interstitial scarring, which were accompanied by a proinflammatory transition. We demonstrate evidence for oxidative stress in the kidney through 3-nitrotyrosine and protein radical formation on high-fat diet with a contribution from iNOS and NOX-4 as well as increased generation of mitochondrial oxidants on carbohydrate- and lipid-based substrates. The increased H2O2 emission in the mitochondria suggests altered redox balance and mitochondrial ROS generation, contributing to the overall oxidative stress. No major derailments were observed in respiratory function or biogenesis, indicating preserved and initially improved bioenergetic parameters and energy production. We suggest that, regardless of the oxidative stress events, the kidney developed an adaptation to maintain normal respiratory function as a possible response to an increased lipid overload. These findings provide new insights into the complex role of oxidative stress and mitochondrial redox status in the pathogenesis of the kidney in obesity and indicate that early oxidative stress-related changes, but not mitochondrial bioenergetic dysfunction, may contribute to the pathogenesis and development of obesity-linked chronic kidney diseases. PMID:21386058

Valsartan Protects Against Contrast-Induced Acute Kidney Injury in Rats by Inhibiting Endoplasmic Reticulum Stress-Induced Apoptosis.

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Sun, Yan; Peng, Ping-An; Ma, Yue; Liu, Xiao-Li; Yu, Yi; Jia, Shuo; Xu, Xiao-Han; Wu, Si-Jing; Zhou, Yu-Jie

2017-01-01

Contrast-induced acute kidney injury (CI-AKI) is a serious complication of the administration of iodinated contrast media (CM) for diagnostic and interventional cardiovascular procedures and is associated with substantial morbidity and mortality. While the preventative measures can mitigate the risk of CI-AKI, there remains a need for novel and effective therapeutic approaches. The pathogenesis of CI-AKI is complex and not completely understood. CM-induced renal tubular cell apoptosis caused by the activation of endoplasmic reticulum (ER) stress is involved in CIAKI. We previously demonstrated that valsartan alleviated CM-induced human renal tubular cell apoptosis by inhibiting ER stress in vitro. However, the nephroprotective effect of valsartan on CI-AKI in vivo has not been investigated. Therefore, the aim of this study was to explore the protective effect of valsartan in a rat model of CI-AKI by measuring the amelioration of renal damage and the changes in ER stressrelated biomarkers. Our results showed that the radiocontrast agent meglumine diatrizoate caused significant renal insufficiency, renin-angiotensin system (RAS) activation, and renal tubular apoptosis by triggering ER stress through activation of glucose-regulated protein 78 (GRP78), activating transcription factor 4 (ATF4), caspase 12, CCAAT/enhancer-binding protein-homologous protein (CHOP) and c-Jun N-terminal protein kinase (JNK) (Pvalsartan significantly alleviated renal dysfunction, pathological injury, and apoptosis along with the inhibition of ER stressrelated biomarkers (PValsartan could protect against meglumine diatrizoate-induced kidney injury in rats by inhibiting the ER stress-induced apoptosis, making it a promising strategy for preventing CI-AKI. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Stage effect of chronic kidney disease in erectile function

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Márcio Rodrigues Costa

Full Text Available ABSTRACT Purpose The study aims to assess the influence of the stage of chronic kidney disease and glomerular filtration rate on prevalence and degree of erectile dysfunction. Materials and Methods This transversal study, conducted from May 2013 to December 2015, included patients with chronic kidney disease in conservative treatment, stages III/IV/V. Erectile dysfunction was evaluated by the International Index of Erectile Function. Data classically associated with erectile dysfunction were obtained by medical record review. Erectile dysfunction, degree of erectile dysfunction, and other main variables associated with erectile dysfunction were compared between patients with chronic kidney disease on conservative treatment stages III versus IV/V using the Chi-square test. The relationship between score of the International Index of Erectile Dysfunction and glomerular filtration rate was established by Pearson correlation coefficient. Results Two hundred and forty five patients with chronic kidney disease in conservative treatment participated of the study. The prevalence of erectile dysfunction in patients with chronic kidney disease in stages IV/V was greater than in stage III. Glomerular filtration rate positively correlated with score of the International Index of Erectile Dysfunction. Conclusions The study suggests that chronic kidney disease progression (glomerular filtration rate decrease and advance in chronic kidney disease stages worsen erectile function. Hypothetically, diagnosis and treatment of erectile dysfunction may be anticipated with the analysis of chronic kidney disease progression.

Long-term cadmium exposure induces anemia in rats through hypoinduction of erythropoietin in the kidneys

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Horiguchi, Hyogo [Department of Public Health, Fukushima Medical College, Fukushima (Japan); Sato, Masao [Department of Biomolecular Sciences, Institute of Biomedical Sciences, Fukushima Medical College, Fukushima (Japan); Konno, Nobuhiro [Department of Public Health, Fukushima Medical College, Fukushima (Japan); Fukushima, Masaaki [Department of Public Health, Fukushima Medical College, Fukushima (Japan)

1996-11-01

Cadmium (Cd), a highly toxic heavy metal, is distributed widely in the general environment of today. The characteristic clinical manifestations of chronic Cd intoxication include renal proximal tubular dysfunction, general osteomalacia with severe pains, and anemia. We have recently reported that the serum level of erythropoietin (EPO) remained low despite the severe anemia in patients with Itai-itai disease, the most severe form of chronic Cd intoxication. In order to prove that the anemia observed in chronic Cd intoxication arises from low production of EPO in the kidneys following the renal injury, we administered Cd to rats for a long period and performed the analysis of EPO mRNA inducibility in the kidneys. The rats administered Cd for 6 and 9 months showed anemia with low levels of plasma EPO as well as biochemical and histological renal tubular damage, and also hypoinduction of EPO mRNA in the kidneys. The results indicate that chronic Cd intoxication causes anemia by disturbing the EPO-production capacity of renal cells. (orig.). With 4 figs., 4 tabs.

Effect of zymosan and poly (I:C) adjuvants on responses to microneedle immunization coated with whole inactivated influenza vaccine.

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Shin, Ju-Hyung; Noh, Jin-Yong; Kim, Kwon-Ho; Park, Jae-Keun; Lee, Ji-Ho; Jeong, Seong Dong; Jung, Dae-Yoon; Song, Chang-Seon; Kim, Yeu-Chun

2017-11-10

Microneedles are the micrometer size devices used for the delivery of vaccines and biotherapeutics. In order to increase the vaccine efficacy and reduce the antigen dose, there is a significant need to find some adjuvants for the microneedle vaccination. In this study, zymosan, which is the cell wall preparation of Saccharomyces cerevisiae, or poly (I:C) was coated on a microneedle with inactivated influenza virus, and then immunized into BALB/c mouse to determine the immunogenicity, protection and synergetic effect between two adjuvants. As a result, the group administered with zymosan and vaccine antigen showed significantly stronger IgG response, HI titer and IgG subtypes without any adverse effects, compared to the group immunized with the vaccine antigen alone. Also, there were enhanced cellular immune responses in the group received adjuvant with vaccine antigen. In addition, they showed superior protection and lung viral reduction against lethal viral challenge. Taken together, this study confirms that zymosan can be used as an immunostimulant for microneedle vaccination. Copyright © 2017 Elsevier B.V. All rights reserved.

Acute Kidney Injury by Radiographic Contrast Media: Pathogenesis and Prevention

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Faga, Teresa; Pisani, Antonio; Michael, Ashour

2014-01-01

It is well known that iodinated radiographic contrast media may cause kidney dysfunction, particularly in patients with preexisting renal impairment associated with diabetes. This dysfunction, when severe, will cause acute renal failure (ARF). We may define contrast-induced Acute Kidney Injury (AKI) as ARF occurring within 24–72 hrs after the intravascular injection of iodinated radiographic contrast media that cannot be attributed to other causes. The mechanisms underlying contrast media nephrotoxicity have not been fully elucidated and may be due to several factors, including renal ischaemia, particularly in the renal medulla, the formation of reactive oxygen species (ROS), reduction of nitric oxide (NO) production, and tubular epithelial and vascular endothelial injury. However, contrast-induced AKI can be prevented, but in order to do so, we need to know the risk factors. We have reviewed the risk factors for contrast-induced AKI and measures for its prevention, providing a long list of references enabling readers to deeply evaluate them both. PMID:25197639

The potential use of biomarkers in predicting contrast-induced acute kidney injury

Directory of Open Access Journals (Sweden)

Andreucci M

2016-09-01

Full Text Available Michele Andreucci,1 Teresa Faga,1 Eleonora Riccio,2 Massimo Sabbatini,2 Antonio Pisani,2 Ashour Michael,1 1Department of Health Sciences, University “Magna Graecia” of Catanzaro, Catanzaro, 2Department of Public Health, University of Naples Federico II, Naples, Italy Abstract: Contrast-induced acute kidney injury (CI-AKI is a problem associated with the use of iodinated contrast media, causing kidney dysfunction in patients with preexisting renal failure. It accounts for 12% of all hospital-acquired kidney failure and increases the length of hospitalization, a situation that is worsening with increasing numbers of patients with comorbidities, including those requiring cardiovascular interventional procedures. So far, its diagnosis has relied upon the rise in creatinine levels, which is a late marker of kidney damage and is believed to be inadequate. Therefore, there is an urgent need for biomarkers that can detect CI-AKI sooner and more reliably. In recent years, many new biomarkers have been characterized for AKI, and these are discussed particularly with their use in known CI-AKI models and studies and include neutrophil gelatinase-associated lipocalin, cystatin C (Cys-C, kidney injury molecule-1, interleukin-18, N-acetyl-β-d-glucosaminidase, and L-type fatty acid-binding protein (L-FABP. The potential of miRNA and metabolomic technology is also mentioned. Early detection of CI-AKI may lead to early intervention and therefore improve patient outcome, and in future any one or a combination of several of these markers together with development in technology for their analysis may prove effective in this respect. Keywords: radiocontrast media, acute renal failure, markers, renal injury

Oxidative burst and nitric oxide responses in carp macrophages induced by zymosan, MacroGard® and selective dectin-1 agonists suggest recognition by multiple pattern recognition receptors

DEFF Research Database (Denmark)

Pietretti, D.; Jiménez, Natalia Ivonne Vera; Hoole, D.

2013-01-01

phosphatase (SEAP) reporter gene. In addition, dectin-1-specific ligands in mammals i.e. zymosan treated to deplete the TLR-stimulating properties and curdlan, were monitored for their effects on carp macrophages by measuring reactive oxygen and nitrogen radicals production, as well as cytokine gene...

Protective effect of Petroselinum crispum extract in abortion using prostadin-induced renal dysfunction in female rats

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Maryam Rezazad

2014-09-01

Full Text Available Objective: Present study investigated the effects of parsley extract on pregnant rat kidneys which have undergone clinical abortion using prostaglandins. The renal protective effect of parsley extract was evaluated in pregnant rats which had an abortion. Parsley was used due to its antioxidant properties. Materials and Methods:  Fifty-four female rats were divided in 9 groups of 6: control pregnant, two pregnant groups which received parsley extract and prostadin, two non-pregnant groups treated with parsley extract and prostadin, a group administered with both treatments, and three groups which received parsley extract in pre-implantation, implantation, and post-implantation periods of embryos. Ethanolic extract (5 mg/kg was given daily to animals for 18 days of pregnancy period. Parameters such as malondialdehyde (MDA, total antioxidant statues (TAS, creatinine, and urea were measured using biochemical assays. Histopathologic studies were also done with Hematoxylin-Eosin staining method. Results: After 18 days of treatment, significant differences were observed in serum creatinine, urea, and MDA and TAS levels. Kidney cross-sections showed edema in prostadin-treated rats while improvements in parsley + prostadin -treated rats were observed. Conclusion: These results suggested that ethanolic extract of Petroselinum crispum reduced the dysfunction in rats kidney caused by prostadin-induced abortion and could have beneficial effect in reducing the progression of prostaglandin-induced edema.

Effect of Fenugreek (Trigonella Foenum-Graecum) Supplementation on Radiation-Induced Oxidative Stress in Liver and Kidney of Rats

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EI-Tawil, G A [Radiation Biology Department, National Centre for Radiation Research and Technology (NCRRT), Atomic Energy Authority, Cairo (Egypt)

2009-07-01

Whole body exposure to ionizing radiation provokes oxidative damage, organ dysfunction and metabolic disturbances. Fenugreek (Trigonella foenumgraecum L. Leguminosae), one of the oldest medicinal plants rich in polyphenolic compounds is known to possess antioxidant properties. The present study was designed to determine the possible protective effect of fenugreek, against {gamma}-radiation-induced oxidative stress in liver and kidney tissues of rats. In parallel, the alteration in the activity of serum alkaline phosphatase (ALP), aspartate aminotransferase (AST) and alanine aminotransferase (ALT), as markers of liver function, creatinine and urea levels as markers of kidney function. In addition, serum glucose and insulin levels were determined as markers for carbohydrate metabolism. Irradiated rats were whole body exposed to 3.5 Gy (Acute dose) {gamma}-radiations. Fenugreek-treated irradiated rats received 1g fenugreek seed powder/kg body weight/day, by gavages, during 7 days before irradiation. Animals were sacrificed on the 1 sl day after irradiation. The results obtained demonstrated that exposure to ionizing radiation induced significant decreases in SOD and CAT activities and GSH content associated to significant increase of TBARS levels in liver and kidney. Fenugreek treatment has significantly attenuated radiation-induced oxidative stress in both tissues, which was substantiated by the significant amelioration of serum ALP, AST and ALT activities, creatinine, urea, glucose, and insulin levels. It could be concluded that fenugreek would protect from oxidative damage and metabolic disturbances induced by ionizing irradiation.

Effect of Fenugreek (Trigonella Foenum-Graecum) Supplementation on Radiation-Induced Oxidative Stress in Liver and Kidney of Rats

International Nuclear Information System (INIS)

EI-Tawil, G.A.

2009-01-01

Whole body exposure to ionizing radiation provokes oxidative damage, organ dysfunction and metabolic disturbances. Fenugreek (Trigonella foenumgraecum L. Leguminosae), one of the oldest medicinal plants rich in polyphenolic compounds is known to possess antioxidant properties. The present study was designed to determine the possible protective effect of fenugreek, against γ-radiation-induced oxidative stress in liver and kidney tissues of rats. In parallel, the alteration in the activity of serum alkaline phosphatase (ALP), aspartate aminotransferase (AST) and alanine aminotransferase (ALT), as markers of liver function, creatinine and urea levels as markers of kidney function. In addition, serum glucose and insulin levels were determined as markers for carbohydrate metabolism. Irradiated rats were whole body exposed to 3.5 Gy (Acute dose) γ-radiations. Fenugreek-treated irradiated rats received 1g fenugreek seed powder/kg body weight/day, by gavages, during 7 days before irradiation. Animals were sacrificed on the 1 sl day after irradiation. The results obtained demonstrated that exposure to ionizing radiation induced significant decreases in SOD and CAT activities and GSH content associated to significant increase of TBARS levels in liver and kidney. Fenugreek treatment has significantly attenuated radiation-induced oxidative stress in both tissues, which was substantiated by the significant amelioration of serum ALP, AST and ALT activities, creatinine, urea, glucose, and insulin levels. It could be concluded that fenugreek would protect from oxidative damage and metabolic disturbances induced by ionizing irradiation

Tempol, a superoxide dismutase mimetic agent, ameliorates cisplatin-induced nephrotoxicity through alleviation of mitochondrial dysfunction in mice.

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Lamiaa A Ahmed

Full Text Available Mitochondrial dysfunction is a crucial mechanism by which cisplatin, a potent chemotherapeutic agent, causes nephrotoxicity where mitochondrial electron transport complexes are shifted mostly toward imbalanced reactive oxygen species versus energy production. In the present study, the protective role of tempol, a membrane-permeable superoxide dismutase mimetic agent, was evaluated on mitochondrial dysfunction and the subsequent damage induced by cisplatin nephrotoxicity in mice.Nephrotoxicity was assessed 72 h after a single i.p. injection of cisplatin (25 mg/kg with or without oral administration of tempol (100 mg/kg/day. Serum creatinine and urea as well as glucosuria and proteinuria were evaluated. Both kidneys were isolated for estimation of oxidative stress markers, adenosine triphosphate (ATP content and caspase-3 activity. Moreover, mitochondrial oxidative phosphorylation capacity, complexes I-IV activities and mitochondrial nitric oxide synthase (mNOS protein expression were measured along with histological examinations of renal tubular damage and mitochondrial ultrastructural changes. Tempol was effective against cisplatin-induced elevation of serum creatinine and urea as well as glucosuria and proteinuria. Moreover, pretreatment with tempol notably inhibited cisplatin-induced oxidative stress and disruption of mitochondrial function by restoring mitochondrial oxidative phosphorylation, complexes I and III activities, mNOS protein expression and ATP content. Tempol also provided significant protection against apoptosis, tubular damage and mitochondrial ultrastructural changes. Interestingly, tempol did not interfere with the cytotoxic effect of cisplatin against the growth of solid Ehrlich carcinoma.This study highlights the potential role of tempol in inhibiting cisplatin-induced nephrotoxicity without affecting its antitumor activity via amelioration of oxidative stress and mitochondrial dysfunction.

Heat stroke induced cerebellar dysfunction: A “forgotten syndrome”

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Kosgallana, Athula D; Mallik, Shreyashee; Patel, Vishal; Beran, Roy G

2013-01-01

We report a case of heat stroke induced acute cerebellar dysfunction, a rare neurological disease characterized by gross cerebellar dysfunction with no acute radiographic changes, in a 61 years old ship captain presenting with slurred speech and gait ataxia. A systematic review of the literature on heat stroke induced cerebellar dysfunction was performed, with a focus on investigations, treatment and outcomes. After review of the literature and detailed patient investigation it was concluded that this patient suffered heat stroke at a temperature less than that quoted in the literature. PMID:24340279

Linezolid-induced thrombocytopenia in two patients with renal dysfunction

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Engin Melek

2016-12-01

Full Text Available Linezolid is an oxazolidinone antibiotic, active against gram positive bacteria that are resistant to other antibiotics including glycopeptides. Thrombocytopenia is an adverse effect of linezolid. Although various risk factors have been suggested, the mechanisms behind this side effect are largely unknown. Here, we report two adolescents with the diagnosis of chronic kidney disease who developed thrombocytopenia following treatment with linezolid. Our purpose in highlighting these cases is to increase the clinical awareness concerning this side effect of linezolid. While it is well known that thrombocytopenia may develop during linezolid treatment, it is relatively unknown that patients with renal dysfunction have an increased risk for the development of thrombocytopenia compared to patients without renal dysfunction. [Cukurova Med J 2016; 41(4.000: 808-810

Omega-3 Polyunsaturated Fatty Acids Attenuate Radiation-induced Oxidative Stress and Organ Dysfunctions in Rats

International Nuclear Information System (INIS)

Abdel Aziz, N.; Yacoub, S.F.

2013-01-01

The Aim of the present study was to determine the possible protective effect of omega-3 polyunsaturated fatty acids (omega-3 PUFA) against radiation-induced oxidative stress associated with organ dysfunctions. Omega-3 PUFA was administered by oral gavages to male albino rats at a dose of 0.4 g/ kg body wt daily for 4 weeks before whole body γ-irradiation with 4Gy. Significant increase of serum lipid peroxidation end product as malondialdehyde (MDA) along with the reduction in blood glutathione (GSH) content, superoxide dismutase (SOD) and glutathione peroxidase (GPX) enzyme activities were recorded on 3rd and 8th days post-irradiation. Oxidative stress was associated with a significant increase in lactate dehydrogenase (LDH) and creatine phosphokinase (CPK) enzyme activities, markers of heart damage, significant increases in uric acid, urea and creatinine levels, markers of kidney damage, significant increases of alkaline phosphatase (ALP) and transaminases (ALT and AST) activities, markers of liver damage. Moreover significant increases in total cholesterol and triglycerides levels were recorded. Omega-3 PUFA administration pre-irradiation significantly attenuated the radiation-induced oxidative stress and organ dysfunctions tested in this study. It could be concluded that oral supplementation of omega-3 PUFA before irradiation may afford protection against radiation-induced oxidative stress and might preserve the integrity of tissue functions of the organs under investigations.

Multiple organ dysfunction caused by parathyroid adenoma‑induced ...

African Journals Online (AJOL)

We present a 27‑year‑old male with multiple organ dysfunction caused by parathyroid adenoma‑induced primary hyperparathyroidism (PHPT). Initially, the patient experienced a sudden onset of gastrointestinal symptoms, polyuria, polydipsia, bone pain, renal dysfunction, nephrolithiasis, and acute pancreatitis, symptoms ...

CT perfusion technique for assessment of early kidney allograft dysfunction: preliminary results

Energy Technology Data Exchange (ETDEWEB)

Helck, A.; Notohamiprodjo, M.; Schoen, F.; Nikolaou, K.; Clevert, D.A.; Reiser, M.; Becker, C. [Ludwig-Maximilians-University of Munich, Department of Clinical Radiology, University Hospitals Grosshadern, Munich (Germany); Wessely, M.; Schoenermarck, U.; Fischereder, M. [Ludwig-Maximilians-University of Munich, Department of Internal Medicine IV, Nephrology, University Hospitals Grosshadern, Munich (Germany); Klotz, E. [Siemens Healthcare, Computed Tomography, Forchheim (Germany)

2013-09-15

To assess the benefit of quantitative computed tomography (CT) perfusion for differentiating acute tubular necrosis (ATN) and acute rejection (AR) in kidney allografts. Twenty-two patients with acute kidney allograft dysfunction caused by either AR (n = 6) or ATN (n = 16) were retrospectively included in the study. All patients initially underwent a multiphase CT angiography (CTA) protocol (12 phases, one phase every 3.5 s) covering the whole graft to exclude acute postoperative complications. Multiphase CT dataset and dedicated software were used to calculate renal blood flow. Renal biopsy or clinical course of disease served as the standard of reference. Mean effective radiation dose and mean amount of contrast media were calculated. Renal blood flow values were significantly lower (P = 0.001) in allografts undergoing AR (48.3 {+-} 21 ml/100 ml/min) compared with those with ATN (77.5 {+-} 21 ml/100 ml/min). No significant difference (P = 0.71) was observed regarding creatinine level with 5.65 {+-} 3.1 mg/dl in AR and 5.3 {+-} 1.9 mg/dl in ATN. The mean effective radiation dose of the CT perfusion protocol was 13.6 {+-} 5.2 mSv; the mean amount of contrast media applied was 34.5 {+-} 5.1 ml. All examinations were performed without complications. CT perfusion of kidney allografts may help to differentiate between ATN and rejection. (orig.)

Consensus Guideline for Use of Glucarpidase in Patients with High-Dose Methotrexate Induced Acute Kidney Injury and Delayed Methotrexate Clearance

DEFF Research Database (Denmark)

Ramsey, Laura B; Balis, Frank M; O'Brien, Maureen M

2018-01-01

Acute kidney injury due to high-dose methotrexate (HDMTX) is a serious, life-threatening toxicity that can occur in pediatric and adult patients. Glucarpidase is a treatment approved by the Food and Drug Administration for high methotrexate concentrations in the context of kidney dysfunction...... is above 30 µM, 42-hour concentration is above 10 µM, or 48-hour concentration is above 5 µM and the serum creatinine is significantly elevated relative to the baseline measurement (indicative of HDMTX-induced acute kidney injury), glucarpidase may be indicated. After a 36- to 42-hour HDMTX infusion......: Glucarpidase is a rarely used medication that is less effective when given after more than 60 hours of exposure to high-dose methotrexate, so predicting early which patients will need it is imperative. There are no currently available consensus guidelines for the use of this medication. The indication...

Leukemia kidney infiltration can cause secondary polycythemia by activating hypoxia-inducible factor (HIF) pathway.

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Osumi, Tomoo; Awazu, Midori; Fujimura, Eriko; Yamazaki, Fumito; Hashiguchi, Akinori; Shimada, Hiroyuki

2013-06-01

Secondary polycythemia with increased production of erythropoietin (EPO) is known to occur in kidney diseases such as hydronephrosis and cystic disease, but the mechanism remains unclear. We report an 18-year-old female with isolated renal relapse of acute lymphoblastic leukemia accompanied by polycythemia. At the relapse, she presented with bilateral nephromegaly, mild renal dysfunction, and erythrocytosis with increased serum EPO levels up to 52.1 mIU/mL (9.1-32.8). Renal biopsy demonstrated diffuse lymphoblastic infiltration. The expression of hypoxia-inducible factor (HIF)-1α, which is undetectable in normal kidney, was observed in the renal tubule epithelium compressed by lymphoblastic cells. These findings suggest that erythrocytosis was caused by renal ischemia due to leukemic infiltration. Polycythemia probably became apparent because of the lack of leukemic involvement of the bone marrow. With chemotherapy, the serum EPO level rapidly decreased to normal range accompanied by the normalization of kidney size and function. Renal leukemic infiltration may enhance EPO production, although not recognized in the majority of cases because of bone marrow involvement. Our case has clarified the mechanism of previously reported polycythemia associated with renal diseases as renal ischemia. Furthermore, we have added renal ischemia resulting from tumor infiltration to the list of causes of secondary polycythemia.

CD147/basigin reflects renal dysfunction in patients with acute kidney injury.

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Nagaya, Hiroshi; Kosugi, Tomoki; Maeda-Hori, Mayuko; Maeda, Kayaho; Sato, Yuka; Kojima, Hiroshi; Hayashi, Hiroki; Kato, Noritoshi; Ishimoto, Takuji; Sato, Waichi; Yuzawa, Yukio; Matsuo, Seiichi; Kadomatsu, Kenji; Maruyama, Shoichi

2014-10-01

Acute tubular necrosis (ATN) describes a form of intrinsic acute kidney injury (AKI) that results from persistent hypoperfusion and subsequent activation of the immune system. A glycosylated transmembrane protein, CD147/basigin, is involved in the pathogenesis of renal ischemia and fibrosis. The present study investigated whether CD147 can reflect pathological features and renal dysfunction in patients with AKI. Plasma and spot urine samples were collected from 24 patients (12 controls and 12 with ATN) who underwent renal biopsy between 2008 and 2012. In another study, patients undergoing open surgery to treat abdominal aortic aneurysms (AAAs) were enrolled in 2004. We collected urine and plasma samples from seven patients with AKI and 33 patients without AKI, respectively. In these experiments, plasma and urinary CD147, and urinary L-fatty acid-binding protein (L-FABP) levels were measured, and the former expression in kidneys was examined by immunostaining. In biopsy tissues of ATN with severe histological features, CD147 induction was strikingly present in inflammatory cells such as macrophages and lymphocytes in the injured interstitium, but not in damaged tubules representing atrophy. Both plasma and urinary CD147 levels were strikingly increased in ATN patients; both values showed greater correlations with renal dysfunction compared to urinary L-FABP. In patients who had undergone open AAA surgery, urinary and plasma CD147 values in AKI patients were significantly higher than in non-AKI patients at post-operative day 1, similar to the profile of urinary L-FABP. CD147 was prominent in its ability to detect AKI and may allow the start of preemptive medication.

Antioxidant protection of statins in acute kidney injury induced by sepsis

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Franciele do Nascimento Santos

2014-10-01

Full Text Available Objective Evaluating the effect of preconditioning with simvastatin in acute kidney injury induced by sepsis. Method Male adult Wistar rats were divided into the following groups: SHAM (control; SHAM+Statin (0.5 mg/kg simvastatin, orally; Sepsis (cecal puncture ligation – CPL; Sepsis+Statin. Physiological parameters, peritoneal fluid culture, renal function, oxidative metabolites, severity of acute kidney injury and animal survival were evaluated. Results The treatment with simvastatin in induced sepsis showed elevation of creatinine clearance with attenuation of generation of oxidative metabolites, lower severity of acute kidney injury and reduced mortality. Conclusion This investigation confirmed the renoprotection with antioxidant principle of the simvastatin in acute kidney injury induced by sepsis in an experimental model.

Selective Serotonin Reuptake Inhibitor-Induced Sexual Dysfunction in Adolescents: A Review.

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Scharko, Alexander M.

2004-01-01

Objective: To review the existing literature on selective serotonin reuptake inhibitor (SSRI)-induced sexual dysfunction in adolescents. Method: A literature review of SSRI-induced adverse effects in adolescents focusing on sexual dysfunction was done. Nonsexual SSRI-induced adverse effects were compared in adult and pediatric populations.…

Hydrogen-rich water inhibits glucose and α,β -dicarbonyl compound-induced reactive oxygen species production in the SHR.Cg-Leprcp/NDmcr rat kidney

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Katakura Masanori

2012-07-01

Full Text Available Abstract Background Reactive oxygen species (ROS production induced by α,β-dicarbonyl compounds and advanced glycation end products causes renal dysfunction in patients with type 2 diabetes and metabolic syndrome. Hydrogen-rich water (HRW increases the H2 level in blood and tissues, thus reducing oxidative stress in animals as well as humans. In this study, we investigated the effects of HRW on glucose- and α,β-dicarbonyl compound-induced ROS generation in vitro and in vivo. Methods Kidney homogenates from Wistar rats were incubated in vitro with glucose and α,β-dicarbonyl compounds containing HRW, following which ROS levels were measured. In vivo animal models of metabolic syndrome, SHR.Cg-Leprcp/NDmcr rats, were treated with HRW for 16 weeks, following which renal ROS production and plasma and renal α,β-dicarbonyl compound levels were measured by liquid chromatograph mass spectrometer. Results HRW inhibited glucose- and α,β-dicarbonyl compound-induced ROS production in kidney homogenates from Wistar rats in vitro. Furthermore, SHR.Cg-Leprcp/NDmcr rats treated with HRW showed a 34% decrease in ROS production. Moreover, their renal glyoxal, methylglyoxal, and 3-deoxyglucosone levels decreased by 81%, 77%, and 60%, respectively. Positive correlations were found between renal ROS levels and renal glyoxal (r = 0.659, p = 0.008 and methylglyoxal (r = 0.782, p = 0.001 levels. Conclusion These results indicate that HRW inhibits the production of α,β-dicarbonyl compounds and ROS in the kidneys of SHR.Cg-Leprcp/NDmcr rats. Therefore, it has therapeutic potential for renal dysfunction in patient with type 2 diabetes and metabolic syndrome.

Effects of quercetin on kidney injury induced by doxorubicin.

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Yagmurca, M; Yasar, Z; Bas, O

2015-01-01

The anthracycline antitumor drug doxorubicine causes severe nephrotoxicity in a variety of experimental animals and may be nephrotoxic to humans. The aim of present study was to determine the protective effects of quercetin against doxorubicin-induced kidney injury with light microscopy. Forty male Wistar albino rats were divided into four groups: control, doxorubicin, doxorubicin+quercetin and quercetin. A single dose of 20 mg/kg/ i.p. doxorubicin was used to induce injury. Quercetin was administrated orally against doxorubicin toxicity. The kidneys were examined under light microscopy after H-E (hematoxylin-eosin) staining and the changes were scored. Significant tissue injury was observed in doxorubicin-administered group. Among these injuries, renal tubular dilatation, tubular vacuolar changes, glomerular vacuolization, decrease in bowman space, bowman capsule thickening, and interstitial infiltration were evident. However, the injury induced by doxorubicin was attenuated with quercetin administration. Quercetin decreased doxorubicin-induced kidney damage (Tab. 1, Fig. 4, Ref. 27).

Tempol, a Superoxide Dismutase Mimetic Agent, Ameliorates Cisplatin-Induced Nephrotoxicity through Alleviation of Mitochondrial Dysfunction in Mice

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Ahmed, Lamiaa A.; Shehata, Nagwa I.; Abdelkader, Noha F.; Khattab, Mahmoud M.

2014-01-01

Background Mitochondrial dysfunction is a crucial mechanism by which cisplatin, a potent chemotherapeutic agent, causes nephrotoxicity where mitochondrial electron transport complexes are shifted mostly toward imbalanced reactive oxygen species versus energy production. In the present study, the protective role of tempol, a membrane-permeable superoxide dismutase mimetic agent, was evaluated on mitochondrial dysfunction and the subsequent damage induced by cisplatin nephrotoxicity in mice. Methods and Findings Nephrotoxicity was assessed 72 h after a single i.p. injection of cisplatin (25 mg/kg) with or without oral administration of tempol (100 mg/kg/day). Serum creatinine and urea as well as glucosuria and proteinuria were evaluated. Both kidneys were isolated for estimation of oxidative stress markers, adenosine triphosphate (ATP) content and caspase-3 activity. Moreover, mitochondrial oxidative phosphorylation capacity, complexes I–IV activities and mitochondrial nitric oxide synthase (mNOS) protein expression were measured along with histological examinations of renal tubular damage and mitochondrial ultrastructural changes. Tempol was effective against cisplatin-induced elevation of serum creatinine and urea as well as glucosuria and proteinuria. Moreover, pretreatment with tempol notably inhibited cisplatin-induced oxidative stress and disruption of mitochondrial function by restoring mitochondrial oxidative phosphorylation, complexes I and III activities, mNOS protein expression and ATP content. Tempol also provided significant protection against apoptosis, tubular damage and mitochondrial ultrastructural changes. Interestingly, tempol did not interfere with the cytotoxic effect of cisplatin against the growth of solid Ehrlich carcinoma. Conclusion This study highlights the potential role of tempol in inhibiting cisplatin-induced nephrotoxicity without affecting its antitumor activity via amelioration of oxidative stress and mitochondrial dysfunction

A novel approach to adenine-induced chronic kidney disease associated anemia in rodents.

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Asadur Rahman

Full Text Available To date, good experimental animal models of renal anemia are not available. Therefore, the purpose of this study was to establish a novel approach to induce chronic kidney disease (CKD with severe anemia by oral administration of adenine in rodents. Adenine was administered to 6-week-old male C57BL/6 mice (25 and 50 mg/kg body weight by oral gavage daily for 28 days. Serum creatinine and BUN as well as hematocrit, hemoglobin (Hb and plasma erythropoietin (EPO levels were monitored to assess renal function and anemia, respectively. Adenine at 25 mg/kg for 28 days slightly increased plasma creatinine levels, but did not induce anemia. In contrast, 50 mg/kg of adenine daily for 28 days showed severe renal dysfunction (plasma creatinine 1.9 ± 0.10 mg/dL and anemia (hematocrit 36.5 ± 1.0% and EPO 28 ± 2.4 pg/mL as compared with vehicle-treated mice (0.4 ± 0.02 mg/dL, 49.6 ± 1.6% and 61 ± 4.0 pg/mL, respectively. At the end of experiment, level of Hb also significantly reduced in 50 mg/kg adenine administration group. Remarkable histological changes of kidney tissues characterized by interstitial fibrosis and cystic appearance in tubules were observed in 50 mg/kg of adenine treatment group. These results have demonstrated that oral dosing with adenine at 50 mg/kg for 28 days is suitable to induce a stable anemia associated with CKD in mice.

Upregulation of microRNA 142-3p in the peripheral blood and urinary cells of kidney transplant recipients with post-transplant graft dysfunction

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T.D. Domenico

Full Text Available We analyzed microRNA (miR-142-3p expression in leucocytes of the peripheral blood and urinary sediment cell samples obtained from kidney transplant recipients who developed graft dysfunction. Forty-one kidney transplant recipients with kidney graft dysfunction and 8 stable patients were included in the study. The groups were divided according to histological analysis into acute rejection group (n=23, acute tubular necrosis group (n=18 and stable patients group used as a control for gene expression (n=8. Percutaneous biopsies were performed and peripheral blood samples and urine samples were obtained. miR-142-3p was analyzed by real-time polymerase chain reaction. The group of patients with acute tubular necrosis presented significantly higher expressions in peripheral blood (P<0.05 and urine (P<0.001 compared to the stable patients group. Also, in the peripheral blood, miR-142-3p expression was significantly higher in the acute tubular necrosis group compared to the acute rejection group (P<0.05. Urine samples of the acute rejection group presented higher expression compared to the stable patients group (P<0.001 but the difference between acute tubular necrosis and acute rejection groups was not significant in the urinary analyzes (P=0.079. miR-142-3p expression has a distinct pattern of expression in the setting of post-operative acute tubular necrosis after kidney transplantation and may potentially be used as a non-invasive biomarker for renal graft dysfunction.

Cerebral energy metabolism during induced mitochondrial dysfunction

DEFF Research Database (Denmark)

Nielsen, T H; Bindslev, TT; Pedersen, S M

2013-01-01

In patients with traumatic brain injury as well as stroke, impaired cerebral oxidative energy metabolism may be an important factor contributing to the ultimate degree of tissue damage. We hypothesize that mitochondrial dysfunction can be diagnosed bedside by comparing the simultaneous changes...... in brain tissue oxygen tension (PbtO(2)) and cerebral cytoplasmatic redox state. The study describes cerebral energy metabolism during mitochondrial dysfunction induced by sevoflurane in piglets....

Curcumin attenuates surgery-induced cognitive dysfunction in aged mice.

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Wu, Xiang; Chen, Huixin; Huang, Chunhui; Gu, Xinmei; Wang, Jialing; Xu, Dilin; Yu, Xin; Shuai, Chu; Chen, Liping; Li, Shun; Xu, Yiguo; Gao, Tao; Ye, Mingrui; Su, Wei; Liu, Haixiong; Zhang, Jinrong; Wang, Chuang; Chen, Junping; Wang, Qinwen; Cui, Wei

2017-06-01

Post-operative cognitive dysfunction (POCD) is associated with elderly patients undergoing surgery. However, pharmacological treatments for POCD are limited. In this study, we found that curcumin, an active compound derived from Curcuma longa, ameliorated the cognitive dysfunction following abdominal surgery in aged mice. Further, curcumin prevented surgery-induced anti-oxidant enzyme activity. Curcumin also increased brain-derived neurotrophic factor (BDNF)-positive area and expression of pAkt in the brain, suggesting that curcumin activated BDNF signaling in aged mice. Furthermore, curcumin neutralized cholinergic dysfunction involving choline acetyltransferase expression induced by surgery. These results strongly suggested that curcumin prevented cognitive impairments via multiple targets, possibly by increasing the activity of anti-oxidant enzymes, activation of BDNF signaling, and neutralization of cholinergic dysfunction, concurrently. Based on these novel findings, curcumin might be a potential agent in POCD prophylaxis and treatment.

Clinical Relevance and Predictive Value of Damage Biomarkers of Drug-Induced Kidney Injury.

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Kane-Gill, Sandra L; Smithburger, Pamela L; Kashani, Kianoush; Kellum, John A; Frazee, Erin

2017-11-01

Nephrotoxin exposure accounts for up to one-fourth of acute kidney injury episodes in hospitalized patients, and the associated consequences are as severe as acute kidney injury due to other etiologies. As the use of nephrotoxic agents represents one of the few modifiable risk factors for acute kidney injury, clinicians must be able to identify patients at high risk for drug-induced kidney injury rapidly. Recently, significant advancements have been made in the field of biomarker utilization for the prediction and detection of acute kidney injury. Such biomarkers may have a role both for detection of drug-induced kidney disease and implementation of preventative and therapeutic strategies designed to mitigate injury. In this article, basic principles of renal biomarker use in practice are summarized, and the existing evidence for six markers specifically used to detect drug-induced kidney injury are outlined, including liver-type fatty acid binding protein, neutrophil gelatinase-associated lipocalin, tissue inhibitor of metalloproteinase-2 times insulin-like growth factor-binding protein 7 ([TIMP-2]·[IGFBP7]), kidney injury molecule-1 and N-acetyl-β-D-glucosaminidase. The results of the literature search for these six kidney damage biomarkers identified 29 unique articles with none detected for liver-type fatty acid binding protein and [TIMP-2]·[IGFBP7]. For three biomarkers, kidney injury molecule-1, neutrophil gelatinase-associated lipocalin and N-acetyl-β-D-glucosaminidase, the majority of the studies suggest utility in clinical practice. While many questions need to be answered to clearly articulate the use of biomarkers to predict drug-induced kidney disease, current data are promising.

Antibody-dependent NK cell activation is associated with late kidney allograft dysfunction and the complement-independent alloreactive potential of donor-specific antibodies

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Tristan Legris

2016-08-01

Full Text Available Although kidney transplantation remains the best treatment for end-stage renal failure, it is limited by chronic humoral aggression of the graft vasculature by donor-specific antibodies (DSAs. The complement-independent mechanisms that lead to the antibody-mediated rejection (ABMR of kidney allografts remain poorly understood. Increasing lines of evidence have revealed the relevance of natural killer (NK cells as innate immune effectors of antibody-dependent cellular cytotoxicity, but few studies have investigated their alloreactive potential in the context of solid organ transplantation. Our study aimed to investigate the potential contribution of the antibody-dependent alloreactive function of NK cells to kidney graft dysfunction. We first conducted an observational study to investigate whether the cytotoxic function of NK cells is associated with chronic allograft dysfunction. The NK-Cellular Humoral Activation Test (NK-CHAT was designed to evaluate the recipient and antibody-dependent reactivity of NK cells against allogeneic target cells. The release of CD107a/Lamp1+ cytotoxic granules, resulting from the recognition of rituximab-coated B cells by NK cells, was analyzed in 148 kidney transplant recipients (KTRs, mean graft duration: 6.2 years. Enhanced ADCC responsiveness was associated with reduced graft function and identified as an independent risk factor predicting a decline in the estimated glomerular filtration rate (eGFR over a 1-year period (hazard ratio: 2.83. In a second approach, we used the NK-CHAT to reveal the cytotoxic potential of circulating alloantibodies in vitro. The level of CD16 engagement resulting from the in vitro recognition of serum-coated allogeneic B cells or splenic cells was further identified as a specific marker of DSA-induced ADCC. The NK-CHAT scoring of sera obtained from 40 patients at the time of transplant biopsy was associated with ABMR diagnosis. Our findings indicate that despite the administration

Developing better mouse models to study cisplatin-induced kidney injury.

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Sharp, Cierra N; Siskind, Leah J

2017-10-01

Cisplatin is a potent chemotherapeutic used for the treatment of many types of cancer. However, its dose-limiting side effect is nephrotoxicity leading to acute kidney injury (AKI). Patients who develop AKI have an increased risk of mortality and are more likely to develop chronic kidney disease (CKD). Unfortunately, there are no therapeutic interventions for the treatment of AKI. It has been suggested that the lack of therapies is due in part to the fact that the established mouse model used to study cisplatin-induced AKI does not recapitulate the cisplatin dosing regimen patients receive. In recent years, work has been done to develop more clinically relevant models of cisplatin-induced kidney injury, with much work focusing on incorporation of multiple low doses of cisplatin administered over a period of weeks. These models can be used to recapitulate the development of CKD after AKI and, by doing so, increase the likelihood of identifying novel therapeutic targets for the treatment of cisplatin-induced kidney injury. Copyright © 2017 the American Physiological Society.

Magnetic resonance imaging correlates of bee sting induced multiple organ dysfunction syndrome: A case report.

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Das, Sushant K; Zeng, Li-Chuan; Li, Bing; Niu, Xiang-Ke; Wang, Jing-Liang; Bhetuwal, Anup; Yang, Han-Feng

2014-09-28

Occasionally systemic complications with high risk of death, such as multiple organ dysfunction syndrome (MODS), can occur following multiple bee stings. This case study reports a patient who presented with MODS, i.e., acute kidney injury, hepatic and cardiac dysfunction, after multiple bee stings. The standard clinical findings were then correlated with magnetic resonance imaging (MRI) findings, which demonstrates that MRI may be utilized as a simpler tool to use than other multiple diagnostics.

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.

Protective effects of sea cucumber (Holothuria atra) extract on testicular dysfunction induced by immune suppressant drugs in Wistar rats.

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Saad, D Y; Soliman, M M; Mohamed, A A; Youssef, G B

2018-04-23

The current study was aimed to evaluate the protective effect of Holothurian atra (HA) extract; naturally occurring marine resource, against methotrexate (MTX) induced testicular dysfunction. Mature rats received either MTX (20 mg/kg, intraperitoneally) or saline on the 7th day of experiment al design. Seven days prior and after MTX-injection, rats received HA at dose of 300 mg/kg intragastrically (HA + MTX group; HA group alone). Serum was extracted and testicular tissues were examined for the changes in serum biochemistry (liver & kidney biomarkers, testicular hormones and antioxidants), molecular and histopthological alterations using RT-PCR and immunohistochemistry. MTX-injected rats induced alteration in all testicular parameters. Prior administration of HA ameliorated the MTX-induced oxidative stress. HA administration normalised MTX-induced decrease in serum levels of interleukin-6 (IL-6), tumour necrosis factor alpha (TNF-α), interferon-gamma (IFN-γ), reproductive hormones (FSH, LH and testosterone) and antioxidants GST, SOD and catalase. MTX-injected rats down-regulated mRNA expression of GST, SOD, steroidogenesis associated genes, IFN-γ, Bcl2 and NFKB. MTX up-regulated BAX expression and caspase 9 immunoreactivity that were ameliorated in HA + MTX group. Collectively, HA ameliorated and restored all altered genes. In conclusion, HA is a promising supplement that is helpful in protection against testicular cytotoxicity and dysfunction induced by methotrexate. © 2018 Blackwell Verlag GmbH.

Contrast-induced acute kidney injury: how much contrast is safe?

LENUS (Irish Health Repository)

Keaney, John J

2013-02-14

Iodinated contrast media (CM) are used in many investigations that a patient may undergo during the course of an in-patient stay. For the vast majority of patients, exposure to CM has no sequelae; however, in a small percentage, it can result in a worsening in renal function termed contrast-induced acute kidney injury (CI-AKI). CI-AKI is one of the leading causes of in-hospital renal dysfunction. It is associated with a significant increase in morbidity and mortality as well as an increased length of hospital stay and costs. Unfortunately, the results of extensive research into pharmacological inventions to prevent CI-AKI remain disappointing. In this article, we briefly outline the pathophysiological mechanisms by which iodinated CM may cause CI-AKI and discuss the evidence for reducing CI-AKI by limiting contrast volumes. In particular, we review the data surrounding the use of contrast volume to glomerular filtration rate ratios, which can be used by clinicians to effectively lower the incidence of CI-AKI in their patients.

Exercise induced renal dysfunction demonstrated both in hypertensives and normotensive controls studies by Tc-99m-DTPA

International Nuclear Information System (INIS)

Mizuiri, S.; Hayashi, I.; Ohara, T.; Hirata, K.; Sasaki, Y.

1985-01-01

It was previously reported that the hippurate transport disturbance after exercise is a specific phenomenon to patients with hypertension. The authors' study with Tc-99m-DTPA revealed exercise induced renal dysfunction not only in hypertensives (H) but also in normotensive controls (N). The details of the investigation is presented. Tc-99m-DTPA was intravenously injected at rest and during bicycle ergometric stress to 14 H and 14 N in sitting position. Serial dynamic renal images were taken, of which data were simultaneously stored in a data processor for later analysis. The renogram was drawn setting ROI on each kidney. Peak counts (PC) of vascular phase, peak time (PT) of secretory phase and radioisotope retention rate (RR) at 10 minutes were the parameters being compared between at rest and at exercise. GFR of each kidney was determined. Blood samples were obtained at rest and at the end of exercise for the measurement of aldosterone (ALD), plasma renin activity (PRA) and catecholamines (A, NA). Exercise caused significant lowering of PC, prolongation of PT and increase in RR (10 min. counts/peak counts) both in H and N. GFR (miota/min.) during exercise was significantly lower than at rest in both H (80 +- 22 vs 93.8 +- 16.9, p<0.02) and N (84 +- 17 vs 102 +- 15, p<0.01). ALD, PRA, A and NA are all elevated during exercise both in H and N. None of the rest-exercise differences significantly differed between H and N. The data indicate the exercise induced renal dysfunction demonstrated by Tc-99m-DTPA renograms is not specified to H but can also be observed in N, which may be resulted from the common changes in H and N of GFR and humoral factors

Factors influencing fluoxetine-induced sexual dysfunction in female rats

Science.gov (United States)

Adams, Sarah; Heckard, Danyeal; Hassell, James; Uphouse, Lynda

2012-01-01

Treatment with selective serotonin reuptake inhibitors, such as fluoxetine, produces sexual side effects with low sexual desire being the most prevalent effect in females. In few studies have preclinical models for such antidepressant-induced sexual dysfunction been fruitful. In the current manuscript, the effects of fluoxetine on multiple measures of female sexual motivation and sexual receptivity were examined. Ovariectomized, Fischer rats were primed with 10 μg estradiol benzoate and 500 μg progesterone. Partner preference, active investigation of the male, and measures of sexual behavior were examined after injection with 15 mg/kg fluoxetine. Factors (pretesting for sexual behavior, size of the test arena, non-contact time with a male) that differ among experiments designed to study antidepressant-induced female rat sexual dysfunction were studied. The male preference ratio was not affected by fluoxetine treatment but active investigation of the male was reduced; lordosis behavior was inhibited and pretesting for sexual receptivity amplified fluoxetine's inhibition; size of the testing arena or non-contact experience with the male had no effect. Regardless of test condition, when given the opportunity to escape from the male, fluoxetine-treated females displayed escape behavior. Measures of male preference and active investigation, but not lordosis behavior, appeared to be affected by fluoxetine's impact on activity. The collective data provided a behavioral profile of fluoxetine-induced sexual dysfunction. These findings reinforce the value of multiple measures when attempting to model antidepressant-induced female sexual dysfunction. PMID:22835821

Rescue therapy with Tanshinone IIA hinders transition of acute kidney injury to chronic kidney disease via targeting GSK3β

Science.gov (United States)

Jiang, Chunming; Zhu, Wei; Yan, Xiang; Shao, Qiuyuan; Xu, Biao; Zhang, Miao; Gong, Rujun

2016-01-01

Acute kidney injury (AKI) remains challenging for clinical practice and poses a risk of developing progressive chronic kidney disease (CKD) with no definitive treatment available yet. Tanshinone IIA, an active ingredient of Chinese herbal Salvia miltiorrhiza, has been widely used in Asia for the remarkable organoprotective activities. Its effect on established AKI, however, remains unknown. In mice with folic acid-induced AKI, delayed treatment with Tanshinone IIA, commenced early or late after injury, diminished renal expression of kidney injury markers, reduced apoptosis and improved kidney dysfunction, concomitant with mitigated histologic signs of AKI to CKD transition, including interstitial fibrosis and tubular atrophy, and with an ameliorated inflammatory infiltration in tubulointerstitium and a favored M2-skewed macrophage polarization. Mechanistically, Tanshinone IIA blunted glycogen synthase kinase (GSK)3β overactivity and hyperactivation of its downstream mitogen-activated protein kinases that are centrally implicated in renal fibrogenesis and inflammation. Inhibition of GSK3β is likely a key mechanism mediating the therapeutic activity of Tanshinone IIA, because sodium nitroprusside, a GSK3β activator, largely offset its renoprotective effect. In confirmatory studies, rescue treatment with Tanshinone IIA likewise ameliorated ischemia/reperfusion-induced kidney destruction in mice. Our data suggest that Tanshinone IIA represents a valuable treatment that improves post-AKI kidney salvage via targeting GSK3β. PMID:27857162

Chronic Kidney Disease in Pregnancy.

Science.gov (United States)

Koratala, Abhilash; Bhattacharya, Deepti; Kazory, Amir

2017-09-01

With the increasing prevalence of chronic kidney disease (CKD) worldwide, the number of pregnant women with various degrees of renal dysfunction is expected to increase. There is a bidirectional relation between CKD and pregnancy in which renal dysfunction negatively affects pregnancy outcomes, and the pregnancy can have a deleterious impact on various aspects of kidney disease. It has been shown that even mild renal dysfunction can increase considerably the risk of adverse maternal and fetal outcomes. Moreover, data suggest that a history of recovery from acute kidney injury is associated with adverse pregnancy outcomes. In addition to kidney dysfunction, maternal hypertension and proteinuria predispose women to negative outcomes and are important factors to consider in preconception counseling and the process of risk stratification. In this review, we provide an overview of the physiologic renal changes during pregnancy as well as available data regarding CKD and pregnancy outcomes. We also highlight the important management strategies in women with certain selected renal conditions that are seen commonly during the childbearing years. We call for future research on underexplored areas such as the concept of renal functional reserve to develop a potential clinical tool for prognostication and risk stratification of women at higher risk for complications during pregnancy.

Fractional Excretion of Survivin, Extracellular Matrix Metalloproteinase Inducer, and Matrix Metalloproteinase 7 in Children with Chronic Kidney Disease

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Agnieszka Bargenda

2016-07-01

Full Text Available Background: Epithelial–mesenchymal transition (EMT is defined as a transformation of tubular epithelial cells into mesenchymal ones. These cells migrate through the extracellular matrix and change into active myofibroblasts, which are responsible for excessive matrix deposition. Such changes may lead to tubular dysfunction and fibrosis of the renal parenchyma, characteristic of chronic kidney disease (CKD. However, there are no data on potential EMT markers in children with CKD. The aim of our study was to assess the usefulness of fractional excretion (FE of survivin, E-cadherin, extracellular matrix metalloproteinase inducer (EMMPRIN, matrix metalloproteinase (MMP7, and transforming growth factor beta 1 (TGF-β1 as potential markers of CKD-related complications such as tubular damage and fibrosis. Methods: Forty-one pre-dialysis children with CKD Stages 3–5 and 23 age-matched controls were enrolled in the study. The serum and urine concentrations of analysed parameters were assessed by an enzyme-linked immunosorbent assay test. Results: Tubular reabsorption of all analysed parameters was >99% in the control group. All FE values rose significantly in children with CKD, yet they remained 1%. Conclusions: FE of the examined markers may become a useful tool in the assessment of tubular dysfunction during the course of CKD. The FE of survivin, EMMPRIN, and MMP7 warrant further research as potential independent markers of kidney-specific EMT.

Renal Dysfunction after Off-Pump Coronary Artery Bypass Surgery- Risk Factors and Preventive Strategies

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Gaurab Maitra

2009-01-01

Full Text Available Postoperative renal dysfunction is a relatively common and one of the serious complications of cardiac surgery. Though off-pump coronary artery bypass surgery technique avoids cardiopulmonary bypass circuit induced adverse effects on renal function, multiple other factors cause postoperative renal dysfunction in these groups of patients. Acute kidney injury is generally defined as an abrupt and sustained decrease in kidney function. There is no consen-sus on the amount of dysfunction that defines acute kidney injury, with more than 30 definitions in use in the literature today. Although serum creatinine is widely used as a marker for changes in glomerular filtration rate, the criteria used to define renal dysfunction and acute renal failure is highly variable. The variety of definitions used in clinical studies may be partly responsible for the large variations in the reported incidence. Indeed, the lack of a uniform definition for acute kidney injury is believed to be a major impediment to research in the field. To establish a uniform definition for acute kidney injury, the Acute Dialysis Quality Initiative formulated the Risk, Injury, Failure, Loss, and End-stage Kidney (RIFLE classification. RIFLE , defines three grades of increasing severity of acute kidney injury -risk (class R, injury (class I and failure (class F - and two outcome classes (loss and end-stage kidney disease. Various perioperative risk factors for postoperative renal dysfunction and failure have been identified. Among the important preoperative factors are advanced age, reduced left ventricular function, emergency surgery, preoperative use of intraaortic balloon pump, elevated preoperative serum glucose and creatinine. Most important intraoperative risk factor is the intraoperative haemodynamic instability and all the causes of postoperative low output syndrome com-prise the postoperative risk factors. The most important preventive strategies are the identification of the

Protective effects of exogenous β-hydroxybutyrate on paraquat toxicity in rat kidney

Energy Technology Data Exchange (ETDEWEB)

Wei, Teng; Tian, Wulin; Liu, Fangning; Xie, Guanghong, E-mail: xiegh@jlu.edu.cn

2014-05-16

Highlights: • β-Hydroxybutyrate inhibits paraquat-induced toxicity in rat kidney. • β-Hydroxybutyrate inhibits lipid peroxidation and caspase-mediated apoptosis. • β-Hydroxybutyrate increases the activities of SOD and CAT. • The study describes a novel finding for the renoprotective ability of β-hydroxybutyrate. - Abstract: In this study, we demonstrated the protective effects of β-hydroxybutyrate (β-HB) against paraquat (PQ)-induced kidney injury and elucidated the underlying molecular mechanisms. By histological examination and renal dysfunction specific markers (serum BUN and creatinine) assay, β-HB could protect the PQ-induced kidney injury in rat. PQ-induced kidney injury is associated with oxidative stress, which was measured by increased lipid peroxidation (MDA) and decreased intracellular anti-oxidative abilities (SOD, CAT and GSH). β-HB pretreatment significantly attenuated that. Caspase-mediated apoptosis pathway contributed importantly to PQ toxicity, as revealed by the activation of caspase-9/-3, cleavage of PARP, and regulation of Bcl-2 and Bax, which were also effectively blocked by β-HB. Moreover, treatment of PQ strongly decreased the nuclear Nrf2 levels. However, pre-treatment with β-HB effectively suppressed this action of PQ. This may imply the important role of β-HB on Nrf2 pathway. Taken together, this study provides a novel finding that β-HB has a renoprotective ability against paraquat-induced kidney injury.

Predictors of Cognitive Dysfunction among Patients with Moderate to Severe Chronic Kidney Disease

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Uduak Effiong Williams

2017-04-01

Full Text Available Cognitive dysfunction including dementia is a common complication of chronic kidney disease (CKD that has just been recently appreciated. It has negative outcomes in the management of patients with CKD. This study explored the possible biochemical and clinical features of patients with CKD that can predict the occurrence of cognitive impairment in patients with moderate to severe CKD. We evaluate patients with stages 3-5 CKD for the occurrence and predictors of cognitive impairment. Multiple areas of cognitive function were tested in this single-center study using Community Screening Interview for Dementia (CSID and Trial-Making Test A (TMTA/Trial-Making Test B (TMTB. Cognitive impairment was correlated with patients’ routine biochemical, hematological, and selected clinical parameters. We observed a negative correlation between cognitive impairment and patient’s serum calcium (r = 0.240; p = 0.033 and estimated Glomerular filtration rate (eGFR (r = 0.379; p = 0.0006. Therefore, eGFR is an accurate predictor of cognitive dysfunction in patients with moderate to severe CKD. Early evaluation of cognitive function in CKD is indeed advised for optimal outcome in the management of patients with CKD.

TVP1022 attenuates cardiac remodeling and kidney dysfunction in experimental volume overload-induced congestive heart failure.

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Abassi, Zaid A; Barac, Yaron D; Kostin, Sawa; Roguin, Ariel; Ovcharenko, Elena; Awad, Hoda; Blank, Ayelet; Bar-Am, Orit; Amit, Tamar; Schaper, Jutta; Youdim, Moussa; Binah, Ofer

2011-07-01

Despite the availability of many pharmacological and mechanical therapies, the mortality rate among patients with congestive heart failure (CHF) remains high. We tested the hypothesis that TVP1022 (the S-isomer of rasagiline; Azilect), a neuroprotective and cytoprotective molecule, is also cardioprotective in the settings of experimental CHF in rats. In rats with volume overload-induced CHF, we investigated the therapeutic efficacy of TVP1022 (7.5 mg/kg) on cardiac function, structure, biomarkers, and kidney function. Treatment with TVP1022 for 7 days before CHF induction prevented the increase in left ventricular end-diastolic area and end-systolic area, and the decrease in fractional shortening measured 14 days after CHF induction. Additionally, TVP1022 pretreatment attenuated CHF-induced cardiomyocyte hypertrophy, fibrosis, plasma and ventricular B-type natriuretic peptide levels, and reactive oxygen species expression. Further, in CHF rats, TVP1022 decreased cytochrome c and caspase 3 expression, thereby contributing to the cardioprotective efficacy of the drug. TVP1022 also enhanced the urinary Na(+) excretion and improved the glomerular filtration rate. Similar cardioprotective effects were obtained when TVP1022 was given to rats after CHF induction. TVP1022 attenuated the adverse functional, structural, and molecular alterations in CHF, rendering this drug a promising candidate for improving cardiac and renal function in this disease state.

Preclinical evaluation of nephroprotective potential of a probiotic formulation LOBUN on Cyclosporine-A induced renal dysfunction in Wistar rats

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Kambham Venkateswarlu

2017-06-01

Full Text Available ABSTRACT The aim of present study was to evaluate the nephroprotective effect of probiotic formulation LOBUN on Cyclosporine A (CsA induced renal dysfunction in Wistar rats. CsA (20 mg/kg body weight s.c was administered for 15 days to cause renal dysfunction in Wistar rats. The probiotic formulation LOBUN was administered with the dose of 500 mg/kg body weight (p.o for twice (TGI and thrice a day (TGII. The samples were analyzed for the parameters like blood urine nitrogen (BUN, serum creatinine, serum uric acid, total serum protein and urine proteins, urine potassium, urine sodium. The renal functional and histopathological studies revealed that the oral administration of probiotic formulation LOBUN has provided appreciable renoprotection and possibly alleviated the symptoms of Chronic Kidney Disease (CKD at the dose of 500 mg/kg body weight administered thrice a day and also the results were supported by histopathological findings.

Tetracycline Reduces Kidney Damage Induced by Loxosceles Spider Venom

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Cinthya Kimori Okamoto

2017-03-01

Full Text Available Envenomation by Loxosceles spider can result in two clinical manifestations: cutaneous and systemic loxoscelism, the latter of which includes renal failure. Although incidence of renal failure is low, it is the main cause of death, occurring mainly in children. The sphingomyelinase D (SMase D is the main component in Loxosceles spider venom responsible for local and systemic manifestations. This study aimed to investigate the toxicity of L. intermedia venom and SMase D on kidney cells, using both In vitro and in vivo models, and the possible involvement of endogenous metalloproteinases (MMP. Results demonstrated that venom and SMase D are able to cause death of human kidney cells by apoptosis, concomitant with activation and secretion of extracellular matrix metalloproteases, MMP-2 and MMP-9. Furthermore, cell death and MMP synthesis and secretion can be prevented by tetracycline. In a mouse model of systemic loxoscelism, Loxosceles venom-induced kidney failure was observed, which was abrogated by administration of tetracycline. These results indicate that MMPs may play an important role in Loxosceles venom-induced kidney injury and that tetracycline administration may be useful in the treatment of human systemic loxoscelism.

Environmental exposure to cadmium at a level insufficient to induce renal tubular dysfunction does not affect bone density among female Japanese farmers

International Nuclear Information System (INIS)

Horiguchi, Hyogo; Oguma, Etsuko; Sasaki, Satoshi; Miyamoto, Kayoko; Ikeda, Yoko; Machida, Munehito; Kayama, Fujio

2005-01-01

Some recent research suggests that environmental exposure to cadmium, even at low levels, may increase the risk of osteoporosis, and that the bone demineralization is not just a secondary effect of renal dysfunction induced by high doses of cadmium as previously reported. To investigate the effect of exposure to cadmium at a level insufficient to induce kidney damage on bone mineral density (BMD) and bone metabolism, we conducted health examinations on 1380 female farmers from five districts in Japan who consumed rice contaminated by low-to-moderate levels of cadmium. We collected peripheral blood and urine samples and medical and nutritional information, and measured forearm BMD. Analysis of the data for subjects grouped by urinary cadmium level and age-related menstrual status suggested that cadmium accelerates both the increase of urinary calcium excretion around the time of menopause and the subsequent decrease in bone density after menopause. However, multivariate analyses showed no significant contribution of cadmium to bone density or urinary calcium excretion, indicating that the results mentioned above were confounded by other factors. These results indicate that environmental exposure to cadmium at levels insufficient to induce renal dysfunction does not increase the risk of osteoporosis, strongly supporting the established explanation for bone injury induced by cadmium as a secondary effect

Hypoxia-induced dysfunction of rat diaphragm: role of peroxynitrite.

NARCIS (Netherlands)

Zhu, X.; Heunks, L.M.A.; Versteeg, E.M.M.; Heijden, E. van der; Ennen, L.; Kuppevelt, A.H.M.S.M. van; Vina, J.; Dekhuijzen, P.N.R.

2005-01-01

Oxidants may play a role in hypoxia-induced respiratory muscle dysfunction. In the present study we hypothesized that hypoxia-induced impairment in diaphragm contractility is associated with elevated peroxynitrite generation. In addition, we hypothesized that strenuous contractility of the diaphragm

Evaluation of the gender difference in the protective effects of ischemic postconditioning on ischemia-reperfusion-induced acute kidney injury in rats

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Atefeh Mahmoudi

2013-11-01

Full Text Available Background: Several studies indicate that gender differences exist in tolerance of the kidney to ischemia reperfusion (IR injury. Recently, postconditioning (POC, induction of brief repetitive periods of IR, has been introduced to reduce the extent of the damage to the kidney. This method was shown to attenuate renal IR injury by modifying oxidative stress and reducing lipid peroxidation. Considering the gender effect on the results of several treatment methods, in this study, we investigated the impact of gender on the protective effect of POC on the rat kidney.Methods: In this study, after right nephrectomy, 48 male and female rats were randomly divided into 6 groups of 8 rats: In IR group, with the use of bulldog clamp, 45 minutes of left renal artery ischemia was induced followed by 24 hours of reperfusion. In the sham group, all of the above surgical procedures were applied except that IR was not induced. In the POC group, after the induction of 45 minutes ischemia, 4 cycles of 10 seconds of intermittent ischemia and reperfusion were applied before restoring of blood to the kidney. 24 hours later, serum and renal tissue samples were collected for renal functional monitoring and oxidative stress evaluation.Results: Postconditioning attenuated renal dysfunction considering the significant decrease in plasma creatinine and BUN compared with IR group only in male rats (P<0.05. Also, POC attenuated oxidative stress in male rats’ kidney tissues as demonstrated by a significantly reduced malondialdehyde (MDA level and increased superoxide dismutase (SOD activity (P<0.05. In female rats, there were no changes in functional markers and oxidative stress status in POC group compared to IR group. Conclusion: Considering gender difference, POC had protective effect against IR injury by attenuating functional and oxidative stress markers in male rat kidneys. This protective effect was not seen in female rats.

Early Liver and Kidney Dysfunction Associated with Occupational Exposure to Sub-Threshold Limit Value Levels of Benzene, Toluene, and Xylenes in Unleaded Petrol

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Masoud Neghab

2015-12-01

Conclusion: The average exposure of petrol station workers to BTX did not exceed the current threshold limit values (TLVs for these chemicals. However, evidence of subtle, subclinical and prepathologic early liver and kidney dysfunction was evident in exposed individuals.

Overexpression of Hypoxia-Inducible Factor-1α Exacerbates Endothelial Barrier Dysfunction Induced by Hypoxia

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Pei Wang

2013-09-01

Full Text Available Background/Aims: The mechanisms involved in endothelial barrier dysfunction induced by hypoxia are incompletely understood. There is debate about the role of hypoxia-inducible factor-1α (HIF-1α in endothelial barrier disruption. The aim of this study was to investigate the effect of genetic overexpression of HIF-1α on barrier function and the underlying mechanisms in hypoxic endothelial cells. Methods: The plasmid pcDNA3.1/V5-His-HIF-1α was stably transfected into human endothelial cells. The cells were exposed to normoxia or hypoxia. The mRNA and protein expressions of HIF-1α were detected by RT-PCR and Western blot respectively. The barrier function was assessed by measuring the transendothelial electrical resistance (TER. The Western blot analysis was used to determine the protein expression of glucose transporter-1 (GLUT-1, zonular occludens-1 (ZO-1, occludin, and myosin light chain kinase (MLCK in endothelial cells. The mRNA expression of proinflammatory cytokines was detected by qRT-PCR. Results: Genetic overexpression of HIF-1α significantly increased the mRNA and protein expression of HIF-1α in endothelial cells. The overexpression of HIF-1α enhanced the hypoxia-induced increase of HIF-1α and GLUT-1 protein expression. HIF-1α overexpression not only exacerbated hypoxia-induced endothelial barrier dysfunction but also augmented hypoxia-induced up-regulation of MLCK protein expression. HIF-1α overexpression also enhanced IL-1β, IL-6 and TNF-α mRNA expression. Conclusion: We provide evidence that genetic overexpression of HIF-1α aggravates the hypoxia-induced endothelial barrier dysfunction via enhancing the up-regulation of MLCK protein expression caused by hypoxia, suggesting a potential role for HIF-1α in the pathogenesis of endothelial barrier dysfunction in hypoxia.

Arctigenin: A two-edged sword in ischemia/reperfusion induced acute kidney injury.

Science.gov (United States)

Han, Feng; Xia, Xin-Xin; Dou, Meng; Wang, Yu-Xiang; Xue, Wu-Jun; Ding, Xiao-Ming; Zheng, Jin; Ding, Chen-Guang; Tian, Pu-Xun

2018-04-27

Arctigenin (ATG) is one of the main active substances in fruit derived from Arctium lappa L. Previous studies have reported that ATG have antitumor, neuroprotective, antioxidant, antifibrosis and anti-inflammatory functions. However, the actions of ATG in kidney with acute injury following ischemia/ reperfusion (I/R) is still uncertain. In our study, mice were subjected to kidney I/R by having the kidney pedicles clamped and administered with vehicle or ATG (1, 3 or 9 mg/kg/d) via oral gavage for 7 consecutive days prior to I/R. Notably, ATG aggravated kidney I/R injury with the concentration increases. Multiple biochemical assays and histological examination showed ATG significantly alleviated the inflammatory response as reflected by a decreased expression of proinflammatory cytokine, TLR4/MyD88, and NF-κB, along with the infiltration of CD68 + macrophage and CD11b + Gr1 + neutrophil in the kidneys. Meanwhile, ATG alleviated I/R-induced oxidative stress proved by increasing kidney manganese superoxide dismutase and glutathione peroxidase activity but reducing levels of malonaldehyde and inducible nitric oxide synthase. On the contrary, apoptosis was significantly increased in kidneys of ATG-treated mice compared with vehicle-treated controls, especially in tubular cells. There were increased numbers of TUNEL positive cells and increased Bcl-2, Bax, cleaved-caspase-3, and cleaved-caspase-9 expression. The current study demonstrates that pretreatment of ATG aggravates I/R induced acute kidney injury by increasing apoptosis of tubular cells despite reducing infiltrating inflammatory cells and proinflammatory cytokine. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Optimal conditions of LDR to protect the kidney from diabetes

Science.gov (United States)

Cheng, Jie; Li, Fengsheng; Cui, Jiuwei; Guo, Weiying; Li, Cai; Li, Wei; Wang, Guixia; Xing, Xiao; Gao, Ying; Ge, Yuanyuan; Wang, Guanjun; Cai, Lu

2014-01-01

Aims We reported the attenuation of diabetes-induced renal dysfunction by exposure to multiple low-dose radiation (LDR) at 25 mGy every other day via suppressing renal oxidative damage. We here explored the optimal conditions of LDR to protect the kidney from diabetes. Main methods Type 1 diabetic mice were induced with multiple injections of low-dose streptozotocin in male C57BL/6J mice. Diabetic mice received whole body X-irradiation at dose of 12.5, 25 or 50 mGy every other day for either 4 or 8 weeks. Age-matched normal mice were similarly irradiated at the dose of 25 mGy for 4 or 8 weeks. The renal function and histopathological changes were examined at the 4th and 8th week of the study. Key findings Diabetes induced renal dysfunction, shown by the decreased creatinine and increased microalbumin in urinary. Renal oxidative damage, detected by protein nitration and lipid oxidation, and remodeling, reflected by increased expression of connective tissue growth factor, collagen IV and fibronectin, were significantly increased in diabetic mice. All these renal pathological and function changes in diabetic mice were significantly attenuated by exposure to LDR at all regimens, among which, however, exposure to LDR at 12.5 mGy for 8 weeks provided the best preventive effect on the kidney of diabetic mice. Significance Our results suggest that whole-body LDR at 12.5 mGy every other day for 8 weeks is the optimal condition of LDR to protect the kidney from diabetes. PMID:24631139

Protective role of cabbage extract versus cadmium-induced oxidative renal and thyroid hormones dysfunctions in rats

International Nuclear Information System (INIS)

FARAG, M. F. S.; OSMAN, N. N.; DARWISH, M.M.

2011-01-01

Cadmium (Cd) is an environmental and industrial pollutant that affects various organs in human and experimental animals. A body of evidence has accumulated implicating the free radical generation with subsequent oxidative stress in the biochemical and molecular mechanisms of Cd damage. Cabbage is economically an important cole crop grown and consumed worldwide. It belongs the Cruciferous vegetables (Brassica), which have been reported to have a wide range of pharmacological properties. Since kidney is the critical target organ of chronic Cd damage, we carried out this study to investigate the effects of cabbage extract (C.E.) on Cd-induced dysfunction in the kidney of rats. The thyroid hormones values were also determined. Male Wistar rats were provided with cadmium chloride (100 mg/ L water) as the only drinking fluid and/or cabbage extract (C.E.) (5 ml/ kg body weight /day) for 4 weeks. Oral administration of Cd significantly induced the renal damage which was evident from the significantly (p < 0.05) increased levels of serum urea, uric acid and creatinine with a significant (p < 0.05) decrease in creatinine clearance. It also significantly declined the levels of urea, uric acid and creatinine in urine. Intoxication of Cd to rats reduced serum triiodothyronine (T3) and thyroxine (T4) concentrations. Reduced glutathione (GSH), and enzymatic antioxidants (superoxide dismutase (SOD) and catalase (CAT) were also significantly (p < 0.05) depressed with a concomitant marked enhancement in lipid peroxidation marker (thiobarbituric acid reactive substances, TBARS). Co-administration of C.E. along with Cd resulted in a reversal of the Cd-induced biochemical variables in kidney accompanied by a significant reduction in lipid peroxidation and a higher levels of renal antioxidant defense system. However, incorporation of C.E. to rats whether applied alone or in combination with Cd did not reveal any change in the thyroid hormones levels, which reflect significant drop in

Sexual dysfunction after simultaneous pancreas-kidney transplantation

DEFF Research Database (Denmark)

Jürgensen, J S; Ulrich, C; Hörstrup, J H

2008-01-01

such as quality of life (QoL) have recently received increased attention among transplant recipients. However, the impact of erectile dysfunction on patient QoL has not been investigated in this high-risk group with a history of diabetes and uremia. We applied the International Index of Erectile Function (IIEF...... their sexual function to be worse than before, and 51% did not note any change. The QWB index was highest among the group of patients without erectile dysfunction, decreasing gradually but significantly with increasing severity. A direct impact of erectile dysfunction on QoL, as well as a confounding effect...

Acute Superoxide Radical Scavenging Reduces Blood Pressure but Does Not Influence Kidney Function in Hypertensive Rats with Postischemic Kidney Injury

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Zoran Miloradović

2014-01-01

Full Text Available Acute kidney injury (AKI is associated with significant morbidity and mortality in hypertensive surroundings. We investigated superoxide radical molecules influence on systemic haemodynamic and kidney function in spontaneously hypertensive rats (SHR with induced postischemic AKI. Experiment was performed in anesthetized adult male SHR. The right kidney was removed, and left renal artery was subjected to ischemia by clamping for 40 minutes. The treated group received synthetic superoxide dismutase mimetic TEMPOL in the femoral vein 5 minutes before, during, and 175 minutes after the period of reperfusion, while the control AKI group received the vehicle via the same route. All parameters were measured 24 h after renal reperfusion. TEMPOL treatment significantly decreased mean arterial pressure and total peripheral resistance P<0.05 compared to AKI control. It also increased cardiac output and catalase activity P<0.05. Lipid peroxidation and renal vascular resistance were decreased in TEMPOL P<0.05. Plasma creatinine and kidney morphological parameters were unchanged among TEMPOL treated and control groups. Our study shows that superoxide radicals participate in haemodynamic control, but acute superoxide scavenging is ineffective in glomerular and tubular improvement, probably due to hypertension-induced strong endothelial dysfunction which neutralizes beneficial effects of O2− scavenging.

Comparative Study of Experimentally Induced Cancer of the Kidney in Mice and Rats with X-Rays

Energy Technology Data Exchange (ETDEWEB)

Maldague, P. [Cancer Institute, University of Louvain (Belgium)

1969-11-15

Local irradiation of a kidney in rats and mice results in the development of radiation- induced cancers in the irradiated kidney. The production of these cancers is considerably greater in rats than in mice, and their frequency depends on: (1) The X-ray dose absorbed by the kidney; (2) The latency period which is longer for carcinomas than for sarcomas; and (3) The degree and extent of renal radiation- induced lesions. A study of the relationship between dose and carcinogenic effect has enabled us to define three types of X-ray dose: (a) An ineffective dose of 570 rads at which the inducement of cancer is zero; (b) An optimum dose of 1700 rads at which the frequency of renal tumours is maximal (85%); and (c) Excessive doses between 7000 and 14 000 rads after which the frequency of radiation-induced cancers of the kidney approaches zero. Studies of the latent period have shown that radiation-induced cancers of the kidney in mice do not appear until 790 days after irradiation, whereas in rats the first cancers appear after 280 days. As regards the mechanism of the inducement of renal cancer by radiation, we have been able to establish that cancers of the kidney only develop from visible renal lesions. Radiation-induced cancers have not been observed in rats or mice whose kidneys were morphologically and functionally normal. (author)

Bilirubin-Induced Neurological Dysfunction: A Clinico-Radiological-Neurophysiological Correlation in 30 Consecutive Children.

Science.gov (United States)

van Toorn, Ronald; Brink, Philip; Smith, Johan; Ackermann, Christelle; Solomons, Regan

2016-12-01

The clinical expression of bilirubin-induced neurological dysfunction varies according to severity and location of the disease. Definitions have been proposed to describe different bilirubin-induced neurological dysfunction subtypes. Our objective was to describe the severity and clinico-radiological-neurophysiological correlation in 30 consecutive children with bilirubin-induced neurological dysfunction seen over a period of 5 years. Thirty children exposed to acute neonatal bilirubin encephalopathy were included in the study. The mean peak total serum bilirubin level was 625 μmol/L (range 480-900 μmol/L). Acoustic brainstem responses were abnormal in 73% (n = 22). Pallidal hyperintensity was observed on magnetic resonance imaging in 20 children. Peak total serum bilirubin levels correlated with motor severity (P = .03). Children with severe motor impairment were likely to manifest severe auditory neuropathy (P bilirubin-induced neurological dysfunction subtype, and the majority of children had abnormal acoustic brainstem responses and magnetic resonance imaging. © The Author(s) 2016.

Parameters to evaluate the immunostimulant effect of Zymosan A in head kidney leucocytes (HKL of salmonids Parámetros para la evaluación del efecto de Zimosán A como inmunoestimulante sobre leucocitos de rinón cefálico (HKL de salmónidos

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Andrés Abarca

2012-09-01

Full Text Available The interest in characterizing fish immune responses against pathogens or discovering new immunostimulant molecules requires the use of mass screening techniques. The classical model has been the challenge in 1000 L tanks, using a high number of fishes, resulting in high economic cost. In this work, the purpose was to minimize the costs of such tests using in vitro cellular models. In primary cultures of head kidney leucocytes (HKL immune response to Zymosan A, a type of β-glucan, was evaluated. The quantification and detection of pro-inflammatory cytokines was done based on both enzymatic activity and ELISA. The activity of phagocyte oxidase and inducible nitric oxide synthase (iNOS was measured indirectly through NBT reduction by reactive oxygen species and Griess reaction to nitric oxide, respectively. For detecting pro-inflammatory cytokines such as TNF-α, IL-6 and IL-Ιβ, monospecific antibodies generated in our laboratory were used by indirect ELISA. The immune parameters were evaluated at different concentration of Zymosan A and the evolution of the immune response over time was established. The results suggest the better time for evaluating the immunostimulant capacity of glucans and the appropriate dose of it, which is required to demonstrate the activation of macrophages (ROS and iNOS and the production of pro-inflammatory molecules, both as indicators of good immune response. Currently, work is being conducted improving these methods, creating an ELISA sandwich and generating antibodies against total proteins of HKL for pre-absorption of induced samples. In particular, the implementation of ELISA for the characterization of cytokine secretion profiles is a biotechnological contribution in aquaculture, which has not been implemented before this work.El interés en la caracterización de la respuesta inmune de peces contra patógenos o el descubrimiento de nuevas moléculas inmunoestimulantes, requiere el uso de técnicas de uso

Curcumin ameliorates cardiac dysfunction induced by mechanical trauma.

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Li, Xintao; Cao, Tingting; Ma, Shuo; Jing, Zehao; Bi, Yue; Zhou, Jicheng; Chen, Chong; Yu, Deqin; Zhu, Liang; Li, Shuzhuang

2017-11-05

Curcumin, a phytochemical component derived from turmeric (Carcuma longa), has been extensively investigated because of its anti-inflammatory and anti-oxidative properties. Inflammation and oxidative stress play critical roles in posttraumatic cardiomyocyte apoptosis, which contributes to secondary cardiac dysfunction. This research was designed to identify the protective effect of curcumin on posttraumatic cardiac dysfunction and investigate its underlying mechanism. Noble-Collip drum was used to prepare a mechanical trauma (MT) model of rats, and the hemodynamic responses of traumatized rats were observed by ventricular intubation 12h after trauma. Myocardial apoptosis was determined through terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and caspase-3 activity assay. Tumor necrosis factor-α (TNF-α) and reactive oxygen species (ROS) generated by monocytes and myocardial cells were identified through enzyme-linked immunosorbent assay (ELISA), and the intracellular alteration of Ca 2+ in cardiomyocytes was examined through confocal microscopy. In vivo, curcumin effectively ameliorated MT-induced secondary cardiac dysfunction and significantly decreased the apoptotic indices of the traumatized myocardial cells. In vitro, curcumin inhibited TNF-α production by monocytes and reduced the circulating TNF-α levels. With curcumin pretreatment, ROS production and Ca 2+ overload in H9c2 cells were attenuated when these cells were incubated with traumatic plasma. Therefore, curcumin can effectively ameliorate MT-induced cardiac dysfunction mainly by inhibiting systemic inflammatory responses and by weakening oxidative stress reaction and Ca 2+ overload in cardiomyocytes. Copyright © 2017 Elsevier B.V. All rights reserved.

Optimal conditions of LDR to protect the kidney from diabetes: exposure to 12.5 mGy X-rays for 8 weeks efficiently protects the kidney from diabetes.

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Cheng, Jie; Li, Fengsheng; Cui, Jiuwei; Guo, Weiying; Li, Cai; Li, Wei; Wang, Guixia; Xing, Xiao; Gao, Ying; Ge, Yuanyuan; Wang, Guanjun; Cai, Lu

2014-05-08

We reported the attenuation of diabetes-induced renal dysfunction by exposure to multiple low-dose radiation (LDR) at 25 mGy every other day by suppressing renal oxidative damage. We here explored the optimal conditions of LDR to protect the kidney from diabetes. Male C57BL/6J mice with type 1 diabetes were induced with multiple injections of low-dose streptozotocin. Diabetic mice received whole body X-irradiation at a dose of 12.5, 25 or 50 mGy every other day for either 4 or 8 weeks. Age-matched normal mice were similarly irradiated at the dose of 25 mGy for 4 or 8 weeks. The renal function and histopathological changes were examined at the 4th and 8th weeks of the study. Diabetes induced renal dysfunction is shown by the decreased creatinine and increased microalbumin in the urine. Renal oxidative damage, detected by protein nitration and lipid oxidation, and remodeling, reflected by increased expression of connective tissue growth factor, collagen IV and fibronectin, were significantly increased in diabetic mice. All these renal pathological and function changes in diabetic mice were significantly attenuated by exposure to LDR at all regimens, among which, however, exposure to LDR at 12.5 mGy for 8 weeks provided the best protective effect on the kidney of diabetic mice. Our results suggest that whole-body LDR at 12.5 mGy every other day for 8 weeks is the optimal condition of LDR to protect the kidney from diabetes. Copyright © 2014 Elsevier Inc. All rights reserved.

Immunotherapy using dendritic cells and cytokine-induced killer for kidney cancer

International Nuclear Information System (INIS)

Chen Lijun; Xu Yuanbin; Zhao Li; Qu Nan; Sun Zhenpeng; Li Xuechao; Zhao Jiyu; Wang Bin; Wang Huixian

2008-01-01

Objective: To investigate the clinical efficacy of immunotherapy using dendritic cells (DC) and cytokine-induced killer (CIK)in treatment of patients with kidney cancer. Methods: Sixty patients with kidney cancer were divided into 2 groups randomly: the control group and immunotherapy group. Peripheral blood mononuclear cells (PBMC) were seperated from the patients who received immunotherapy first, then DC and CIK were induced and cultured with GM-CSF and IL4 in vitro. The immunotherapy group received DC four times and CIK twice at an interval of 14 days after routine treatment. The control group received only chemotherapy. T lymphocyte subtypes and NK cells in peripheral blood, the white cells and the values of liver and kidney biochemistry of two group of patients were analyzed and clinical efficacy were ob- served, so were side effects. Results: Clinical efficacy showed significant statistical difference between the two groups (P + , CD4 + , CD4 + /CD8 + and NK cell in the immunotherapy group increased after treatment, which showed significant statistical difference compared with those before treatment(P value was 0.010, 0.026, 0.021, 0.016, respectively). Changes in cell immune indexes (CD3 + , CD4 + , CD4 + /CD8 + ) in immunotherapy group and Control group showed significant statistical difference (P value was 0.001,0.023,0.012, respectively). Conclusion: Immunotherapy using dendritic cells and cytokine-induced killer combined with routine treatment can improve T lymphocyte subtypes and NK cell ratio in peripheral blood of the patients with kidney cancer, and may play an important role in the treatment of kidney cancer. It can enhance clinical efficacy in patients with kidney cancer and can improve prognosis. (authors)

Transcription regulator TRIP-Br2 mediates ER stress-induced brown adipocytes dysfunction.

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Qiang, Guifen; Whang Kong, Hyerim; Gil, Victoria; Liew, Chong Wee

2017-01-09

In contrast to white adipose tissue, brown adipose tissue (BAT) is known to play critical roles for both basal and inducible energy expenditure. Obesity is associated with reduction of BAT function; however, it is not well understood how obesity promotes BAT dysfunction, especially at the molecular level. Here we show that the transcription regulator TRIP-Br2 mediates ER stress-induced inhibition of lipolysis and thermogenesis in BAT. Using in vitro, ex vivo, and in vivo approaches, we demonstrate that obesity-induced inflammation upregulates brown adipocytes TRIP-Br2 expression via the ER stress pathway and amelioration of ER stress in mice completely abolishes high fat diet-induced upregulation of TRIP-Br2 in BAT. We find that increased TRIP-Br2 significantly inhibits brown adipocytes thermogenesis. Finally, we show that ablation of TRIP-Br2 ameliorates ER stress-induced inhibition on lipolysis, fatty acid oxidation, oxidative metabolism, and thermogenesis in brown adipocytes. Taken together, our current study demonstrates a role for TRIP-Br2 in ER stress-induced BAT dysfunction, and inhibiting TRIP-Br2 could be a potential approach for counteracting obesity-induced BAT dysfunction.

Treating gout in kidney transplant recipients.

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Baroletti, Steven; Bencivenga, Gina Ann; Gabardi, Steven

2004-06-01

To review the etiology, treatment, and preventive strategies of hyperuricemia and gout in kidney transplant recipients. Primary literature was obtained via Medline (1966-June 2003). Studies evaluating treatment and prevention of hyperuricemia and gout in kidney transplantation were considered for evaluation. English-language studies were selected for inclusion. Approximately 14,000 kidney transplantations were performed in the United States in 2003, and of those transplant recipients, nearly 13% will experience a new onset of gout. The prevalence of hyperuricemia is even greater. There are several mechanisms by which hyperuricemia and gout develop in kidney transplant recipients. Medication-induced hyperuricemia and renal dysfunction are 2 of the more common mechanisms. Prophylactic and treatment options include allopurinol, colchicine, corticosteroids, and, if absolutely necessary, nonsteroidal antiinflammatory drugs. It is generally recommended to decide whether the risks of prophylactic therapy and treatment outweigh the benefits. Often, the risk of adverse events associated with agents to treat these ailments tends to outweigh the benefits; therefore, treatment is usually reserved for symptomatic episodes of acute gout. Practitioners must also decide if changes in immunosuppressive regimens may be of benefit on a patient-by-patient basis.

Diclofenac induces proteasome and mitochondrial dysfunction in murine cardiomyocytes and hearts.

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Ghosh, Rajeshwary; Goswami, Sumanta K; Feitoza, Luis Felipe B B; Hammock, Bruce; Gomes, Aldrin V

2016-11-15

One of the most common nonsteroidal anti-inflammatory drugs (NSAIDs) used worldwide, diclofenac (DIC), has been linked to increased risk of cardiovascular disease (CVD). The molecular mechanism(s) by which DIC causes CVD is unknown. Proteasome activities were studied in hearts, livers, and kidneys from male Swiss Webster mice treated with either 100mg/kg DIC for 18h (acute treatment) or 10mg/kg DIC for 28days (chronic treatment). Cultured H9c2 cells and neonatal cardiomyocytes were also treated with different concentrations of DIC and proteasome function, cell death and ROS generation studied. Isolated mouse heart mitochondria were utilized to determine the effect of DIC on various electron transport chain complex activities. DIC significantly inhibited the chymotrypsin-like proteasome activity in rat cardiac H9c2 cells, murine neonatal cardiomyocytes, and mouse hearts, but did not affect proteasome subunit expression levels. Proteasome activity was also affected in liver and kidney tissues from DIC treated animals. The levels of polyubiquitinated proteins increased in hearts from DIC treated mice. Importantly, the levels of oxidized proteins increased while the β5i immunoproteasome activity decreased in hearts from DIC treated mice. DIC increased ROS production and cell death in H9c2 cells and neonatal cardiomyocytes while the cardioprotective NSAID, aspirin, had no effect on ROS levels or cell viability. DIC inhibited mitochondrial Complex III, a major source of ROS, and impaired mitochondrial membrane potential suggesting that mitochondria are the major sites of ROS generation. These results suggest that DIC induces cardiotoxicity by a ROS dependent mechanism involving mitochondrial and proteasome dysfunction. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Protective Activity of Dendropanax Morbifera Against Cisplatin-Induced Acute Kidney Injury

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Eun-Sun Kim

2015-01-01

Full Text Available Background/Aims: Drug-induced acute kidney injury (AKI has been a severe threat to hospitalized patients, raising the urgent needs to develop strategies to reduce AKI. We investigated the protective activity of Dendropanax morbifera (DP, a medicinal plant which has been widely used to treat infectious and pain diseases, on acute kidney injury (AKI using cisplatin-induced nephropathic models. Methods: Both in vitro renal tubular cells (NRK-52E and in vivo rat models were used to demonstrate the nephroprotective effect of DP. Results: Methanolic extract from DP significantly reduced cisplatin-induced toxicity in renal tubular cells. Through successive liquid extraction, the extract of DP was separated into n-hexane, CHCl3, EtOAc, n-BuOH, and H2O fractions. Among these, the CHCl3 fraction (DPCF was found to be most potent. The protective activity of DPCF was found to be mediated through anti-oxidant, mitochondrial protective, and anti-apoptotic activities. In in vivo rat models of AKI, treatment with DPCF significantly reversed the cisplatin-induced increase in blood urea nitrogen and serum creatinine and histopathologic damage, recovered the level of anti-oxidant enzymes, and inhibited renal apoptosis. Conclusion: We demonstrated that DP extracts decreased cisplatin-induced renal toxicity, indicating its potential to ameliorate drug-associated acute kidney damage.

Renoprotective effect of paricalcitol via a modulation of the TLR4-NF-κB pathway in ischemia/reperfusion-induced acute kidney injury

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Lee, Jae-Won, E-mail: maestro97@hanmail.net; Kim, Sun Chul, E-mail: linefe99@hanmail.net; Ko, Yoon Sook, E-mail: rainboweyes@hanmail.net; Lee, Hee Young, E-mail: cell1023@hanmail.net; Cho, Eunjung, E-mail: icdej@naver.com; Kim, Myung-Gyu, E-mail: gyu219@hanmail.net; Jo, Sang-Kyung, E-mail: sang-kyung@korea.ac.kr; Cho, Won Yong, E-mail: wonyong@korea.ac.kr; Kim, Hyoung Kyu, E-mail: hyoung@korea.ac.kr

2014-02-07

Highlights: • Paricalcitol. • Attenuation of renal inflammation. • Modulation of TLR4-NF-κB signaling. - Abstract: Background: The pathophysiology of ischemic acute kidney injury (AKI) is thought to include a complex interplay between vascular endothelial cell dysfunction, inflammation, and tubular cell damage. Several lines of evidence suggest a potential anti-inflammatory effect of vitamin D in various kidney injury models. In this study, we investigated the effect of paricalcitol, a synthetic vitamin D analog, on renal inflammation in a mouse model of ischemia/reperfusion (I/R) induced acute kidney injury (AKI). Methods: Paricalcitol was administered via intraperitoneal (IP) injection at 24 h before ischemia, and then I/R was performed through bilateral clamping of the renal pedicles. Twenty-four hours after I/R, mice were sacrificed for the evaluation of injury and inflammation. Additionally, an in vitro experiment using HK-2 cells was also performed to examine the direct effect of paricalcitol on tubular cells. Results: Pre-treatment with paricalcitol attenuated functional deterioration and histological damage in I/R induced AKI, and significantly decreased tissue neutrophil and macrophage infiltration and the levels of chemokines, the pro-inflammatory cytokine interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1). It also decreased IR-induced upregulation of Toll-like receptor 4 (TLR4), and nuclear translocation of p65 subunit of NF-κB. Results from the in vitro study showed pre-treatment with paricalcitol suppressed the TNF-α-induced depletion of cytosolic IκB in HK-2 cells. Conclusion: These results demonstrate that pre-treatment with paricalcitol has a renoprotective effect in ischemic AKI, possibly by suppressing TLR4-NF-κB mediated inflammation.

Renal transplantation induces mitochondrial uncoupling, increased kidney oxygen consumption, and decreased kidney oxygen tension

NARCIS (Netherlands)

Papazova, Diana A.; Friederich-Persson, Malou; Joles, Jaap A.; Verhaar, Marianne C.

2015-01-01

Hypoxia is an acknowledged pathway to renal injury and ischemia-reperfusion (I/R) and is known to reduce renal oxygen tension (PO2). We hypothesized that renal I/R increases oxidative damage and induces mitochondrial uncoupling, resulting in increased oxygen consumption and hence kidney

Nuclear medicine in the detection of radiation associated normal tissue damage of kidney, brain and salivary glands

International Nuclear Information System (INIS)

Liu Xiaomei; Li Dongxue; Pan Liping

2005-01-01

The radiation induced damage of kidney, brain and salivary glands is an important complicating disease after limit radiotherapy. The routine technology of nuclear medicine, such as tracing and imaging technique conduce to dose-effect calculations used in the planning of modern radiotherapy to three major organ systems and early detection of irradiation induced organ dysfunctions, as well as increased availability of radiotherapy. (authors)

Reversal of renal dysfunction by targeted administration of VEGF into the stenotic kidney: a novel potential therapeutic approach.

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Chade, Alejandro R; Kelsen, Silvia

2012-05-15

Renal microvascular (MV) damage and loss contribute to the progression of renal injury in renovascular disease (RVD). Whether a targeted intervention in renal microcirculation could reverse renal damage is unknown. We hypothesized that intrarenal vascular endothelial growth factor (VEGF) therapy will reverse renal dysfunction and decrease renal injury in experimental RVD. Unilateral renal artery stenosis (RAS) was induced in 14 pigs, as a surrogate of chronic RVD. Six weeks later, renal blood flow (RBF) and glomerular filtration rate (GFR) were quantified in vivo in the stenotic kidney using multidetector computed tomography (CT). Then, intrarenal rhVEGF-165 or vehicle was randomly administered into the stenotic kidneys (n = 7/group), they were observed for 4 additional wk, in vivo studies were repeated, and then renal MV density was quantified by 3D micro-CT, and expression of angiogenic factors and fibrosis was determined. RBF and GFR, MV density, and renal expression of VEGF and downstream mediators such as p-ERK 1/2, Akt, and eNOS were significantly reduced after 6 and at 10 wk of untreated RAS compared with normal controls. Remarkably, administration of VEGF at 6 wk normalized RBF (from 393.6 ± 50.3 to 607.0 ± 45.33 ml/min, P < 0.05 vs. RAS) and GFR (from 43.4 ± 3.4 to 66.6 ± 10.3 ml/min, P < 0.05 vs. RAS) at 10 wk, accompanied by increased angiogenic signaling, augmented renal MV density, and attenuated renal scarring. This study shows promising therapeutic effects of a targeted renal intervention, using an established clinically relevant large-animal model of chronic RAS. It also implies that disruption of renal MV integrity and function plays a pivotal role in the progression of renal injury in the stenotic kidney. Furthermore, it shows a high level of plasticity of renal microvessels to a single-dose VEGF-targeted intervention after established renal injury, supporting promising renoprotective effects of a novel potential therapeutic intervention to

Effect of AST-120 on Endothelial Dysfunction in Adenine-Induced Uremic Rats

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Yuko Inami

2014-01-01

Full Text Available Aim. Chronic kidney disease (CKD represents endothelial dysfunction. Monocyte adhesion is recognized as the initial step of arteriosclerosis. Indoxyl sulfate (IS is considered to be a risk factor for arteriosclerosis in CKD. Oral adsorbent AST-120 retards deterioration of renal function, reducing accumulation of IS. In the present study, we determined the monocyte adhesion in the adenine-induced uremic rats in vivo and effects of AST-120 on the adhesion molecules. Methods. Twenty-four rats were divided into control, control+AST-120, adenine, and adenine+AST-120 groups. The number of monocytes adherent to the endothelium of thoracic aorta by imaging the entire endothelial surface and the mRNA expressions of adhesion and atherosclerosis-related molecules were examined on day 49. The mRNA expressions of ICAM-1 and VCAM-1 in human umbilical vein endothelial cells were also examined. Results. Adenine increased the number of adherent monocytes, and AST-120 suppressed the increase. The monocyte adhesion was related to serum creatinine and IS in sera. Overexpression of VCAM-1 and TGF-β1 mRNA in the arterial walls was observed in uremic rats. IS induced increase of the ICAM-1 and VCAM-1 mRNA expressions in vitro. Conclusion. It appears that uremic condition introduces the monocyte adhesion to arterial wall and AST-120 might inhibit increasing of the monocyte adherence with CKD progression.

Metabolomics insights into activated redox signaling and lipid metabolism dysfunction in chronic kidney disease progression

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Hua Chen

2016-12-01

Full Text Available Early detection is critical in prevention and treatment of kidney disease. However currently clinical laboratory and histopathological tests do not provide region-specific and accurate biomarkers for early detection of kidney disease. The present study was conducted to identify sensitive biomarkers for early detection and progression of tubulo-interstitial nephropathy in aristolochic acid I-induced rats at weeks 4, 8 and 12. Biomarkers were validated using aristolochic acid nephropathy (AAN rats at week 24, adenine-induced chronic kidney disease (CKD rats and CKD patients. Compared with control rats, AAN rats showed anemia, increased serum urea and creatinine, progressive renal interstitial fibrosis, activation of nuclear factor-kappa B, and up-regulation of pro-inflammatory, pro-oxidant, and pro-fibrotic proteins at weeks 8 and 12. However, no significant difference was found at week 4. Metabolomics identified 12-ketodeoxycholic acid, taurochenodesoxycholic acid, LPC(15:0 and docosahexaenoic acid as biomarkers for early detection of tubulo-interstitial nephropathy. With prolonging aristolochic acid I exposure, LPE(20:2, cholic acid, chenodeoxycholic acid and LPC(17:0 were identified as biomarkers for progression from early to advanced AAN and lysoPE(22:5, indoxyl sulfate, uric acid and creatinine as biomarkers of advanced AAN. These biomarkers were reversed by treatment of irbesartan and ergone in AAN rats at week 24 and adenine-induced CKD rats. In addition, these biomarkers were also reversed by irbesartan treatment in CKD patients.

The effect of antiepileptic drugs on the kidney function and structure.

Science.gov (United States)

Hamed, Sherifa Ahmed

2017-09-01

Long-term use of antiepileptic drugs (AEDs) is associated with number of somatic conditions. Data from experimental, cross-sectional and prospective studies have evidence for the deleterious effect of some AEDs on the kidney. Areas covered: This review summarized the current knowledge of the effect of AEDs on the kidney including evidence and mechanisms. Fanconi syndrome was reported with valproate (VPA) therapy in severely disabled children with epilepsy. Renal tubular acidosis and urolithiasis were reported with acetazolamide, topirmate and zonisamide, drugs with carbonic anhydrase inhibition properties. Increased levels of urinary N-acetyl-beta-D-glucosaminidase (NAG) to urinary creatinine (U-NAG/UCr), urinary excretion of α1-micrglobulin, β-galactosidase activity; and urinary malondialdehyde to creatinine (MDA/Cr), markers of renal glomerular and tubular injury, were reported with chronic use of some AEDs (VPA, carbamazepine and phenytoin). The mechanism(s) of kidney dysfunction/injury induced by AEDs is unknown. Experimental and clinical studies have shown that VPA induces oxidative stress, mitochondrial deficits, carnitine deficiency and inflammation and fibrosis in renal tissue in mice and in vitro studies. Expert commentary: It seems reasonable to monitor kidney function during treating patients with epilepsy at high risk of kidney injury (e.g. on combined therapy with more than one AED, severely disabled children, etc).

Inhibition of miR-155 Protects Against LPS-induced Cardiac Dysfunction and Apoptosis in Mice

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Hui Wang

2016-01-01

Full Text Available Sepsis-induced myocardial dysfunction represents a major cause of death in intensive care units. Dysregulated microRNAs (miR-155 has been implicated in multiple cardiovascular diseases and miR-155 can be induced by lipopolysaccharide (LPS. However, the role of miR-155 in LPS-induced cardiac dysfunction is unclear. Septic cardiac dysfunction in mice was induced by intraperitoneal injection of LPS (5 mg/kg and miR-155 was found to be significantly increased in heart challenged with LPS. Pharmacological inhibition of miR-155 using antagomiR improved cardiac function and suppressed cardiac apoptosis induced by LPS in mice as determined by echocardiography, terminal deoxynucleotidyl transferase nick-end labeling (TUNEL assay, and Western blot for Bax and Bcl-2, while overexpression of miR-155 using agomiR had inverse effects. Pea15a was identified as a target gene of miR-155, mediating its effects in controlling apoptosis of cardiomyocytes as evidenced by luciferase reporter assays, quantitative real time-polymerase chain reaction, Western blot, and TUNEL staining. Noteworthy, miR-155 was also found to be upregulated in the plasma of patients with septic cardiac dysfunction compared to sepsis patients without cardiac dysfunction, indicating a potential clinical relevance of miR-155. The receiver-operator characteristic curve indicated that plasma miR-155 might be a biomarker for sepsis patients developing cardiac dysfunction. Therefore, inhibition of miR-155 represents a novel therapy for septic myocardial dysfunction.

The protective role of bee honey against the toxic effect of melamine in the male rat kidney.

Science.gov (United States)

Al-Seeni, Madeha N; El Rabey, Haddad A; Al-Solamy, Suad M

2015-06-01

This study aimed to test the protective role of natural bee honey against melamine toxicity in the kidney of male albino rats. The dietary supplementation of melamine at a dose of 20,000 ppm for 28 days induced renal dysfunction, as reflected by a significant increase in kidney function parameters (urea, creatinine, and uric acid) and an increase in potassium levels. In addition, a decrease in catalase and glutathione-S-transferase and an increase in lipid peroxide in the kidney tissue homogenate were also observed. Histological changes in the melamine-treated group revealed hyperplasia and damage in kidney cells and the accumulation of melamine crystals in kidney tissues. Honey treatment for 28 days in rats concurrently administered melamine at a dose of 2.5 g/kg body weight for 28 days improved the kidney function, increased antioxidant enzymes, and decreased lipid peroxide levels. The morphology of the kidney cells of the melamine-fed rats was also improved as a result of honey treatment. In conclusion, this study revealed that natural bee honey protects the kidney against the adverse effects induced by melamine toxicity in male albino rats. © The Author(s) 2014.

Blockade of Drp1 rescues oxidative stress-induced osteoblast dysfunction

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Gan, Xueqi; Huang, Shengbin; Yu, Qing [Department of Pharmacology and Toxicology and Higuchi Bioscience Center, University of Kansas, Lawrence, KS, 66047 (United States); State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041 (China); Yu, Haiyang [State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041 (China); Yan, Shirley ShiDu, E-mail: shidu@ku.edu [Department of Pharmacology and Toxicology and Higuchi Bioscience Center, University of Kansas, Lawrence, KS, 66047 (United States)

2015-12-25

Osteoblast dysfunction, induced by oxidative stress, plays a critical role in the pathophysiology of osteoporosis. However, the underlying mechanisms remain unclarified. Imbalance of mitochondrial dynamics has been closely linked to oxidative stress. Here, we reveal an unexplored role of dynamic related protein 1(Drp1), the major regulator in mitochondrial fission, in the oxidative stress-induced osteoblast injury model. We demonstrate that levels of phosphorylation and expression of Drp1 significantly increased under oxidative stress. Blockade of Drp1, through pharmaceutical inhibitor or gene knockdown, significantly protected against H{sub 2}O{sub 2}-induced osteoblast dysfunction, as shown by increased cell viability, improved cellular alkaline phosphatase (ALP) activity and mineralization and restored mitochondrial function. The protective effects of blocking Drp1 in H{sub 2}O{sub 2}-induced osteoblast dysfunction were evidenced by increased mitochondrial function and suppressed production of reactive oxygen species (ROS). These findings provide new insights into the role of the Drp1-dependent mitochondrial pathway in the pathology of osteoporosis, indicating that the Drp1 pathway may be targetable for the development of new therapeutic approaches in the prevention and the treatment of osteoporosis. - Highlights: • Oxidative stress is an early pathological event in osteoporosis. • Imbalance of mitochondrial dynamics are linked to oxidative stress in osteoporosis. • The role of the Drp1-dependent mitochondrial pathway in osteoporosis.

Endothelial mineralocorticoid receptor activation mediates endothelial dysfunction in diet-induced obesity.

Science.gov (United States)

Schäfer, Nicola; Lohmann, Christine; Winnik, Stephan; van Tits, Lambertus J; Miranda, Melroy X; Vergopoulos, Athanasios; Ruschitzka, Frank; Nussberger, Jürg; Berger, Stefan; Lüscher, Thomas F; Verrey, François; Matter, Christian M

2013-12-01

Aldosterone plays a crucial role in cardiovascular disease. 'Systemic' inhibition of its mineralocorticoid receptor (MR) decreases atherosclerosis by reducing inflammation and oxidative stress. Obesity, an important cardiovascular risk factor, is an inflammatory disease associated with increased plasma aldosterone levels. We have investigated the role of the 'endothelial' MR in obesity-induced endothelial dysfunction, the earliest stage in atherogenesis. C57BL/6 mice were exposed to a normal chow diet (ND) or a high-fat diet (HFD) alone or in combination with the MR antagonist eplerenone (200 mg/kg/day) for 14 weeks. Diet-induced obesity impaired endothelium-dependent relaxation in response to acetylcholine, whereas eplerenone treatment of obese mice prevented this. Expression analyses in aortic endothelial cells isolated from these mice revealed that eplerenone attenuated expression of pro-oxidative NADPH oxidase (subunits p22phox, p40phox) and increased expression of antioxidative genes (glutathione peroxidase-1, superoxide dismutase-1 and -3) in obesity. Eplerenone did not affect obesity-induced upregulation of cyclooxygenase (COX)-1 or prostacyclin synthase. Endothelial-specific MR deletion prevented endothelial dysfunction in obese (exhibiting high 'endogenous' aldosterone) and in 'exogenous' aldosterone-infused lean mice. Pre-incubation of aortic rings from aldosterone-treated animals with the COX-inhibitor indomethacin restored endothelial function. Exogenous aldosterone administration induced endothelial expression of p22phox in the presence, but not in the absence of the endothelial MR. Obesity-induced endothelial dysfunction depends on the 'endothelial' MR and is mediated by an imbalance of oxidative stress-modulating mechanisms. Therefore, MR antagonists may represent an attractive therapeutic strategy in the increasing population of obese patients to decrease vascular dysfunction and subsequent atherosclerotic complications.

Aspirin-triggered resolvin D1 down-regulates inflammatory responses and protects against endotoxin-induced acute kidney injury

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Chen, Jiao [Center for Research on Environmental Disease, University of Kentucky, Lexington, KY 40536 (United States); Shetty, Sreerama [Center for Biomedical Research, University of Texas Health Science Center at Tyler, Tyler, TX 75708 (United States); Zhang, Ping [State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041 (China); Gao, Rong; Hu, Yuxin [Center for Research on Environmental Disease, University of Kentucky, Lexington, KY 40536 (United States); Wang, Shuxia [Graduate Center for Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536 (United States); Li, Zhenyu [Division of Cardiovascular Medicine, University of Kentucky, Lexington, KY 40536 (United States); Fu, Jian, E-mail: jian.fu@uky.edu [Center for Research on Environmental Disease, University of Kentucky, Lexington, KY 40536 (United States); Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40536 (United States)

2014-06-01

The presence of endotoxin in blood can lead to acute kidney injury (AKI) and septic shock. Resolvins, the endogenous lipid mediators derived from docosahexaenoic acid, have been reported to exhibit potent anti-inflammatory action. Using a mouse model of lipopolysaccharide (LPS)-induced AKI, we investigated the effects of aspirin-triggered resolvin D1 (AT-RvD1) on inflammatory kidney injury. Administration of AT-RvD1 1 h after LPS challenge protected the mice from kidney injury as indicated by the measurements of blood urea nitrogen, serum creatinine, and morphological alterations associated with tubular damage. The protective effects were evidenced by decreased neutrophil infiltration in the kidney indicating reduction in inflammation. AT-RvD1 treatment restored kidney cell junction protein claudin-4 expression, which was otherwise reduced after LPS challenge. AT-RvD1 treatment inhibited endotoxin-induced NF-κB activation and suppressed LPS-induced ICAM-1 and VCAM-1 expression in the kidney. Moreover, AT-RvD1 treatment markedly decreased LPS-induced IL-6 level in the kidney and blocked IL-6-mediated signaling including STAT3 and ERK phosphorylation. Our findings demonstrate that AT-RvD1 is a potent anti-inflammatory mediator in LPS-induced kidney injury, and AT-RvD1 has therapeutic potential against AKI during endotoxemia.

Aspirin-triggered resolvin D1 down-regulates inflammatory responses and protects against endotoxin-induced acute kidney injury

International Nuclear Information System (INIS)

Chen, Jiao; Shetty, Sreerama; Zhang, Ping; Gao, Rong; Hu, Yuxin; Wang, Shuxia; Li, Zhenyu; Fu, Jian

2014-01-01

The presence of endotoxin in blood can lead to acute kidney injury (AKI) and septic shock. Resolvins, the endogenous lipid mediators derived from docosahexaenoic acid, have been reported to exhibit potent anti-inflammatory action. Using a mouse model of lipopolysaccharide (LPS)-induced AKI, we investigated the effects of aspirin-triggered resolvin D1 (AT-RvD1) on inflammatory kidney injury. Administration of AT-RvD1 1 h after LPS challenge protected the mice from kidney injury as indicated by the measurements of blood urea nitrogen, serum creatinine, and morphological alterations associated with tubular damage. The protective effects were evidenced by decreased neutrophil infiltration in the kidney indicating reduction in inflammation. AT-RvD1 treatment restored kidney cell junction protein claudin-4 expression, which was otherwise reduced after LPS challenge. AT-RvD1 treatment inhibited endotoxin-induced NF-κB activation and suppressed LPS-induced ICAM-1 and VCAM-1 expression in the kidney. Moreover, AT-RvD1 treatment markedly decreased LPS-induced IL-6 level in the kidney and blocked IL-6-mediated signaling including STAT3 and ERK phosphorylation. Our findings demonstrate that AT-RvD1 is a potent anti-inflammatory mediator in LPS-induced kidney injury, and AT-RvD1 has therapeutic potential against AKI during endotoxemia

Mitochondrial mislocalization underlies Abeta42-induced neuronal dysfunction in a Drosophila model of Alzheimer's disease.

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Kanae Iijima-Ando

2009-12-01

Full Text Available The amyloid-beta 42 (Abeta42 is thought to play a central role in the pathogenesis of Alzheimer's disease (AD. However, the molecular mechanisms by which Abeta42 induces neuronal dysfunction and degeneration remain elusive. Mitochondrial dysfunctions are implicated in AD brains. Whether mitochondrial dysfunctions are merely a consequence of AD pathology, or are early seminal events in AD pathogenesis remains to be determined. Here, we show that Abeta42 induces mitochondrial mislocalization, which contributes to Abeta42-induced neuronal dysfunction in a transgenic Drosophila model. In the Abeta42 fly brain, mitochondria were reduced in axons and dendrites, and accumulated in the somata without severe mitochondrial damage or neurodegeneration. In contrast, organization of microtubule or global axonal transport was not significantly altered at this stage. Abeta42-induced behavioral defects were exacerbated by genetic reductions in mitochondrial transport, and were modulated by cAMP levels and PKA activity. Levels of putative PKA substrate phosphoproteins were reduced in the Abeta42 fly brains. Importantly, perturbations in mitochondrial transport in neurons were sufficient to disrupt PKA signaling and induce late-onset behavioral deficits, suggesting a mechanism whereby mitochondrial mislocalization contributes to Abeta42-induced neuronal dysfunction. These results demonstrate that mislocalization of mitochondria underlies the pathogenic effects of Abeta42 in vivo.

Perinatal programming of metabolic dysfunction and obesity-induced inflammation

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Ingvorsen, Camilla; Hellgren, Lars; Pedersen, Susanne Brix

The number of obese women in the childbearing age is drastically increasing globally. As a consequence, more children are born by obese mothers. Unfortunately, maternal obesity and/ or high fat intake during pregnancy increase the risk of developing obesity, type-2 diabetes, cardiovascular disease...... and non-alcoholic fatty liver disease in the children, which passes obesity and metabolic dysfunction on from generation to generation. Several studies try to elucidate causative effects of maternal metabolic markers on the metabolic imprinting in the children; however diet induced obesity is also...... associated with chronic low grade inflammation. Nobody have yet investigated the role of this inflammatory phenotype, but here we demonst rate that obesity induced inflammation is reversed during pregnancy in mice, and is therefore less likely to affect the fetal programming of metabolic dysfunction. Instead...

Immobilisation-induced hypercalcemia following spinal cord injury affecting the kidney function in two young native Greenlanders

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Linstow, Michael V; Biering-Sørensen, Fin

2017-01-01

INTRODUCTION: Immobilisation-induced hypercalcemia following SCI affecting the kidney function, is a rare but potentially serious condition. We report immobilisation-induced hypercalcemia affecting the kidney function in two young native Greenlanders with spinal cord injury (SCI). CASE...... PRESENTATIONS: Two 15- and 24-year-old male native Greenlanders, both with traumatic C5 SCI were admitted to our spinal cord unit. They were non-smokers without history of daily alcohol intake pre- or immediately post-injury. No physical demanding activities pre-injury. Due to complaints of nausea/vomiting 10...... the last 20 years our spinal cord unit has only experienced immobilisation-induced hypercalcemia following SCI affecting the kidney function in two young male native Greenlanders. This finding of immobilisation-induced hypercalcemia following SCI affecting the kidney function in two young native...

Lycopene Protects the Diabetic Rat Kidney Against Oxidative Stress-mediated Oxidative Damage Induced by Furan

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Dilek Pandir

2016-01-01

Full Text Available Furan is a food and environmental contaminant and a potent carcinogen in animals. Lycopene is one dietary carotenoid found in fruits such as tomato, watermelon and grapefruit. The present study was designed to explore the protective effect of lycopene against furan-induced oxidative damage in streptozotocin (STZ-induced diabetic rat kidney. At the end of the experimental period (28 days, we found that lycopene markedly decreased the malondialdehide (MDA levels in the kidney, urea, uric acid and creatinine levels in the serum of furan-treated rats. The increase of histopathology in the kidney of furan-treated rats were effectively suppressed by lycopene. Furthermore, lycopene markedly restored superoxide dismutase (SOD, catalase (CAT, glutathione peroxidase (GPx and glutathione-S-transferase (GST activities in the kidney of furan-treated rats. In conclusion, these results suggested that lycopene could protect the rat kidney against furan-induced injury by improving renal function, attenuating histopathologic changes, reducing MDA production and renewing the activities of antioxidant enzymes.

Subunits Rip1 and Cox9p of the respiratory chain contribute to diclofenac-induced mitochondrial dysfunction

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van Leeuwen, J.S.; Orij, R.; Luttik, M.A.; Smits, G.J.; Vermeulen, N.P.E.; Vos, J.C.

2010-01-01

The widely used drug diclofenac can cause serious heart, liver and kidney injury, which may be related to its ability to cause mitochondrial dysfunction. Using Saccharomyces cerevisiae as a model system, we studied the mechanisms of diclofenac toxicity and the role of mitochondria therein. We found

Role of TRPV1 channels in ischemia/reperfusion-induced acute kidney injury.

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Lan Chen

Full Text Available OBJECTIVES: Transient receptor potential vanilloid 1 (TRPV1 -positive sensory nerves are widely distributed in the kidney, suggesting that TRPV1-mediated action may participate in the regulation of renal function under pathophysiological conditions. Stimulation of TRPV1 channels protects against ischemia/reperfusion (I/R-induced acute kidney injury (AKI. However, it is unknown whether inhibition of these channels is detrimental in AKI or not. We tested the role of TRPV1 channels in I/R-induced AKI by modulating these channels with capsaicin (TRPV1 agonist, capsazepine (TRPV1 antagonist and using Trpv1-/- mice. METHODS AND RESULTS: Anesthetized C57BL/6 mice were subjected to 25 min of renal ischemia and 24 hrs of reperfusion. Mice were pretreated with capsaicin (0.3 mg/kg body weight or capsazepine (50 mg/kg body weight. Capsaicin ameliorated the outcome of AKI, as measured by serum creatinine levels, tubular damage,neutrophil gelatinase-associated lipocalin (NGAL abundance and Ly-6B.2 positive polymorphonuclear inflammatory cells in injured kidneys. Neither capsazepine nor deficiency of TRPV1 did deteriorate renal function or histology after AKI. Measurements of endovanilloids in kidney tissue indicate that 20-hydroxyeicosatetraeonic acid (20-HETE or epoxyeicosatrienoic acids (EETs are unlikely involved in the beneficial effects of capsaicin on I/R-induced AKI. CONCLUSIONS: Activation of TRPV1 channels ameliorates I/R-induced AKI, but inhibition of these channels does not affect the outcome of AKI. Our results may have clinical implications for long-term safety of renal denervation to treat resistant hypertension in man, with respect to the function of primary sensory nerves in the response of the kidney to ischemic stimuli.

Methimazole-induced hypothyroidism causes cellular damage in the spleen, heart, liver, lung and kidney.

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Cano-Europa, Edgar; Blas-Valdivia, Vanessa; Franco-Colin, Margarita; Gallardo-Casas, Carlos Angel; Ortiz-Butrón, Rocio

2011-01-01

It is known that a hypothyroidism-induced hypometabolic state protects against oxidative damage caused by toxins. However, some workers demonstrated that antithyroid drug-induced hypothyroidism can cause cellular damage. Our objective was to determine if methimazole (an antithyroid drug) or hypothyroidism causes cellular damage in the liver, kidney, lung, spleen and heart. Twenty-five male Wistar rats were divided into 5 groups: euthyroid, false thyroidectomy, thyroidectomy-induced hypothyroidism, methimazole-induced hypothyroidism (60 mg/kg), and treatment with methimazole (60 mg/kg) and a T₄ injection (20 μg/kg/d sc). At the end of the treatments (4 weeks for the pharmacological groups and 8 weeks for the surgical groups), the animals were anesthetized with sodium pentobarbital and they were transcardially perfused with 10% formaldehyde. The spleen, heart, liver, lung and kidney were removed and were processed for embedding in paraffin wax. Coronal sections were stained with hematoxylin-eosin. At the end of treatment, animals with both the methimazole- and thyroidectomy-induced hypothyroidism had a significant reduction of serum concentration of thyroid hormones. Only methimazole-induced hypothyroidism causes cellular damage in the kidney, lung, liver, heart, kidney and spleen. In addition, animals treated with methimazole and T₄ showed cellular damage in the lung, spleen and renal medulla with lesser damage in the liver, renal cortex and heart. The thyroidectomy only altered the lung structure. The alterations were prevented by T₄ completely in the heart and partially in the kidney cortex. These results indicate that tissue damage found in hypothyroidism is caused by methimazole. Copyright © 2009 Elsevier GmbH. All rights reserved.

Specific macrophage subtypes influence the progression of rhabdomyolysis-induced kidney injury.

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Belliere, Julie; Casemayou, Audrey; Ducasse, Laure; Zakaroff-Girard, Alexia; Martins, Frédéric; Iacovoni, Jason S; Guilbeau-Frugier, Céline; Buffin-Meyer, Bénédicte; Pipy, Bernard; Chauveau, Dominique; Schanstra, Joost P; Bascands, Jean-Loup

2015-06-01

Rhabdomyolysis can be life threatening if complicated by AKI. Macrophage infiltration has been observed in rat kidneys after glycerol-induced rhabdomyolysis, but the role of macrophages in rhabdomyolysis-induced AKI remains unknown. Here, in a patient diagnosed with rhabdomyolysis, we detected substantial macrophage infiltration in the kidney. In a mouse model of rhabdomyolysis-induced AKI, diverse renal macrophage phenotypes were observed depending on the stage of the disease. Two days after rhabdomyolysis, F4/80(low)CD11b(high)Ly6b(high)CD206(low) kidney macrophages were dominant, whereas by day 8, F4/80(high)CD11b(+)Ly6b(low)CD206(high) cells became the most abundant. Single-cell gene expression analyses of FACS-sorted macrophages revealed that these subpopulations were heterogeneous and that individual cells simultaneously expressed both M1 and M2 markers. Liposomal clodronate-mediated macrophage depletion significantly reduced the early infiltration of F4/80(low)CD11b(high)Ly6b(high)CD206(low) macrophages. Furthermore, transcriptionally regulated targets potentially involved in disease progression, including fibronectin, collagen III, and chemoattractants that were identified via single-cell analysis, were verified as macrophage-dependent in situ. In vitro, myoglobin treatment induced proximal tubular cells to secrete chemoattractants and macrophages to express proinflammatory markers. At day 30, liposomal clodronate-mediated macrophage depletion reduced fibrosis and improved both kidney repair and mouse survival. Seven months after rhabdomyolysis, histologic lesions were still present but were substantially reduced with prior depletion of macrophages. These results suggest an important role for macrophages in rhabdomyolysis-induced AKI progression and advocate the utility of long-term follow-up for patients with this disease. Copyright © 2015 by the American Society of Nephrology.

Vitamin D attenuates pressure overload-induced cardiac remodeling and dysfunction in mice.

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Zhang, Liang; Yan, Xiao; Zhang, Yun-Long; Bai, Jie; Hidru, Tesfaldet Habtemariam; Wang, Qing-Shan; Li, Hui-Hua

2018-04-01

Vitamin D (VD) and its analogues play critical roles in metabolic and cardiovascular diseases. Recent studies have demonstrated that VD exerts a protective role in cardiovascular diseases. However, the beneficial effect of VD on pressure overload-induced cardiac remodeling and dysfunction and its underlying mechanisms are not fully elucidated. In this study, cardiac dysfunction and hypertrophic remodeling in mice were induced by pressure overload. Cardiac function was evaluated by echocardiography, and myocardial histology was detected by H&E and Masson's trichrome staining. Cardiomyocyte size was detected by wheat germ agglutinin staining. The protein levels of signaling mediators were examined by western blotting while mRNA expression of hypertrophic and fibrotic markers was examined by qPCR analysis. Oxidative stress was detected by dihydroethidine staining. Our results showed that administration of VD3 significantly ameliorates pressure overload-induced contractile dysfunction, cardiac hypertrophy, fibrosis and inflammation in mice. In addition, VD3 treatment also markedly inhibited cardiac oxidative stress and apoptosis. Moreover, protein levels of calcineurin A, ERK1/2, AKT, TGF-β, GRP78, cATF6, and CHOP were significantly reduced whereas SERCA2 level was upregulated in the VD3-treated hearts compared with control. These results suggest that VD3 attenuates cardiac remodeling and dysfunction induced by pressure overload, and this protective effect is associated with inhibition of multiple signaling pathways. Copyright © 2018 Elsevier Ltd. All rights reserved.

Ameliorative effects of pine bark extract on cisplatin-induced acute kidney injury in rats.

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Lee, In-Chul; Ko, Je-Won; Park, Sung-Hyeuk; Shin, Na-Rae; Shin, In-Sik; Kim, Yun-Bae; Kim, Jong-Choon

2017-11-01

This study investigated the dose-response effects of pine bark extract (PBE, pycnogenol ® ) on oxidative stress-mediated apoptotic changes induced by cisplatin (Csp) in rats. The ameliorating potential of PBE was evaluated after orally administering PBE at doses of 10 or 20 mg/kg for 10 days. Acute kidney injury was induced by a single intraperitoneal injection of Csp at 7 mg/kg on test day 5. Csp treatment caused acute kidney injury manifested by elevated levels of serum blood urea nitrogen (BUN) and creatinine (CRE) with corresponding histopathological changes, including degeneration of tubular epithelial cells, hyaline casts in the tubular lumen, and inflammatory cell infiltration (interstitial nephritis). Csp also induced significant apoptotic changes in renal tubular cells. In addition, Csp treatment induced high levels of oxidative stress, as evidenced by an increased level of malondialdehyde, depletion of the reduced glutathione (GSH) content, and decreased activities of glutathione S-transferase, superoxide dismutase, and catalase in kidney tissues. On the contrary, PBE treatment lowered BUN and CRE levels and effectively attenuated histopathological alterations and apoptotic changes induced by Csp. Additionally, treatment with PBE suppressed lipid peroxidation, prevented depletion of GSH, and enhanced activities of the antioxidant enzymes in kidney tissue. These results indicate that PBE has a cytoprotective effect against oxidative stress-mediated apoptotic changes caused by Csp in the rat kidney, which may be attributed to both increase of antioxidant enzyme activities and inhibition of lipid peroxidation.

Evolving paradigms in the treatment of opioid-induced bowel dysfunction.

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Poulsen, Jakob Lykke; Brock, Christina; Olesen, Anne Estrup; Nilsson, Matias; Drewes, Asbjørn Mohr

2015-11-01

In recent years prescription of opioids has increased significantly. Although effective in pain management, bothersome gastrointestinal adverse effects are experienced by a substantial proportion of opioid-treated patients. This can lead to difficulties with therapy and subsequently inadequate pain relief. Collectively referred to as opioid-induced bowel dysfunction, these adverse effects are the result of binding of exogenous opioids to opioid receptors in the gastrointestinal tract. This leads to disturbance of three important gastrointestinal functions: motility, coordination of sphincter function and secretion. In the clinic this manifests in a wide range of symptoms such as reflux, bloating, abdominal cramping, hard, dry stools, and incomplete evacuation, although the most known adverse effect is opioid-induced constipation. Traditional treatment with laxatives is often insufficient, but in recent years a number of novel pharmacological approaches have been introduced. In this review the pathophysiology, symptomatology and prevalence of opioid-induced bowel dysfunction is presented along with the benefits and caveats of a suggested consensus definition for opioid-induced constipation. Finally, traditional treatment is appraised and compared with the latest pharmacological developments. In conclusion, opioid antagonists restricted to the periphery show promising results, but use of different definitions and outcome measures complicate comparison. However, an international working group has recently suggested a consensus definition for opioid-induced constipation and relevant outcome measures have also been proposed. If investigators within this field adapt the suggested consensus and include symptoms related to dysfunction of the upper gut, it will ease comparison and be a step forward in future research.

Arsenic toxicity induced endothelial dysfunction and dementia: Pharmacological interdiction by histone deacetylase and inducible nitric oxide synthase inhibitors

Energy Technology Data Exchange (ETDEWEB)

Sharma, Bhupesh, E-mail: drbhupeshresearch@gmail.com; Sharma, P.M.

2013-11-15

Arsenic toxicity has been reported to damage all the major organs including the brain and vasculature. Dementia including Alzheimer's disease (AD) and vascular dementia (VaD) are posing greater risk to the world population as it is now increasing at a faster rate. We have investigated the role of sodium butyrate, a selective histone deacetylase (HDAC) inhibitor and aminoguanidine, a selective inducible nitric oxide synthase (iNOS) inhibitor in pharmacological interdiction of arsenic toxicity induced vascular endothelial dysfunction and dementia in rats. Arsenic toxicity was done by administering arsenic drinking water to rats. Morris water-maze (MWM) test was used for assessment of learning and memory. Endothelial function was assessed using student physiograph. Oxidative stress (aortic superoxide anion, serum and brain thiobarbituric acid reactive species, brain glutathione) and nitric oxide levels (serum nitrite/nitrate) were also measured. Arsenic treated rats have shown impairment of endothelial function, learning and memory, reduction in serum nitrite/nitrate and brain GSH levels along with increase in serum and brain TBARS. Sodium butyrate as well as aminoguanidine significantly convalesce arsenic induced impairment of learning, memory, endothelial function, and alterations in various biochemical parameters. It may be concluded that arsenic induces endothelial dysfunction and dementia, whereas, sodium butyrate, a HDAC inhibitor as well as aminoguanidine, a selective iNOS inhibitor may be considered as potential agents for the management of arsenic induced endothelial dysfunction and dementia. - Highlights: • As has induced endothelial dysfunction (Edf) and vascular dementia (VaD). • As has increased oxidative stress, AChE activity and decreased serum NO. • Inhibitors of HDAC and iNOS have attenuated As induced Edf and VaD. • Both the inhibitors have attenuated As induced biochemical changes. • Inhibitor of HDAC and iNOS has shown good potential

Arsenic toxicity induced endothelial dysfunction and dementia: Pharmacological interdiction by histone deacetylase and inducible nitric oxide synthase inhibitors

International Nuclear Information System (INIS)

Sharma, Bhupesh; Sharma, P.M.

2013-01-01

Arsenic toxicity has been reported to damage all the major organs including the brain and vasculature. Dementia including Alzheimer's disease (AD) and vascular dementia (VaD) are posing greater risk to the world population as it is now increasing at a faster rate. We have investigated the role of sodium butyrate, a selective histone deacetylase (HDAC) inhibitor and aminoguanidine, a selective inducible nitric oxide synthase (iNOS) inhibitor in pharmacological interdiction of arsenic toxicity induced vascular endothelial dysfunction and dementia in rats. Arsenic toxicity was done by administering arsenic drinking water to rats. Morris water-maze (MWM) test was used for assessment of learning and memory. Endothelial function was assessed using student physiograph. Oxidative stress (aortic superoxide anion, serum and brain thiobarbituric acid reactive species, brain glutathione) and nitric oxide levels (serum nitrite/nitrate) were also measured. Arsenic treated rats have shown impairment of endothelial function, learning and memory, reduction in serum nitrite/nitrate and brain GSH levels along with increase in serum and brain TBARS. Sodium butyrate as well as aminoguanidine significantly convalesce arsenic induced impairment of learning, memory, endothelial function, and alterations in various biochemical parameters. It may be concluded that arsenic induces endothelial dysfunction and dementia, whereas, sodium butyrate, a HDAC inhibitor as well as aminoguanidine, a selective iNOS inhibitor may be considered as potential agents for the management of arsenic induced endothelial dysfunction and dementia. - Highlights: • As has induced endothelial dysfunction (Edf) and vascular dementia (VaD). • As has increased oxidative stress, AChE activity and decreased serum NO. • Inhibitors of HDAC and iNOS have attenuated As induced Edf and VaD. • Both the inhibitors have attenuated As induced biochemical changes. • Inhibitor of HDAC and iNOS has shown good potential in

Salidroside Improves Homocysteine-Induced Endothelial Dysfunction by Reducing Oxidative Stress

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Sin Bond Leung

2013-01-01

Full Text Available Hyperhomocysteinemia is associated with an increased risk for cardiovascular diseases through increased oxidative stress. Salidroside is an active ingredient of the root of Rhodiola rosea with documented antioxidative, antihypoxia and neuroprotective properties. However, the vascular benefits of salidroside against endothelial dysfunction have yet to be explored. The present study, therefore, aimed to investigate the protective effect of salidroside on homocysteine-induced endothelial dysfunction. Functional studies on the rat aortas were performed to delineate the vascular effect of salidroside. DHE imaging was used to evaluate the reactive oxygen species (ROS level in aortic wall and endothelial cells. Western blotting was performed to assess the protein expression associated with oxidative stress and nitric oxide (NO bioavailability. Exposure to homocysteine attenuated endothelium-dependent relaxations in rat aortas while salidroside pretreatment rescued it. Salidroside inhibited homocystein-induced elevation in the NOX2 expression and ROS overproduction in both aortas and cultured endothelial cells and increased phosphorylation of eNOS which was diminished by homocysteine. The present study shows that salidroside is effective in preserving the NO bioavailability and thus protects against homocysteine-induced impairment of endothelium-dependent relaxations, largely through inhibiting the NOX2 expression and ROS production. Our results indicate a therapeutic potential of salidroside in the management of oxidative-stress-associated cardiovascular dysfunction.

Salidroside Improves Homocysteine-Induced Endothelial Dysfunction by Reducing Oxidative Stress

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Leung, Sin Bond; Zhang, Huina; Lau, Chi Wai; Huang, Yu; Lin, Zhixiu

2013-01-01

Hyperhomocysteinemia is associated with an increased risk for cardiovascular diseases through increased oxidative stress. Salidroside is an active ingredient of the root of Rhodiola rosea with documented antioxidative, antihypoxia and neuroprotective properties. However, the vascular benefits of salidroside against endothelial dysfunction have yet to be explored. The present study, therefore, aimed to investigate the protective effect of salidroside on homocysteine-induced endothelial dysfunction. Functional studies on the rat aortas were performed to delineate the vascular effect of salidroside. DHE imaging was used to evaluate the reactive oxygen species (ROS) level in aortic wall and endothelial cells. Western blotting was performed to assess the protein expression associated with oxidative stress and nitric oxide (NO) bioavailability. Exposure to homocysteine attenuated endothelium-dependent relaxations in rat aortas while salidroside pretreatment rescued it. Salidroside inhibited homocystein-induced elevation in the NOX2 expression and ROS overproduction in both aortas and cultured endothelial cells and increased phosphorylation of eNOS which was diminished by homocysteine. The present study shows that salidroside is effective in preserving the NO bioavailability and thus protects against homocysteine-induced impairment of endothelium-dependent relaxations, largely through inhibiting the NOX2 expression and ROS production. Our results indicate a therapeutic potential of salidroside in the management of oxidative-stress-associated cardiovascular dysfunction. PMID:23589720

Hypermethylations of RASAL1 and KLOTHO is associated with renal dysfunction in a Chinese population environmentally exposed to cadmium

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Zhang, Chen; Liang, Yihuai [School of Public Health, Fudan University, 130 DongAn Road, Shanghai 200032 (China); Key Laboratory of Public Health Safety, Ministry of Education, 130 DongAn Road, Shanghai 200032 (China); Lei, Lijian [Department of Epidemiology, School of Public Health, Shanxi Medical University, Shanxi (China); Zhu, Guoying; Chen, Xiao [Department of Bone Metabolism, Institute of Radiation Medicine, Fudan University, Shanghai (China); Jin, Taiyi, E-mail: tyjin@shmu.edu.cn [School of Public Health, Fudan University, 130 DongAn Road, Shanghai 200032 (China); Key Laboratory of Public Health Safety, Ministry of Education, 130 DongAn Road, Shanghai 200032 (China); Wu, Qing, E-mail: qingwu@fudan.edu.cn [School of Public Health, Fudan University, 130 DongAn Road, Shanghai 200032 (China); Key Laboratory of Public Health Safety, Ministry of Education, 130 DongAn Road, Shanghai 200032 (China)

2013-08-15

Exposure to cadmium (Cd) can affect both DNA methylation and renal function, but there are few examples of the association between epigenetic markers and Cd-induced kidney damage. It has been suggested that hypermethylation of the genes RASAL1 and KLOTHO is associated with renal fibrogenesis. To investigate whether hypermethylation of RASAL1 and KLOTHO in peripheral blood DNA can be associated with Cd exposure and/or Cd-induced renal dysfunction, the degrees of methylation of RASAL1 and KLOTHO in peripheral blood DNA from 81 residents in Cd-polluted and non-polluted areas were measured using bisulfate-PCR-pyrosequencing. Changes in blood cadmium (BCd), urinary cadmium (UCd), and kidney parameters were measured, and the glomerular filtration rate (eGFR) was estimated. The levels of BCd and UCd correlated positively with the levels of DNA methylation in RASAL1 and in KLOTHO. The more heavily exposed residents (BCd, 4.23–13.22 μg/L; UCd, 8.65–32.90 μg/g creatinine) exhibited obvious renal dysfunction. Notably, when Cd concentration in blood and urine was adjusted, the increased methylation level in RASAL1 was inversely correlated with eGFR (P < 0.01) but the relationship between hypermethylation of KLOTHO and eGFR was not statistically significant. The methylation of RASAL1 increased along with the increased abnormal prevalence of eGFR. Our findings suggest that Cd exposure can induce the hypermethylation of RASAL1 and KLOTHO. Hypermethylation of RASAL1 may be an indicator of the progress for chronic kidney disease. - Highlights: • A long term heavily Cd exposure induced renal dysfunction. • Cd exposure correlated positively with DNA methylation in RASAL1 and KLOTHO. • Hypermethylation of RASAL1 correlated with adjusted renal function indicators.

Allicin protects against cisplatin-induced vestibular dysfunction by inhibiting the apoptotic pathway.

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Wu, Xianmin; Cai, Jing; Li, Xiaofei; Li, He; Li, Jianfeng; Bai, Xiaohui; Liu, Wenwen; Han, Yuechen; Xu, Lei; Zhang, Daogong; Wang, Haibo; Fan, Zhaomin

2017-06-15

Cisplatin is an anticancer drug that causes the impairment of inner ear function as side effects, including hearing loss and balance dysfunction. The purpose of this study was to investigate the effects of allicin against cisplatin-induced vestibular dysfunction in mice and to make clear the mechanism underlying the protective effects of allicin on oto-vestibulotoxicity. Mice intraperitoneally injected with cisplatin exhibited vestibular dysfunction in swimming test, which agreed with impairment in vestibule. However, these impairments were significantly prevented by pre-treatment with allicin. Allicin markedly reduced cisplatin-activated expression of cleaved-caspase-3 in hair cells and vascular layer cells of utricule, saccule and ampulla, but also decreased AIF nuclear translocation of hair cells in utricule, saccule and ampulla. These results showed that allicin played an effective role in protecting vestibular dysfunction induced by cisplatin via inhibiting caspase-dependent and caspase-independent apoptotic pathways. Therefore, allicin may be useful in preventing oto-vestibulotoxicity mediated by cisplatin. Copyright © 2017. Published by Elsevier B.V.

Application of path analysis to urinary findings of cadmium-induced renal dysfunction.

Science.gov (United States)

Abe, T; Kobayashi, E; Okubo, Y; Suwazono, Y; Kido, T; Shaikh, Z A; Nogawa, K

2001-01-01

In order to identify some causal relations among various urinary indices of cadmium-induced renal dysfunction, such as glucose, total protein, amino nitrogen, beta 2-microglobulin (beta 2-m), metallothionein (MT), and cadmium (Cd), we applied path analysis method to previous epidemiological studies targeting the residents of the Cd-polluted Kakehashi River basin of Ishikawa Prefecture, Japan. We obtained a diagram-termed path model, representing some causal relations among the above urinary indices. It shows that urinary Cd is located at the beginning point in the diagram, and Cd-induced renal dysfunction develops in the following order: Cd exposure-->increase of beta 2-m and/or MT excretion-->increase of amino-N and/or total protein excretion-->increase of glucose excretion. It was proved mathematically, that in the case of both males and females, increased excretions of beta 2-m and/or MT were the most sensitive urinary indices of the early stage of chronic Cd-induced renal dysfunction.

Hypoxia-inducible factor 1α regulates branching morphogenesis during kidney development.

Science.gov (United States)

Tsuji, Kenji; Kitamura, Shinji; Makino, Hirofumi

2014-04-25

The kidneys are exposed to hypoxic conditions during development. Hypoxia-inducible factor (HIF), an important mediator of the response to hypoxia, is believed to have an important role in development. However, the relationship between HIF and branching morphogenesis has not been elucidated clearly. In this study, we examined whether HIF regulates kidney development. We harvested kidneys from day 13 rat embryos (E13Ks) and cultured the organs under normoxic (20% O2/5% CO2) or hypoxic (5% O2/5% CO2) conditions. We evaluated the kidneys based on morphology and gene expression. E13Ks cultured under hypoxic conditions had significantly more ureteric bud (UB) branching than the E13Ks cultured under normoxic conditions. In addition, the mRNA levels of GDNF and GDNF receptor (GFR-α1), increased under hypoxic conditions in E13Ks. When we cultured E13Ks with the HIF-1α inhibitor digoxin or with siRNA targeting HIF-1α under hypoxic conditions, we did not observe increased UB branching. In addition, the expression of GDNF and GFR-α1 was inhibited under hypoxic conditions when the kidneys were treated with siRNA targeting HIF-1α. We also elucidated that hypoxia inhibited UB cell apoptosis and promoted the expression of FGF7 mRNA levels in metanephric mesenchymal (MM) cells in vitro. These findings suggest that hypoxic condition has important roles in inducing branching morphogenesis during kidney development. Hypoxia might mediate branching morphogenesis via not only GDNF/Ret but also FGF signaling pathway. Copyright © 2014 Elsevier Inc. All rights reserved.

Physalis minima Leaves Extract Induces Re-Endothelialization in Deoxycorticosterone Acetate-Salt-Induced Endothelial Dysfunction in Rats

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Dian Nugrahenny

2018-02-01

Full Text Available The administration of deoxy-corticosterone acetate (DOCA-salt can induce oxidative stress leading to decrease the bioavailability of nitric oxide (NO, increase senescence of circulating endothelial progenitor cells (EPCs, thus contributing to endothelial dysfunction. This study was aimed to investigate the effects of Physalis minima L. leaves extract on serum NO levels, circulating EPCs number, and histopathology of tail artery endothelial cells in DOCA-salt-induced endothelial dysfunction in rats. Twenty-five male Wistar rats were randomly divided into five groups: rats without any treatment (normal, rats treated with DOCA (10 mg/kgBW s.c. twice weekly and given 0.9% NaCl to drink ad libitum for 6 weeks, and DOCA-salt-induced rats orally supplemented with P. minima leaves extract at doses of 500, 1500, or 2500 mg/kgBW for 4 weeks. Serum NO levels were measured by colorimetry. The number of circulating EPCs (CD34+/CD133+ cells was determined by flow cytometry. The tail artery sections were histologically processed with hematoxylin-eosin staining. DOCA-salt-induced rats showed significantly (p<0.05 decrease in serum NO levels and circulating EPCs number compared to the normal. There was also more detached tail artery endothelial cells in DOCA-salt-induced rats. P. minima leaves extract at a dose of 500 mg/kgBW significantly (p<0.05 increased serum NO level and circulating EPCs number, and also induced an optimal re-endothelialization in DOCA-salt-induced rats. P. minima leave extract dose-dependently increases NO bioavailability contributing to enhanced EPCs mobilization, thereby promoting re-endothelialization in DOCA-salt-induced endothelial dysfunction in rats.

Nicotine protects kidney from renal ischemia/reperfusion injury through the cholinergic anti-inflammatory pathway.

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Claude Sadis

Full Text Available Kidney ischemia/reperfusion injury (I/R is characterized by renal dysfunction and tubular damages resulting from an early activation of innate immunity. Recently, nicotine administration has been shown to be a powerful inhibitor of a variety of innate immune responses, including LPS-induced toxaemia. This cholinergic anti-inflammatory pathway acts via the alpha7 nicotinic acetylcholine receptor (alpha7nAChR. Herein, we tested the potential protective effect of nicotine administration in a mouse model of renal I/R injury induced by bilateral clamping of kidney arteries. Renal function, tubular damages and inflammatory response were compared between control animals and mice receiving nicotine at the time of ischemia. Nicotine pretreatment protected mice from renal dysfunction in a dose-dependent manner and through the alpha7nAChR, as attested by the absence of protection in alpha7nAChR-deficient mice. Additionally, nicotine significantly reduced tubular damages, prevented neutrophil infiltration and decreased productions of the CXC-chemokine KC, TNF-alpha and the proinflammatory high-mobility group box 1 protein. Reduced tubular damage in nicotine pre-treated mice was associated with a decrease in tubular cell apoptosis and proliferative response as attested by the reduction of caspase-3 and Ki67 positive cells, respectively. All together, these data highlight that nicotine exerts a protective anti-inflammatory effect during kidney I/R through the cholinergic alpha7nAChR pathway. In addition, this could provide an opportunity to overcome the effect of surgical cholinergic denervation during kidney transplantation.

Renal sarcoidosis presenting as acute kidney injury with granulomatous interstitial nephritis and vasculitis.

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Agrawal, Varun; Crisi, Giovanna M; D'Agati, Vivette D; Freda, Benjamin J

2012-02-01

Among the various renal manifestations of sarcoidosis, granulomatous inflammation confined to the tubulointerstitial compartment is the most commonly reported finding. We present the case of a 66-year-old man with acute kidney injury, hypercalcemia, mild restrictive pulmonary disease, and neurologic signs of parietal lobe dysfunction. Kidney biopsy showed diffuse interstitial inflammation with noncaseating granulomas that exhibited the unusual feature of infiltrating the walls of small arteries with destruction of the elastic lamina, consistent with granulomatous vasculitis. The findings of granulomatous interstitial nephritis on kidney biopsy, hypercalcemia, and possible cerebral and pulmonary involvement in the absence of other infectious, drug-induced, or autoimmune causes of granulomatous disease established the diagnosis of sarcoidosis. Pulse methylprednisolone followed by maintenance prednisone therapy led to improvement in kidney function, hypercalcemia, and neurologic symptoms. Vasculocentric granulomatous interstitial nephritis with granulomatous vasculitis is a rare and under-recognized manifestation of renal sarcoidosis. Copyright © 2012 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

Milk fat globule-epidermal growth factor-factor VIII attenuates sepsis-induced acute kidney injury.

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Cen, Cindy; Aziz, Monowar; Yang, Weng-Lang; Zhou, Mian; Nicastro, Jeffrey M; Coppa, Gene F; Wang, Ping

2017-06-01

Acute kidney injury (AKI) is most commonly caused by sepsis in critically ill patients, and it is associated with high morbidity and mortality. The pathophysiology of sepsis-induced AKI is generally accepted to include direct inflammatory injury, endothelial cell dysfunction, and apoptosis. Milk fat globule-epidermal growth factor-factor VIII (MFG-E8) is a secretory glycoprotein with a known role in the enhancement of apoptotic cell clearance and regulation of inflammation. We hypothesize that administration of recombinant mouse MFG-E8 (rmMFG-E8) can protect mice from kidney injuries caused by sepsis. Sepsis was induced in 8-wk-old male C57BL/6 mice by cecal ligation and puncture (CLP). rmMFG-E8 or phosphate-buffered saline (vehicle) was injected intravenously at a dosage of 20 μg/kg body weight at time of CLP (n = 5-8 mice per group). After 20 h, serum and renal tissue were harvested for various analyses. The renal injury markers blood urea nitrogen (BUN) and creatinine were determined by enzymatic and chemical reactions, respectively. The gene expression analysis was carried out by real-time quantitative polymerase chain reaction. At 20 h after CLP, serum levels of BUN and creatinine were both significantly increased in the vehicle group compared with the sham group, whereas the mice treated with rmMFG-E8 had a significant reduction in BUN and creatinine levels by 28% and 24.1%, respectively (BUN: 197.7 ± 23.6 versus 142.3 ± 20.7 mg/dL; creatinine: 0.83 ± 0.12 versus 0.63 ± 0.06 mg/dL; P sepsis through inhibiting the production of proinflammatory cytokines and chemokine, as well as through the activation of endothelial cells. Thus, MFG-E8 may have a therapeutic potential for treating AKI induced by sepsis. Copyright © 2017 Elsevier Inc. All rights reserved.

Subunits Rip1p and Cox9p of the respiratory chain contribute to diclofenac-induced mitochondrial dysfunction

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van Leeuwen, J.S.; Orij, R.; Luttik, M.A.H.; Smits, G.J.; Vermeulen, N.P.E.; Vos, J. C.

2011-01-01

The widely used drug diclofenac can cause serious heart, liver and kidney injury, which may be related to its ability to cause mitochondrial dysfunction. Using Saccharomyces cerevisiae as a model system, we studied the mechanisms of diclofenac toxicity and the role of mitochondria therein. We found

Sexual dysfunction in women with ESRD requiring hemodialysis

NARCIS (Netherlands)

Strippoli, G.F.; Vecchio, M.; Palmer, S.; De Berardis, G.; Craig, J.; Lucisano, G.; Johnson, D.; Pellegrini, F.; Nicolucci, A.; Sciancalepore, M.; Saglimbene, V.; Gargano, L.; Bonifati, C.; Ruospo, M.; Navaneethan, S.D.; Montinaro, V.; Stroumza, P.; Zsom, M.; Torok, M.; Celia, E.; Gelfman, R.; Bednarek-Skublewska, A.; Dulawa, J.; Graziano, G.; Gentile, G.; Ferrari, J.N.; Santoro, A.; Zucchelli, A.; Triolo, G.; Maffei, S.; Hegbrant, J.; Wollheim, C.; De Cosmo, S.; Manfreda, V.M.; Steiner, K.; et al.,

2012-01-01

BACKGROUND AND OBJECTIVES: The few existing studies of sexual dysfunction in women on hemodialysis are limited by small sample size. This large, cross-sectional study evaluated the prevalence and correlates of female sexual dysfunction in advanced kidney disease. DESIGN, SETTING, PARTICIPANTS,

Radiation-induced erectile dysfunction: Recent advances and future directions

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Javed Mahmood, PhD

2016-07-01

Full Text Available Prostate cancer is one of the most prevalent cancers and the second leading cause of cancer-related deaths in men in the United States. A large number of patients undergo radiation therapy (RT as a standard care of treatment; however, RT causes erectile dysfunction (radiation-induced erectile dysfunction; RiED because of late side effects after RT that significantly affects quality of life of prostate cancer patients. Within 5 years of RT, approximately 50% of patients could develop RiED. Based on the past and current research findings and number of publications from our group, the precise mechanism of RiED is under exploration in detail. Recent investigations have shown prostate RT induces significant morphologic arterial damage with aberrant alterations in internal pudendal arterial tone. Prostatic RT also reduces motor function in the cavernous nerve which may attribute to axonal degeneration may contributing to RiED. Furthermore, the advances in radiogenomics such as radiation induced somatic mutation identification, copy number variation and genome-wide association studies has significantly facilitated identification of biomarkers that could be used to monitoring radiation-induced late toxicity and damage to the nerves; thus, genomic- and proteomic-based biomarkers could greatly improve treatment and minimize arterial tissue and nerve damage. Further, advanced technologies such as proton beam therapy that precisely target tumor and significantly reduce off-target damage to vital organs and healthy tissues. In this review, we summarize recent advances in RiED research and novel treatment modalities for RiED. We also discuss the possible molecular mechanism involved in the development of RiED in prostate cancer patients. Further, we discuss various readily available methods as well as novel strategies such as stem cell therapies, shockwave therapy, nerve grafting with tissue engineering, and nutritional supplementations might be used to

Renoprotective mechanisms of chlorogenic acid in cisplatin-induced kidney injury

International Nuclear Information System (INIS)

Domitrović, Robert; Cvijanović, Olga; Šušnić, Vesna; Katalinić, Nataša

2014-01-01

Highlights: • Chlorogenic acid attenuated cisplatin-induced renal oxidative stress by reducing the expression of 4-HNE, HO-1 and CYP2E1. • The inhibition of inflammatory response was achieved through the reduction of TNF-α and COX-2 expression. • The expression of p53, Bax, active caspase-3 and LC3B was suppressed, suggesting the inhibition of apoptosis and autophagy. • Attenuation of Mrp1 and Mrp2 expression and the increase in Oct2 expression indicated reduced burden of tubular cells. • The recovery of kidneys form cisplatin injury was accompanied by the suppression of cyclin D1 and augmented PCNA expression. - Abstract: The aim of this study was to investigate the renoprotective activity of chlorogenic acid (CA) in a murine model of cisplatin (CP)-induced kidney injury. Male BALB/cN mice were gavaged daily with CA at 3, 10 and 30 mg/kg for two successive days, 48 h after intraperitoneal injection of CP (13 mg/kg). On the fifth day, serum creatinine and blood urea nitrogen (BUN) levels were significantly increased in CP-intoxicated mice, which was recovered by CA. Renal oxidative stress, evidenced by increased 4-hydroxynonenal (4-HNE) expression, was significantly reduced with CA. Simultaneously, the overexpression of heme oxygenase 1 (HO-1) and cytochrome P450 E1 (CYP2E1) was attenuated. The inhibition of inflammatory response by CA was achieved through the reduction of tumor necrosis factor-α (TNF-α) and cyclooxygenase-2 (COX-2) expression. Additionally, CA significantly suppressed p53, Bax active caspase-3, cyclin D1 and microtubule-associated protein 1 light chain 3 isoform B (LC3B) expression, suggesting the inhibition of both apoptosis and autophagy. The expression of multidrug resistance-associated proteins (Mrp1 and Mrp2) increased and organic cation transporter 2 (Oct2) decreased by CP, protecting the kidneys from nephrotoxicity by reducing the burden of tubular cells. CA dose-dependently restored Mrp1, Mrp2 and Oct2 expression. The recovery

Epidermal growth factor receptor-induced activato protein 1 activity controls density-dependent growht inhibition in normal rat kidney fibroblasts.

NARCIS (Netherlands)

Hornberg, J.J.; Dekker, H.; Peters, P.H.J.; Langerak, P.; Westerhoff, H.V.; Lankelma, J.; Zoelen, E.J.J.

2006-01-01

Density-dependent growth inhibition secures tissue homeostasis. Dysfunction of the mechanisms, which regulate this type of growth control is a major cause of neoplasia. In confluent normal rat kidney (NRK) fibroblasts, epidermal growth factor (EGF) receptor levels decline, ultimately rendering these

HIV antiretroviral drug combination induces endothelial mitochondrial dysfunction and reactive oxygen species production, but not apoptosis

International Nuclear Information System (INIS)

Jiang Bo; Hebert, Valeria Y.; Li, Yuchi; Mathis, J. Michael; Alexander, J. Steven; Dugas, Tammy R.

2007-01-01

Numerous reports now indicate that HIV patients administered long-term antiretroviral therapy (ART) are at a greater risk for developing cardiovascular diseases. Endothelial dysfunction is an initiating event in atherogenesis and may contribute to HIV-associated atherosclerosis. We previously reported that ART induces direct endothelial dysfunction in rodents. In vitro treatment of human umbilical vein endothelial cells (HUVEC) with ART indicated endothelial mitochondrial dysfunction and a significant increase in the production of reactive oxygen species (ROS). In this study, we determined whether ART-induced endothelial dysfunction is mediated via mitochondria-derived ROS and whether this mitochondrial injury culminates in endothelial cell apoptosis. Two major components of ART combination therapy, a nucleoside reverse transcriptase inhibitor and a protease inhibitor, were tested, using AZT and indinavir as representatives for each. Microscopy utilizing fluorescent indicators of ROS and mitochondria demonstrated the mitochondrial localization of ART-induced ROS. MnTBAP, a cell-permeable metalloporphyrin antioxidant, abolished ART-induced ROS production. As a final step in confirming the mitochondrial origin of the ART-induced ROS, HUVEC were transduced with a cytosolic- compared to a mitochondria-targeted catalase. Transduction with the mitochondria-targeted catalase was more effective than cytoplasmic catalase in inhibiting the ROS and 8-isoprostane (8-iso-PGF 2α ) produced after treatment with either AZT or indinavir. However, both mitochondrial and cytoplasmic catalase attenuated ROS and 8-iso-PGF 2α production induced by the combination treatment, suggesting that in this case, the formation of cytoplasmic ROS may also occur, and thus, that the mechanism of toxicity in the combination treatment group may be different compared to treatment with AZT or indinavir alone. Finally, to determine whether ART-induced mitochondrial dysfunction and ROS production

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.

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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.

UCP3 Ablation Exacerbates High-Salt Induced Cardiac Hypertrophy and Cardiac Dysfunction

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Hongmei Lang

2018-04-01

Full Text Available Background/Aims: Excessive salt intake and left ventricular hypertrophy (LVH are both critical for the development of hypertension and heart failure. The uncoupling protein 3 (UCP3 plays a cardio-protective role in early heart failure development. However, the potential role for UCP3 in salt intake and LVH is unclear. Methods: UCP3-/- and C57BL/6 mice were placed on either a normal-salt (NS, 0.5% or a high-salt (HS, 8% diet for 24 weeks. The cardiac function, endurance capacity, energy expenditure, and mitochondrial functional capacity were measured in each group. Results: Elevated blood pressure was only observed in HS-fed UCP3-/- mice. High salt induced cardiac hypertrophy and dysfunction were observed in both C57BL/6 and UCP3-/- mice. However, the cardiac lesions were more profound in HS-fed UCP3-/- mice. Furthermore, HS-fed UCP3-/-mice experienced more severe mitochondrial respiratory dysfunction compared with HS-fed C57BL/6 mice, represented by the decreased volume of oxygen consumption and heat production at the whole-body level. Conclusion: UCP3 protein was involved in the incidence of high-salt induced hypertension and the progression of cardiac dysfunction in the early stages of heart failure. UCP3 ablation exacerbated high-salt-induced cardiac hypertrophy and cardiac dysfunction.

Synergistic Interaction of Hypertension and Diabetes in Promoting Kidney Injury and the Role of Endoplasmic Reticulum Stress.

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Wang, Zhen; do Carmo, Jussara M; Aberdein, Nicola; Zhou, Xinchun; Williams, Jan M; da Silva, Alexandre A; Hall, John E

2017-05-01

Diabetes mellitus and hypertension are major risk factors for chronic kidney injury, together accounting for >70% of end-stage renal disease. In this study, we assessed interactions of hypertension and diabetes mellitus in causing kidney dysfunction and injury and the role of endoplasmic reticulum (ER) stress. Hypertension was induced by aorta constriction (AC) between the renal arteries in 6-month-old male Goto-Kakizaki (GK) type 2 diabetic and control Wistar rats. Fasting plasma glucose averaged 162±11 and 87±2 mg/dL in GK and Wistar rats, respectively. AC produced hypertension in the right kidney (above AC) and near normal blood pressure in the left kidney (below AC), with both kidneys exposed to the same levels of glucose, circulating hormones, and neural influences. After 8 weeks of AC, blood pressure above the AC (and in the right kidney) increased from 109±1 to 152±5 mm Hg in GK rats and from 106±4 to 141±5 mm Hg in Wistar rats. The diabetic-hypertensive right kidneys in GK-AC rats had much greater increases in albumin excretion and histological injury compared with left kidneys (diabetes mellitus only) of GK rats or right kidneys (hypertension only) of Wistar-AC rats. Marked increases in ER stress and oxidative stress indicators were observed in diabetic-hypertensive kidneys of GK-AC rats. Inhibition of ER stress with tauroursodeoxycholic acid for 6 weeks reduced blood pressure (135±4 versus 151±4 mm Hg), albumin excretion, ER and oxidative stress, and glomerular injury, while increasing glomerular filtration rate in hypertensive-diabetic kidneys. These results suggest that diabetes mellitus and hypertension interact synergistically to promote kidney dysfunction and injury via ER stress. © 2017 American Heart Association, Inc.

Impact of Mannose-Binding Lectin Deficiency on Radiocontrast-Induced Renal Dysfunction

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Michael Osthoff

2013-01-01

Full Text Available Contrast-induced nephropathy (CIN is the third leading cause of acute renal failure in hospitalized patients. Endothelial dysfunction, renal medullary ischemia, and tubular toxicity are regarded as the most important factors in the pathogenesis of CIN. Mannose-binding lectin (MBL, a pattern recognition protein of the lectin pathway of complement, has been found to aggravate and mediate tissue damage during experimental renal ischemia/reperfusion (I/R injury which was alleviated by inhibition with C1 inhibitor, a potent MBL, and lectin pathway inhibitor. In this paper, we highlight the potential role of MBL in the pathogenesis of human CIN. In experimental I/R models, MBL was previously found to induce tubular cell death independent of the complement system. In addition, after binding to vascular endothelial cells, MBL and its associated serine proteases were able to trigger a proinflammatory reaction and contribute to endothelial dysfunction. In humans, urinary MBL was increased after administration of contrast media and in individuals with CIN. Moreover, individuals with normal/high MBL levels were at increased risk to develop radiocontrast-induced renal dysfunction. Hence, MBL and the lectin pathway seem to be a promising target given that a licensed, powerful, human recombinant inhibitor exits to be added to the scarce armamentarium currently available for prophylaxis of CIN.

Role of Lectin-Like Oxidized Low Density Lipoprotein-1 in Fetoplacental Vascular Dysfunction in Preeclampsia

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Felipe A. Zuniga

2014-01-01

Full Text Available The bioavailability of nitric oxide (NO represents a key marker in vascular health. A decrease in NO induces a pathological condition denominated endothelial dysfunction, syndrome observed in different pathologies, such as obesity, diabetes, kidney disease, cardiovascular disease, and preeclampsia (PE. PE is one of the major risks for maternal death and fetal loss. Recent studies suggest that the placenta of pregnant women with PE express high levels of lectin-like oxidized LDL receptor-1 (LOX-1, which induces endothelial dysfunction by increasing reactive oxygen species (ROS and decreasing intracellular NO. Besides LOX-1 activation induces changes in migration and apoptosis of syncytiotrophoblast cells. However, the role of this receptor in placental tissue is still unknown. In this review we will describes the physiological roles of LOX-1 in normal placenta development and the potential involvement of this receptor in the pathophysiology of PE.

SIGNALING MECHANISMS IN SEPSIS-INDUCED IMMUNE DYSFUNCTION

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Hasan, Zirak

2013-01-01

Sepsis and subsequent organ failure remain the major cause of mortality in intensive care units in spite of significant research efforts. The lung is the most vulnerable organ affected by early hyper-inflammatory immune response in septic patients. On the other hand, the septic insult induces immune dysfunction in later phases of sepsis which in turn increases susceptibility to infections. The aim of this thesis was to investigate early and late inflammatory mechanisms in abdominal sepsis ind...

Prognostic significance of endothelial dysfunctional markers of the first stage of chronic kidney disease

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M. M. Mnuskina

2014-01-01

Full Text Available Non-adaptive remodeling of cardiovascular system and progressive kidney damage at chronic kidney disease (CKD is associated with the development of endothelial dysfunction (ED and apoptosis. The aim of this research was to study the changes of indicators of apoptosis and ED in patients with CKD 1 stage throughout 12 months. Complex biochemical, immunoferment and tool methods were applied at patient examinations. Arterial pressure of all observed patients was resolved on target values in 12 months. However, the indicators of endothelium-dependent vasodilation (EDV increased in 55 patients (1st group, and the peak of circulating blood volume in skin microvessels in 22 patients (2nd group wasn't changed: 134±4 % и 136±4 %, p>0.1. The level of the annexin A5 reduced from 3.5±0.47 to 1.27±0.31 ng/ml (p0.1 in 2nd group. Diurnal excretion of sodium chloride decreased from 6.8±0.57 g/d to 2.8±0.39 g/d (p<0.05 in patients of 1st group. Dynamics of these indicators was not marked in patients of 2nd group: accordingly from 7.39±0.63 g/d to 7.01±0.65 g/d. Diurnal excretion of sodium chloride reflected the salt intake in patients with CKD 1 stage is associated with disturbance of endothelial-dependent vasodilation and apoptosis.

Original article. Mitigation of diazinon-induced cardiovascular and renal dysfunction by gallic acid

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Ajibade Temitayo Olabisi

2016-06-01

Full Text Available Studies of the link between environmental pollutants and cardiovascular dysfunction, neglected for decades, have recently provided new insights into the pathology and consequences of these killers. In this study, rats were divided into four groups, each containing 10 rats. The rats in group one served as controls and were administered normal saline, whereas the rats in group two were orally gavaged with 3 mg/kg of diazinon (DZN alone for twenty one consecutive days. The rats in groups 3 and 4 were administered respective 60 mg/kg and 120 mg/kg gallic acid (GA in addition to DZN for twenty one consecutive days. Exposure of rats to diazinon significantly (p<0.05 reduced the activities of superoxide dismutase (SOD, catalase (CAT, glutathione peroxidase (GPx, glutathione-S-transferase (GST and reduced glutathione (GSH content. Malondialdehyde, hydrogen peroxide (H2O2 and nitric oxide (NO contents were also significantly (p<0.05 elevated following DZN exposure. DZN further caused a significant (p<0.05 decrease of heart rate and QT interval prolongation. Hematologic analysis revealed significant reduction (p<0.05 in packed cell volume (PCV, hemoglobin concentration (Hb, red blood cell (RBC count, and total white blood cell count of rats administered only DZN. Observations in this study suggest a modulatory role of gallic acid in diazinon-induced anemia and associated cardiovascular dysfunction in rats. Treatment with gallic acid reversed the oxidative stress markers studied, increased the antioxidant defence system and reduced deleterious effects on hematological parameters in rats. Pathologic findings of the heart and kidney were also found to be lessened.

Mechanisms of pertussis toxin-induced barrier dysfunction in bovine pulmonary artery endothelial cell monolayers.

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Patterson, C E; Stasek, J E; Schaphorst, K L; Davis, H W; Garcia, J G

1995-06-01

We have previously characterized several G proteins in endothelial cells (EC) as substrates for the ADP-ribosyltransferase activity of both pertussis (PT) and cholera toxin and described the modulation of key EC physiological responses, including gap formation and barrier function, by these toxins. In this study, we investigated the mechanisms involved in PT-mediated regulation of bovine pulmonary artery endothelial cells barrier function. PT caused a dose-dependent increase in albumin transfer, dependent upon action of the holotoxin, since neither the heat-inactivated PT, the isolated oligomer, nor the protomer induced EC permeability. PT-induced gap formation and barrier dysfunction were additive to either thrombin- or thrombin receptor-activating peptide-induced permeability, suggesting that thrombin and PT utilize distinct mechanisms. PT did not result in Ca2+ mobilization or alter either basal or thrombin-induced myosin light chain phosphorylation. However, PT stimulated protein kinase C (PKC) activation, and both PKC downregulation and PKC inhibition attenuated PT-induced permeability, indicating that PKC activity is involved in PT-induced barrier dysfunction. Like thrombin-induced permeability, the PT effect was blocked by prior increases in adenosine 3',5'-cyclic monophosphate. Thus PT-catalyzed ADP-ribosylation of a G protein (possibly other than Gi) may regulate cytoskeletal protein interactions, leading to EC barrier dysfunction.

Magnetic ferroferric oxide nanoparticles induce vascular endothelial cell dysfunction and inflammation by disturbing autophagy

Energy Technology Data Exchange (ETDEWEB)

Zhang, Lu, E-mail: chaperones@163.com [College of Bioengineering, Henan University of Technology, Lianhua Street, Zhengzhou 450001 (China); Wang, XueQin; Miao, YiMing; Chen, ZhiQiang; Qiang, PengFei; Cui, LiuQing; Jing, Hongjuan [College of Bioengineering, Henan University of Technology, Lianhua Street, Zhengzhou 450001 (China); Guo, YuQi [Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052 (China)

2016-03-05

Highlights: • B-Fe{sub 3}O{sub 4}NPs did not induce cell apoptosis or necrosis in HUVECs within 24 h. • B-Fe{sub 3}O{sub 4}NPs induced HUVEC dysfunction and inflammation. • B-Fe{sub 3}O{sub 4}NPs induced enhanced autophagic activity and blockade of autophagy flux. • Suppression of autophagy dysfunction attenuated B-Fe{sub 3}O{sub 4}NP-induced HUVEC dysfunction. - Abstract: Despite the considerable use of magnetic ferroferric oxide nanoparticles (Fe{sub 3}O{sub 4}NPs) worldwide, their safety is still an important topic of debate. In the present study, we detected the toxicity and biological behavior of bare-Fe{sub 3}O{sub 4}NPs (B-Fe{sub 3}O{sub 4}NPs) on human umbilical vascular endothelial cells (HUVECs). Our results showed that B-Fe{sub 3}O{sub 4}NPs did not induce cell death within 24 h even at concentrations up to 400 μg/ml. The level of nitric oxide (NO) and the activity of endothelial NO synthase (eNOS) were decreased after exposure to B-Fe{sub 3}O{sub 4}NPs, whereas the levels of proinflammatory cytokines were elevated. Importantly, B-Fe{sub 3}O{sub 4}NPs increased the accumulation of autophagosomes and LC3-II in HUVECs through both autophagy induction and the blockade of autophagy flux. The levels of Beclin 1 and VPS34, but not phosphorylated mTOR, were increased in the B-Fe{sub 3}O{sub 4}NP-treated HUVECs. Suppression of autophagy induction or stimulation of autophagy flux, at least partially, attenuated the B-Fe{sub 3}O{sub 4}NP-induced HUVEC dysfunction. Additionally, enhanced autophagic activity might be linked to the B-Fe{sub 3}O{sub 4}NP-induced production of proinflammatory cytokines. Taken together, these results demonstrated that B-Fe{sub 3}O{sub 4}NPs disturb the process of autophagy in HUVECs, and eventually lead to endothelial dysfunction and inflammation.

Sepsis-induced myocardial dysfunction and myocardial protection from ischemia/reperfusion injury.

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McDonough, Kathleen H; Virag, Jitka Ismail

2006-01-01

Sepsis, bacteremia and inflammation cause myocardial depression. The mechanism of the dysfunction is not clearly established partly because dysfunction can be elicited by many different mechanisms which can all manifest in disruption of myocardial mechanical function. In addition the models of sepsis and bacteremia and inflammation may vary drastically in the sequence of the coordinated immune response to the inflammatory or septic stimulus. Patterns of cytokine expression can vary as can other responses of the immune system. Patterns of neurohumoral activation in response to the stress of sepsis or bacteremia or inflammation can also vary in both magnitude of response and temporal sequence of response. Stress induced activation of the sympathetic nervous system and humoral responses to stress have a wide range of intensity that can be elicited. The fairly uniform response of the myocardium indicating cardiac dysfunction is surprisingly constant. Systolic performance, as measured by stroke volume or cardiac output and pressure work as estimated by ventricular pressure, are impaired when myocardial contraction is compromised. At times, diastolic function, assessed by ventricular relaxation and filling, is impaired. In addition to the dysfunction that occurs, there is a longer term response of the myocardium to sepsis, and this response is similar to that which is elicited in the heart by multiple brief ischemia/reperfusion episodes and by numerous pharmacological agents as well as heat stress and modified forms of lipopolysaccharide. The myocardium develops protection after an initial stress such that during a second stress, the myocardium does not exhibit as much damage as does a non-protected heart. Many agents can induce this protection which has been termed preconditioning. Both early preconditioning (protection that is measurable min to hours after the initial stimulus) and late preconditioning (protection that is measurable hours to days after the initial

The Preinterventional Cystatin-Creatinine-Ratio: A Prognostic Marker for Contrast Medium-Induced Acute Kidney Injury and Long-Term All-Cause Mortality.

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Lüders, Florian; Meyborg, Matthias; Malyar, Nasser; Reinecke, Holger

2015-01-01

Contrast medium-induced acute kidney injury (CI-AKI) is an important iatrogenic complication following the injection of iodinated contrast media. The level of serum creatinine (SCr) is the currently accepted 'gold standard' to diagnose CI-AKI. Cystatin C (CyC) has been detected as a more sensitive marker for renal dysfunction. Both have their limitations. The role of the preinterventional CyC-SCr ratio for evaluating the risk for CI-AKI and long-term all-cause mortality was retrospectively analyzed in the prospective single-center 'Dialysis-versus-Diuresis trial'. CI-AKI was defined and staged according to the Acute Kidney Injury Network classification. Three hundred and seventy-three patients were included (average age 67.4 ± 10.2 years, 16.4% women, 29.2% with diabetes mellitus, mean baseline glomerular filtration rate 56.3 ± 20.2 ml/min/1.73 m(2) [as estimated by Chronic Kidney Disease Epidemiology Collaboration Serum Creatinine Cystatin C equation], 5.1% ejection fraction high significant association between preinterventional CyC-SCr ratio and long-term all-cause mortality (mean follow-up 649 days, hazards ratio 4.096, 95% CI 1.625-10.329, p = 0.003). The preinterventional CyC-SCr ratio is independently associated with CI-AKI and highly significant associated with long-term mortality after heart catheterization. © 2015 S. Karger AG, Basel.

The Relationship Between Pulmonary Emphysema and Kidney Function in Smokers

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Chandra, Divay; Stamm, Jason A.; Palevsky, Paul M.; Leader, Joseph K.; Fuhrman, Carl R.; Zhang, Yingze; Bon, Jessica; Duncan, Steven R.; Branch, Robert A.; Weissfeld, Joel; Gur, David; Gladwin, Mark T.

2012-01-01

Background: It has been reported that the prevalence of kidney dysfunction may be increased in patients exposed to tobacco with airflow obstruction. We hypothesized that kidney dysfunction would associate with emphysema rather than with airflow obstruction measured by the FEV1. Methods: Five hundred eight current and former smokers completed a chest CT scan, pulmonary function tests, medical questionnaires, and measurement of serum creatinine. Glomerular filtration rates (eGFRs) were estimated using the method of the Chronic Kidney Disease Epidemiology Collaboration. Quantitative determinants of emphysema and airway dimension were measured from multidetector chest CT scans. Results: The mean age was 66 ± 7 years, and mean eGFR was 101 ± 22 mL/min/1.73 m2. Univariate and multivariate analysis showed a significant association between radiographically measured emphysema and eGFR: Participants with 10% more emphysema had an eGFR that was lower by 4.4 mL/min/1.73 m2 (P = .01), independent of airflow obstruction (FEV1), age, sex, race, height, BMI, diabetes mellitus, hypertension, coronary artery disease, patient-reported dyspnea, pack-years of smoking, and current smoking. There was no association between eGFR and either FEV1 or quantitative CT scan measures of airway dimension. Conclusions: More severe emphysema, rather than airflow obstruction, is associated with kidney dysfunction in tobacco smokers, independent of common risk factors for kidney disease. This finding adds to recent observations of associations between emphysema and comorbidities of COPD, including osteoporosis and lung cancer, which are independent of the traditional measure of reduced FEV1. The mechanisms and clinical implications of kidney dysfunction in patients with emphysema need further investigation. PMID:22459775

Sexual dysfunction in women with ESRD requiring hemodialysis.

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Strippoli, Giovanni F M; Vecchio, Mariacristina; Palmer, Suetonia; De Berardis, Giorgia; Craig, Jonathan; Lucisano, Giuseppe; Johnson, David; Pellegrini, Fabio; Nicolucci, Antonio; Sciancalepore, Michela; Saglimbene, Valeria; Gargano, Letizia; Bonifati, Carmen; Ruospo, Marinella; Navaneethan, Sankar D; Montinaro, Vincenzo; Stroumza, Paul; Zsom, Marianna; Torok, Mariatta; Celia, Eduardo; Gelfman, Ruben; Bednarek-Skublewska, Anna; Dulawa, Jan; Graziano, Giusi; Gentile, Giorgio; Ferrari, Juan Nin; Santoro, Antonio; Zucchelli, Annalisa; Triolo, Giorgio; Maffei, Stefano; Hegbrant, Jörgen; Wollheim, Charlotta; De Cosmo, Salvatore; Manfreda, Valeria M

2012-06-01

The few existing studies of sexual dysfunction in women on hemodialysis are limited by small sample size. This large, cross-sectional study evaluated the prevalence and correlates of female sexual dysfunction in advanced kidney disease. DESIGN, SETTING, PARTICIPANTS, METHODS: A total of 1472 women with ESRD undergoing hemodialysis were recruited to a multinational, cross-sectional study conducted within a collaborative dialysis network in Europe and South America. Sexual dysfunction was identified by the Female Sexual Function Index. Correlates of self-reported sexual dysfunction were identified by regression analyses. Of the 1472 women, 659 completed questionnaires (45%). More than half (362 of 659 [55%]) lived with a partner, and 232 of 659 (35%) reported being sexually active. Of these 659 respondents, 555 (84%) reported sexual dysfunction. Women with a partner (282 of 362 [78%]) were less likely to report sexual dysfunction than those without a partner (273 of 297 [92%]) (Psymptoms, less education, menopause, diabetes, and diuretic therapy. Nearly all women who were not wait-listed for a kidney transplant and were living without a partner (249 of 260 [96%]) reported sexual dysfunction. More than half (128 of 232 [55%]) of sexually active women reported sexual dysfunction, associated with age, depressive symptoms, menopause, low serum albumin, and diuretic therapy. This descriptive study suggests most women on hemodialysis experience sexual problems. Additional research on the relevance of sexual dysfunction to symptom burden and quality of life in these women is needed.

Obesity-Induced Endoplasmic Reticulum Stress Causes Lung Endothelial Dysfunction and Promotes Acute Lung Injury.

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Shah, Dilip; Romero, Freddy; Guo, Zhi; Sun, Jianxin; Li, Jonathan; Kallen, Caleb B; Naik, Ulhas P; Summer, Ross

2017-08-01

Obesity is a significant risk factor for acute respiratory distress syndrome. The mechanisms underlying this association are unknown. We recently showed that diet-induced obese mice exhibit pulmonary vascular endothelial dysfunction, which is associated with enhanced susceptibility to LPS-induced acute lung injury. Here, we demonstrate that lung endothelial dysfunction in diet-induced obese mice coincides with increased endoplasmic reticulum (ER) stress. Specifically, we observed enhanced expression of the major sensors of misfolded proteins, including protein kinase R-like ER kinase, inositol-requiring enzyme α, and activating transcription factor 6, in whole lung and in primary lung endothelial cells isolated from diet-induced obese mice. Furthermore, we found that primary lung endothelial cells exposed to serum from obese mice, or to saturated fatty acids that mimic obese serum, resulted in enhanced expression of markers of ER stress and the induction of other biological responses that typify the lung endothelium of diet-induced obese mice, including an increase in expression of endothelial adhesion molecules and a decrease in expression of endothelial cell-cell junctional proteins. Similar changes were observed in lung endothelial cells and in whole-lung tissue after exposure to tunicamycin, a compound that causes ER stress by blocking N-linked glycosylation, indicating that ER stress causes endothelial dysfunction in the lung. Treatment with 4-phenylbutyric acid, a chemical protein chaperone that reduces ER stress, restored vascular endothelial cell expression of adhesion molecules and protected against LPS-induced acute lung injury in diet-induced obese mice. Our work indicates that fatty acids in obese serum induce ER stress in the pulmonary endothelium, leading to pulmonary endothelial cell dysfunction. Our work suggests that reducing protein load in the ER of pulmonary endothelial cells might protect against acute respiratory distress syndrome in obese

Close pathological correlations between chronic kidney disease and reproductive organ-associated abnormalities in female cotton rats.

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Ichii, Osamu; Nakamura, Teppei; Irie, Takao; Kouguchi, Hirokazu; Sotozaki, Kozue; Horino, Taro; Sunden, Yuji; Elewa, Yaser Hosny Ali; Kon, Yasuhiro

2018-03-01

Cotton rat ( Sigmodon hispidus) is a useful experimental rodent for the study of human infectious diseases. We previously clarified that cotton rats, particularly females, developed chronic kidney disease characterized by cystic lesions, inflammation, and fibrosis. The present study investigated female-associated factors for chronic kidney disease development in cotton rats. Notably, female cotton rats developed separation of the pelvic symphysis and hypertrophy in the vaginal parts of the cervix with age, which strongly associated with pyometra. The development of pyometra closely associated with the deterioration of renal dysfunction or immunological abnormalities was indicated by blood urea nitrogen and serum creatinine or spleen weight and serum albumin/globulin ratio, respectively. These parameters for renal dysfunction and immunological abnormalities were statistically correlated. These phenotypes found in the female reproductive organs were completely inhibited by ovariectomy. Further, the female cotton rats with pyometra tended to show more severe chronic kidney disease phenotypes and immunological abnormalities than those without pyometra; these changes were inhibited in ovariectomized cotton rats. With regard to renal histopathology, cystic lesions, inflammation, and fibrosis were ameliorated by ovariectomy. Notably, the immunostaining intensity of estrogen receptor α and estrogen receptor β were weak in the healthy kidneys, but both estrogen receptors were strongly induced in the renal tubules showing cystic changes. In conclusion, the close correlations among female reproductive organ-associated abnormalities, immunological abnormalities, and renal dysfunction characterize the chronic kidney disease features of female cotton rats. Thus, the cotton rat is a unique rodent model to elucidate the pathological crosstalk between chronic kidney disease and sex-related factors. Impact statement The increasing number of elderly individuals in the overall

Benfotiamine counteracts smoking-induced vascular dysfunction in healthy smokers.

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Stirban, Alin; Nandrean, Simona; Kirana, Stanley; Götting, Christian; Veresiu, Ioan Andrei; Tschoepe, Diethelm

2012-01-01

Background. Smoking induces endothelial dysfunction (ED) mainly by exacerbating oxidative stress (OS) and inflammation. Benfotiamine, a thiamine prodrug with high bioavailability, prevents nicotine-induced vascular dysfunction in rats. It remained unknown whether this effect also occurs in humans. Methods. Therefore, 20 healthy volunteers (mean age: 38 years) were investigated twice, 7-10 days apart in a randomized, cross-over, and investigator-blinded design. Vascular function was assessed by flow-mediated vasodilatation (FMD) of the brachial artery and by measurements of the soluble vascular cell adhesion molecule (sVCAM)-1. Investigations were performed after an overnight fast as well as 20 minutes after one cigarette smoking. On another day, the same procedure was applied following a 3-day oral therapy with benfotiamine (1050 mg/day). Ten patients were randomized to start with smoking alone, and ten started with benfotiamine. Results. Results are expressed as (mean ± SEM). Smoking acutely induced a decrease in FMD by 50% ((∗∗)P benfotiamine treatment to 25%(∗§) ((∗)P benfotiamine. The endothelium-independent vasodilatation remained unaltered between days. Conclusion. In healthy volunteers, smoking blunts vascular function mirrored by a decrease in FMD and an increase in sVCAM-1. Short-term treatment with benfotiamine significantly reduces these effects, showing protective vascular properties.

Cardiac microvascular rarefaction in hyperthyroidism-induced left ventricle dysfunction.

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Freitas, Felipe; Estato, Vanessa; Carvalho, Vinícius Frias; Torres, Rafael Carvalho; Lessa, Marcos Adriano; Tibiriçá, Eduardo

2013-10-01

The pathophysiology underlying hyperthyroidism-induced left ventricle (LV) dysfunction and hypertrophy directly involves the heart and indirectly involves the neuroendocrine systems. The effects of hyperthyroidism on the microcirculation are still controversial in experimental models. We investigated the effects of hyperthyroidism on the cardiac function and microcirculation of an experimental rat model. Male Wistar rats (170-250 g) were divided into two groups: the euthyroid group (n = 10), which was treated with 0.9% saline solution, and the hyperthyroid group (n = 10), which was treated with l-thyroxine (600 μg/kg/day, i.p.) during 14 days. An echocardiographic study was performed to evaluate the alterations in cardiac function, structure and geometry. The structural capillary density and the expression of angiotensin II AT1 receptor in the LV were analyzed using histochemistry and immunohistochemistry, respectively. Hyperthyroidism was found to induce profound cardiovascular alterations, such as systolic hypertension, tachycardia, LV dysfunction, cardiac hypertrophy, and myocardial fibrosis. This study demonstrates the existence of structural capillary rarefaction and the down-regulation of the cardiac angiotensin II AT1 receptor in the myocardium of hyperthyroid rats in comparison with euthyroid rats. Microvascular rarefaction may be involved in the pathophysiology of hyperthyroidism-induced cardiovascular alterations. © 2013 John Wiley & Sons Ltd.

Activation of the NLRP3 inflammasome induces vascular dysfunction in obese OLETF rats

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Liu, Penghao; Xie, Qihai; Wei, Tong; Chen, Yichen; Chen, Hong; Shen, Weili

2015-01-01

Objective: Obesity-induced vascular dysfunction is related to chronic low-grade systemic inflammation. Recent studies indicate that NLRP3, a multiprotein complex formed by NOD-like receptor (NLR) family members, is a key component mediating internal sterile inflammation, but the role in obesity-related vascular dysfunction is largely unknown. In the present study, we investigate whether NLRP3 activation is involved in vascular inflammation in obese Otsuka Long-Evans Tokushima Fatty rats (OLETF). Methods and results: Male OLETF with their control Long-Evans Tokushima Otsuka rats (LETO) were studied at 3 and 12 months of age. Aortic relaxation in response to acetylcholine decreased gradually with age in both strains, with early and persistent endothelium dysfunction in obese OLETF compared with age-matched LETO controls. These changes are associated with parallel changes of aortic endothelial nitric oxide synthase (eNOS) content, macrophage accumulation and intimal thickening. NLRP3 increased in OLETF rats compared to LETO. Consistent with inflammasome activation, the conversion of procaspase-1 to cleaved and activated forms as well as IL-1β markedly increased in OLETF rats. Additionally, we observed increased expression of dynamin-related protein-1 (Drp1) and decreased fusion-relative protein optic atropy-1(OPA1). Altered mitochondrial dynamics was associated with elevated oxidative stress level in OLETF aortas. Conclusions: These results demonstrate that obesity seems to accelerate endothelial dysfunction in OLETFs via the activation of NLRP3 and mitochondrial dysfunction. - Highlights: • NLRP3 is involved in obesity-induced vascular dysfunction. • Impaired mitochondrial dynamics may have been linked to mitochondrial defect and inflammasome activation. • Obesity seems to accelerate vascular dysfunction via NLRP3 activation and mitochondrial dysfunction.

Activation of the NLRP3 inflammasome induces vascular dysfunction in obese OLETF rats

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Liu, Penghao [State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension and Department of Hypertension, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai (China); Xie, Qihai [Department of Cardiology, Shanghai Jiading District Central Hospital, Shanghai (China); Wei, Tong [State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension and Department of Hypertension, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai (China); Chen, Yichen [Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, Shanghai (China); Chen, Hong, E-mail: hchen100@shsmu.edu.cn [Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, Shanghai (China); Shen, Weili, E-mail: wlshen@sibs.ac.cn [State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension and Department of Hypertension, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai (China)

2015-12-04

Objective: Obesity-induced vascular dysfunction is related to chronic low-grade systemic inflammation. Recent studies indicate that NLRP3, a multiprotein complex formed by NOD-like receptor (NLR) family members, is a key component mediating internal sterile inflammation, but the role in obesity-related vascular dysfunction is largely unknown. In the present study, we investigate whether NLRP3 activation is involved in vascular inflammation in obese Otsuka Long-Evans Tokushima Fatty rats (OLETF). Methods and results: Male OLETF with their control Long-Evans Tokushima Otsuka rats (LETO) were studied at 3 and 12 months of age. Aortic relaxation in response to acetylcholine decreased gradually with age in both strains, with early and persistent endothelium dysfunction in obese OLETF compared with age-matched LETO controls. These changes are associated with parallel changes of aortic endothelial nitric oxide synthase (eNOS) content, macrophage accumulation and intimal thickening. NLRP3 increased in OLETF rats compared to LETO. Consistent with inflammasome activation, the conversion of procaspase-1 to cleaved and activated forms as well as IL-1β markedly increased in OLETF rats. Additionally, we observed increased expression of dynamin-related protein-1 (Drp1) and decreased fusion-relative protein optic atropy-1(OPA1). Altered mitochondrial dynamics was associated with elevated oxidative stress level in OLETF aortas. Conclusions: These results demonstrate that obesity seems to accelerate endothelial dysfunction in OLETFs via the activation of NLRP3 and mitochondrial dysfunction. - Highlights: • NLRP3 is involved in obesity-induced vascular dysfunction. • Impaired mitochondrial dynamics may have been linked to mitochondrial defect and inflammasome activation. • Obesity seems to accelerate vascular dysfunction via NLRP3 activation and mitochondrial dysfunction.

Mitochondria-Targeted Antioxidant Prevents Cardiac Dysfunction Induced by Tafazzin Gene Knockdown in Cardiac Myocytes

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Quan He

2014-01-01

Full Text Available Tafazzin, a mitochondrial acyltransferase, plays an important role in cardiolipin side chain remodeling. Previous studies have shown that dysfunction of tafazzin reduces cardiolipin content, impairs mitochondrial function, and causes dilated cardiomyopathy in Barth syndrome. Reactive oxygen species (ROS have been implicated in the development of cardiomyopathy and are also the obligated byproducts of mitochondria. We hypothesized that tafazzin knockdown increases ROS production from mitochondria, and a mitochondria-targeted antioxidant prevents tafazzin knockdown induced mitochondrial and cardiac dysfunction. We employed cardiac myocytes transduced with an adenovirus containing tafazzin shRNA as a model to investigate the effects of the mitochondrial antioxidant, mito-Tempo. Knocking down tafazzin decreased steady state levels of cardiolipin and increased mitochondrial ROS. Treatment of cardiac myocytes with mito-Tempo normalized tafazzin knockdown enhanced mitochondrial ROS production and cellular ATP decline. Mito-Tempo also significantly abrogated tafazzin knockdown induced cardiac hypertrophy, contractile dysfunction, and cell death. We conclude that mitochondria-targeted antioxidant prevents cardiac dysfunction induced by tafazzin gene knockdown in cardiac myocytes and suggest mito-Tempo as a potential therapeutic for Barth syndrome and other dilated cardiomyopathies resulting from mitochondrial oxidative stress.

[Hydroxyurea (hydroxycarbamide)-induced hepatic dysfunction confirmed by drug-induced lymphocyte stimulation test].

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Shimizu, Takayuki; Mori, Takehiko; Karigane, Daiki; Kikuchi, Taku; Koda, Yuya; Toyama, Takaaki; Nakajima, Hideaki; Okamoto, Shinichiro

2014-01-01

A 62-year-old man with refractory leukemia transformed from myelodysplastic syndrome was placed on hydroxyurea (hydroxycarbamide) at a daily dose of 500 mg. Because of insufficient cytoreductive efficacy, the dose was increased to 1,500 mg five days later. Eight days after the initiation of hydroxyurea, the patient started complaining of chills, fever, and vomiting. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were markedly elevated to 5,098 and 3,880 IU/l from 44 and 59 IU/l in one day, respectively. Tests for hepatitis viruses were all negative. With the discontinuation of hydroxyurea, AST and ALT returned to their former levels within two weeks. A drug-induced lymphocyte stimulation test for hydroxyurea was positive with a stimulating index of 2.0. Hepatic dysfunction has been recognized as one of the side effects of hydroxyurea. However, there have been only a limited number of reports demonstrating drug allergy to have a role in hepatic dysfunction accompanied by fever and gastrointestinal symptoms. The findings of our case strongly suggest that all presentations could be explained by drug allergy. Physicians should be mindful of the potential for acute and severe hepatic dysfunction due to allergic reaction against hydroxyurea.

MicroRNAs in Hyperglycemia Induced Endothelial Cell Dysfunction

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Maskomani Silambarasan

2016-04-01

Full Text Available Hyperglycemia is closely associated with prediabetes and Type 2 Diabetes Mellitus. Hyperglycemia increases the risk of vascular complications such as diabetic retinopathy, diabetic nephropathy, peripheral vascular disease and cerebro/cardiovascular diseases. Under hyperglycemic conditions, the endothelial cells become dysfunctional. In this study, we investigated the miRNA expression changes in human umbilical vein endothelial cells exposed to different glucose concentrations (5, 10, 25 and 40 mM glucose and at various time intervals (6, 12, 24 and 48 h. miRNA microarray analyses showed that there is a correlation between hyperglycemia induced endothelial dysfunction and miRNA expression. In silico pathways analyses on the altered miRNA expression showed that the majority of the affected biological pathways appeared to be associated to endothelial cell dysfunction and apoptosis. We found the expression of ten miRNAs (miR-26a-5p, -26b-5p, 29b-3p, -29c-3p, -125b-1-3p, -130b-3p, -140-5p, -192-5p, -221-3p and -320a to increase gradually with increasing concentration of glucose. These miRNAs were also found to be involved in endothelial dysfunction. At least seven of them, miR-29b-3p, -29c-3p, -125b-1-3p, -130b-3p, -221-3p, -320a and -192-5p, can be correlated to endothelial cell apoptosis.

Benfotiamine Counteracts Smoking-Induced Vascular Dysfunction in Healthy Smokers

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Alin Stirban

2012-01-01

Full Text Available Background. Smoking induces endothelial dysfunction (ED mainly by exacerbating oxidative stress (OS and inflammation. Benfotiamine, a thiamine prodrug with high bioavailability, prevents nicotine-induced vascular dysfunction in rats. It remained unknown whether this effect also occurs in humans. Methods. Therefore, 20 healthy volunteers (mean age: 38 years were investigated twice, 7–10 days apart in a randomized, cross-over, and investigator-blinded design. Vascular function was assessed by flow-mediated vasodilatation (FMD of the brachial artery and by measurements of the soluble vascular cell adhesion molecule (sVCAM-1. Investigations were performed after an overnight fast as well as 20 minutes after one cigarette smoking. On another day, the same procedure was applied following a 3-day oral therapy with benfotiamine (1050 mg/day. Ten patients were randomized to start with smoking alone, and ten started with benfotiamine. Results. Results are expressed as (mean ± SEM. Smoking acutely induced a decrease in FMD by 50% (∗∗P<0.001 versus baseline an effect significantly reduced by benfotiamine treatment to 25%∗§ (∗P<0.05 versus baseline, §P<0.05 versus smoking alone. Smoking-induced elevation in sVCAM-1 was also prevented by benfotiamine. The endothelium-independent vasodilatation remained unaltered between days. Conclusion. In healthy volunteers, smoking blunts vascular function mirrored by a decrease in FMD and an increase in sVCAM-1. Short-term treatment with benfotiamine significantly reduces these effects, showing protective vascular properties.

Myeloperoxidase-derived oxidants induce blood-brain barrier dysfunction in vitro and in vivo.

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Andreas Üllen

Full Text Available Peripheral leukocytes can exacerbate brain damage by release of cytotoxic mediators that disrupt blood-brain barrier (BBB function. One of the oxidants released by activated leukocytes is hypochlorous acid (HOCl formed via the myeloperoxidase (MPO-H2O2-Cl(- system. In the present study we examined the role of leukocyte activation, leukocyte-derived MPO and MPO-generated oxidants on BBB function in vitro and in vivo. In a mouse model of lipopolysaccharide (LPS-induced systemic inflammation, neutrophils that had become adherent released MPO into the cerebrovasculature. In vivo, LPS-induced BBB dysfunction was significantly lower in MPO-deficient mice as compared to wild-type littermates. Both, fMLP-activated leukocytes and the MPO-H2O2-Cl(- system inflicted barrier dysfunction of primary brain microvascular endothelial cells (BMVEC that was partially rescued with the MPO inhibitor 4-aminobenzoic acid hydrazide. BMVEC treatment with the MPO-H2O2-Cl(- system or activated neutrophils resulted in the formation of plasmalogen-derived chlorinated fatty aldehydes. 2-chlorohexadecanal (2-ClHDA severely compromised BMVEC barrier function and induced morphological alterations in tight and adherens junctions. In situ perfusion of rat brain with 2-ClHDA increased BBB permeability in vivo. 2-ClHDA potently activated the MAPK cascade at physiological concentrations. An ERK1/2 and JNK antagonist (PD098059 and SP600125, respectively protected against 2-ClHDA-induced barrier dysfunction in vitro. The current data provide evidence that interference with the MPO pathway could protect against BBB dysfunction under (neuroinflammatory conditions.

Stage-to-stage progression of chronic kidney disease in renal transplantation with chronic allograft dysfunction

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Khalkhali H

2009-11-01

Full Text Available "n Normal 0 false false false EN-US X-NONE AR-SA MicrosoftInternetExplorer4 /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-qformat:yes; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"Times New Roman"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:Arial; mso-bidi-theme-font:minor-bidi;} Background: Although the short-term results of kidney transplantation have improved greatly during the past decades, the long-term results have not improved according. Graft loss due to chronic allograft dysfunction (CAD is a major concern in renal transplant recipients (RTRs. There is little data about disease progression in this patient population. In this paper, we investigated history of kidney function as the pattern, waiting time and rate of pass from intermediate stages in RTR with CAD."n"nMethods: In a single-center retrospective study, 214 RTRs with CAD investigated at the Urmia University Hospital urmia, Iran from 1997 to 2005. Kidney function at each visit assessed with GFR. We apply NKF and K/DOQI classification of chronic kidney disease (CKD staging system to determine pattern of disease progression per stage in this group of patients. "n"nResults: The pure death-censored graft loss was 26% with mean waiting time 81.7 months. 100% of RTRs passed from stage I to II in mean waiting time 26.3 months. The probability of prognostic factors transition from stage II to III was 88.9% with mean waiting time 25.5 months, transition from III to IV was 55.7% with mean waiting time of 24.9 months and transition for

Diglycolic acid, the toxic metabolite of diethylene glycol, chelates calcium and produces renal mitochondrial dysfunction in vitro.

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Conrad, Taylor; Landry, Greg M; Aw, Tak Yee; Nichols, Royce; McMartin, Kenneth E

2016-07-01

Diethylene glycol (DEG) has caused many cases of acute kidney injury and deaths worldwide. Diglycolic acid (DGA) is the metabolite responsible for the renal toxicity, but its toxic mechanism remains unclear. To characterize the mitochondrial dysfunction produced from DGA by examining several mitochondrial processes potentially contributing to renal cell toxicity. The effect of DGA on mitochondrial membrane potential was examined in normal human proximal tubule (HPT) cells. Isolated rat kidney mitochondria were used to assess the effects of DGA on mitochondrial function, including respiratory parameters (States 3 and 4), electron transport chain complex activities and calcium-induced opening of the mitochondrial permeability transition pore. DGA was compared with ethylene glycol tetraacetic acid (EGTA) to determine calcium chelating ability. DGA cytotoxicity was assessed using lactate dehydrogenase leakage from cultured proximal tubule cells. DGA decreased the mitochondrial membrane potential in HPT cells. In rat kidney mitochondria, DGA decreased State 3 respiration, but did not affect State 4 respiration or the ADP/O ratio. DGA reduced glutamate/malate respiration at lower DGA concentrations (0.5 mmol/L) than succinate respiration (100 mmol/L). DGA inhibited Complex II activity without altering Complex I, III or IV activities. DGA blocked calcium-induced mitochondrial swelling, indicating inhibition of the calcium-dependent mitochondrial permeability transition. DGA and EGTA reduced the free calcium concentration in solution in an equimolar manner. DGA toxicity and mitochondrial dysfunction occurred as similar concentrations. DGA inhibited mitochondrial respiration, but without uncoupling oxidative phosphorylation. The more potent effect of DGA on glutamate/malate respiration and the inhibition of mitochondrial swelling was likely due to its chelation of calcium. These results indicate that DGA produces mitochondrial dysfunction by chelating calcium to

Long-Term Outcomes of Renal Transplant in Recipients With Lower Urinary Tract Dysfunction.

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Wilson, Rebekah S; Courtney, Aisling E; Ko, Dicken S C; Maxwell, Alexander P; McDaid, James

2018-01-02

Lower urinary tract dysfunction can lead to chronic kidney disease, which, despite surgical intervention, will progress to end-stage renal disease, requiring dialysis. Urologic pathology may damage a transplanted kidney, limiting patient and graft survival. Although smaller studies have suggested that urinary tract dysfunction does not affect graft or patient survival, this is not universally accepted. Northern Ireland has historically had the highest incidence of neural tube defects in Europe, giving rich local experience in caring for patients with lower urinary tract dysfunction. Here, we analyzed outcomes of renal transplant recipients with lower urinary tract dysfunction versus control recipients. We identified 3 groups of kidney transplant recipients treated between 2001 and 2010; those in group 1 had end-stage renal disease due to lower urinary tract dysfunction with prior intervention (urologic surgery, long-term catheter, or intermittent self-catheterization), group 2 had end-stage renal disease secondary to lower urinary tract dysfunction without intervention, and group 3 had end-stage renal disease due to polycystic kidney disease (chosen as a relatively healthy control cohort without comorbid burden of other causes of end-stage renal disease such as diabetes). The primary outcome measured, graft survival, was death censored, with graft loss defined as requirement for renal replacement therapy or retransplant. Secondary outcomes included patient survival and graft function. In 150 study patients (16 patients in group 1, 64 in group 2, and 70 in group 3), 5-year death-censored graft survival was 93.75%, 90.6%, and 92.9%, respectively, with no significant differences in graft failure among groups (Cox proportional hazards model). Five-year patient survival was 100%, 100%, and 94.3%, respectively. Individuals with a history of lower urinary tract dysfunction had graft and patient survival rates similar to the control group. When appropriately treated, lower

Flavocoxid, a Natural Antioxidant, Protects Mouse Kidney from Cadmium-Induced Toxicity

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Antonio Micali

2018-01-01

Full Text Available Background. Cadmium (Cd, a diffused environmental pollutant, has adverse effects on urinary apparatus. The role of flavocoxid, a natural flavonoid with antioxidant activity, on the morphological and biochemical changes induced in vivo by Cd in mice kidney was evaluated. Methods. C57 BL/6J mice received 0.9% NaCl alone, flavocoxid (20 mg/kg/day i.p. alone, Cd chloride (CdCl2 (2 mg/kg/day i.p. alone, or CdCl2 plus flavocoxid (2 mg/kg/day i.p. plus 20 mg/kg/day i.p. for 14 days. The kidneys were processed for biochemical, structural, ultrastructural, and morphometric evaluation. Results. Cd treatment alone significantly increased urea nitrogen and creatinine, iNOS, MMP-9, and pERK 1/2 expression and protein carbonyl; reduced GSH, GR, and GPx; and induced structural and ultrastructural changes in the glomeruli and in the tubular epithelium. After 14 days of treatment, flavocoxid administration reduced urea nitrogen and creatinine, iNOS, MMP-9, and pERK 1/2 expression and protein carbonyl; increased GSH, GR, and GPx; and showed an evident preservation of the glomerular and tubular structure and ultrastructure. Conclusions. A protective role of flavocoxid against Cd-induced oxidative damages in mouse kidney was demonstrated for the first time. Flavocoxid may have a promising antioxidant role against environmental Cd harmful effects on glomerular and tubular lesions.

An analysis of respiratory induced kidney motion on four-dimensional computed tomography and its implications for stereotactic kidney radiotherapy

International Nuclear Information System (INIS)

Siva, Shankar; Pham, Daniel; Gill, Suki; Bressel, Mathias; Dang, Kim; Devereux, Thomas; Kron, Tomas; Foroudi, Farshad

2013-01-01

Stereotactic ablative body radiotherapy (SABR) is an emerging treatment modality for primary renal cell carcinoma. To account for respiratory-induced target motion, an internal target volume (ITV) concept is often used in treatment planning of SABR. The purpose of this study is to assess patterns of kidney motion and investigate potential surrogates of kidney displacement with the view of ITV verification during treatment. Datasets from 71 consecutive patients with free breathing four-dimensional computed tomography (4DCT) planning scans were included in this study. The displacement of the left and right hemi-diaphragm, liver dome and abdominal wall were measured and tested for correlation with the displacement of the both kidneys and patient breathing frequency. Nine patients were excluded due to severe banding artifact. Of 62 evaluable patients, the median age was 68 years, with 41 male patients and 21 female patients. The mean (range) of the maximum, minimum and average breathing frequency throughout the 4DCTs were 20.1 (11–38), 15.1 (9–24) and 17.3 (9–27.5) breaths per minute, respectively. The mean (interquartile range) displacement of the left and right kidneys was 0.74 cm (0.45-0.98 cm) and 0.75 cm (0.49-0.97) respectively. The amplitude of liver-dome motion was correlated with right kidney displacement (r=0.52, p<0.001), but not with left kidney displacement (p=0.796). There was a statistically significant correlation between the magnitude of right kidney displacement and that of abdominal displacement (r=0.36, p=0.004), but not the left kidney (r=0.24, p=0.056). Hemi-diaphragm displacements were correlated with kidney displacements respectively, with a weaker correlation for the left kidney/left diaphragm (r=0.45, [95% CI 0.22 to 0.63], p=<0.001) than for the right kidney/right diaphragm (r=0.57, [95% CI 0.37 to 0.72], p=<0.001). For the majority of patients, maximal left and right kidney displacement is subcentimeter in magnitude. The magnitude of

Mechanism of Platinum Derivatives Induced Kidney Injury

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Feifei YAN

2015-09-01

Full Text Available Platinum derivatives are the most widely used chemotherapeutic agents to treat solid tumors including ovarian, head and neck, and testicular germ cell tumors, lung cancer, and colorectal cancer. Two major problems exist, however, in the clinic use of platinum derivatives. One is the development of tumor resistance to the drug during therapy, leading to treatment failure. The other is the drug’s toxicity such as the cisplatin’s nephrotoxicity, which limits the dose that can be administered. This paper describes the mechanism of platinum derivatives induced kidney injury.

Manifestations of Renal Impairment in Fructose-induced Metabolic Syndrome.

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Bratoeva, Kameliya; Stoyanov, George S; Merdzhanova, Albena; Radanova, Mariya

2017-11-07

Introduction International studies show an increased incidence of chronic kidney disease (CKD) in patients with metabolic syndrome (MS). It is assumed that the major components of MS - obesity, insulin resistance, dyslipidemia, and hypertension - are linked to renal damage through the systemic release of several pro-inflammatory mediators, such as uric acid (UA), C-reactive protein (CRP), and generalized oxidative stress. The aim of the present study was to investigate the extent of kidney impairment and manifestations of dysfunction in rats with fructose-induced MS. Methods We used a model of high-fructose diet in male Wistar rats with 35% glucose-fructose corn syrup in drinking water over a duration of 16 weeks. The experimental animals were divided into two groups: control and high-fructose drinking (HFD). Serum samples were obtained from both groups for laboratory study, and the kidneys were extracted for observation via light microscopy examination. Results All HFD rats developed obesity, hyperglycemia, hypertriglyceridemia, increased levels of CRP and UA (when compared to the control group), and oxidative stress with high levels of malondialdehyde and low levels of reduced glutathione. The kidneys of the HFD group revealed a significant increase in kidney weight in the absence of evidence of renal dysfunction and electrolyte disturbances. Under light microscopy, the kidneys of the HFD group revealed amyloid deposits in Kimmelstiel-Wilson-like nodules and the walls of the large caliber blood vessels, early-stage atherosclerosis with visible ruptures and scarring, hydropic change (vacuolar degeneration) in the epithelial cells covering the proximal tubules, and increased eosinophilia in the distant tubules when compared to the control group. Conclusion Under the conditions of a fructose-induced metabolic syndrome, high serum UA and CRP correlate to the development of early renal disorders without a clinical manifestation of renal dysfunction. These

Mitochondrial dysfunction in lyssavirus-induced apoptosis.

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Gholami, Alireza; Kassis, Raïd; Real, Eléonore; Delmas, Olivier; Guadagnini, Stéphanie; Larrous, Florence; Obach, Dorothée; Prevost, Marie-Christine; Jacob, Yves; Bourhy, Hervé

2008-05-01

Lyssaviruses are highly neurotropic viruses associated with neuronal apoptosis. Previous observations have indicated that the matrix proteins (M) of some lyssaviruses induce strong neuronal apoptosis. However, the molecular mechanism(s) involved in this phenomenon is still unknown. We show that for Mokola virus (MOK), a lyssavirus of low pathogenicity, the M (M-MOK) targets mitochondria, disrupts the mitochondrial morphology, and induces apoptosis. Our analysis of truncated M-MOK mutants suggests that the information required for efficient mitochondrial targeting and dysfunction, as well as caspase-9 activation and apoptosis, is held between residues 46 and 110 of M-MOK. We used a yeast two-hybrid approach, a coimmunoprecipitation assay, and confocal microscopy to demonstrate that M-MOK physically associates with the subunit I of the cytochrome c (cyt-c) oxidase (CcO) of the mitochondrial respiratory chain; this is in contrast to the M of the highly pathogenic Thailand lyssavirus (M-THA). M-MOK expression induces a significant decrease in CcO activity, which is not the case with M-THA. M-MOK mutations (K77R and N81E) resulting in a similar sequence to M-THA at positions 77 and 81 annul cyt-c release and apoptosis and restore CcO activity. As expected, the reverse mutations, R77K and E81N, introduced in M-THA induce a phenotype similar to that due to M-MOK. These features indicate a novel mechanism for energy depletion during lyssavirus-induced apoptosis.

Exploring metabolic dysfunction in chronic kidney disease

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Slee Adrian D

2012-04-01

Full Text Available Abstract Impaired kidney function and chronic kidney disease (CKD leading to kidney failure and end-stage renal disease (ESRD is a serious medical condition associated with increased morbidity, mortality, and in particular cardiovascular disease (CVD risk. CKD is associated with multiple physiological and metabolic disturbances, including hypertension, dyslipidemia and the anorexia-cachexia syndrome which are linked to poor outcomes. Specific hormonal, inflammatory, and nutritional-metabolic factors may play key roles in CKD development and pathogenesis. These include raised proinflammatory cytokines, such as interleukin-1 and −6, tumor necrosis factor, altered hepatic acute phase proteins, including reduced albumin, increased C-reactive protein, and perturbations in normal anabolic hormone responses with reduced growth hormone-insulin-like growth factor-1 axis activity. Others include hyperactivation of the renin-angiotensin aldosterone system (RAAS, with angiotensin II and aldosterone implicated in hypertension and the promotion of insulin resistance, and subsequent pharmacological blockade shown to improve blood pressure, metabolic control and offer reno-protective effects. Abnormal adipocytokine levels including leptin and adiponectin may further promote the insulin resistant, and proinflammatory state in CKD. Ghrelin may be also implicated and controversial studies suggest activities may be reduced in human CKD, and may provide a rationale for administration of acyl-ghrelin. Poor vitamin D status has also been associated with patient outcome and CVD risk and may indicate a role for supplementation. Glucocorticoid activities traditionally known for their involvement in the pathogenesis of a number of disease states are increased and may be implicated in CKD-associated hypertension, insulin resistance, diabetes risk and cachexia, both directly and indirectly through effects on other systems including activation of the mineralcorticoid

Additional diagnostic value of systolic dysfunction induced by dipyridamole stress cardiac magnetic resonance used in detecting coronary artery disease.

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Husser, Oliver; Bodí, Vicente; Sanchís, Juan; Mainar, Luis; Núñez, Julio; López-Lereu, María P; Monmeneu, José V; Ruiz, Vicente; Rumiz, Eva; Moratal, David; Chorro, Francisco J; Llácer, Angel

2009-04-01

Dipyridamole stress perfusion cardiovascular magnetic resonance (CMR) is used to detect coronary artery disease (CAD). However, few data are available on the diagnostic value of the systolic dysfunction induced by dipyridamole. This study investigated whether the induction of systolic dysfunction supplements the diagnostic information provided by perfusion imaging in the detection of CAD. Overall, 166 patients underwent dipyridamole CMR and quantitative coronary angiography, with CAD being defined as a stenosis > or =70%. Systolic dysfunction at rest, systolic dysfunction with dipyridamole, induced systolic dysfunction, and stress first-pass perfussion deficit (PD) and delayed enhancement were quantified. In the multivariate analysis, PD (hazard ratio [HR]=1.6; 95% confidence interval [CI], 1.33-1.91;Pstatistic for predicting CAD (0.81 vs. 0.87; P=.02). Combining induced systolic dysfunction with perfusion imaging increases the diagnostic accuracy of detecting CAD and enables patients with severe ischemia and a high probability of CAD to be identified.

Post-infectious acute glomerulonephritis with podocytopathy induced by parvovirus B19 infection.

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Hara, Satoshi; Hirata, Masayoshi; Ito, Kiyoaki; Mizushima, Ichiro; Fujii, Hiroshi; Yamada, Kazunori; Nagata, Michio; Kawano, Mitsuhiro

2018-03-01

Human parvovirus B19 infection causes a variety of glomerular diseases such as post-infectious acute glomerulonephritis and collapsing glomerulopathy. Although each of these appears independently, it has not been fully determined why parvovirus B19 provokes such a variety of different glomerular phenotypes. Here, we report a 68-year-old Japanese man who showed endocapillary proliferative glomerulonephritis admixed with podocytopathy in association with parvovirus B19 infection. The patient showed acute onset of heavy proteinuria, microscopic hematuria and kidney dysfunction with arthralgia and oliguria after close contact with a person suffering from erythema infectiosum. In the kidney biopsy specimen, glomeruli revealed diffuse and global endocapillary infiltration of inflammatory cells, with some also showing tuft collapse with aberrant vacuolation, swelling, and hyperplasia of glomerular epithelial cells. Immunofluorescence revealed dense granular C3 deposition that resembled the "starry sky pattern". Intravenous glucocorticoid pulse therapy followed by oral prednisolone and cyclosporine combination therapy resulted in considerable amelioration of the kidney dysfunction and urinary abnormalities. The present case reveals that parvovirus B19 infection can induce different glomerular phenotypes even in the same kidney structure. This finding may provide hints useful for the further elucidation of the pathogenesis of parvovirus B19-induced glomerular lesions. © 2018 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.

Proximal Tubular Cannabinoid-1 Receptor Regulates Obesity-Induced CKD.

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Udi, Shiran; Hinden, Liad; Earley, Brian; Drori, Adi; Reuveni, Noa; Hadar, Rivka; Cinar, Resat; Nemirovski, Alina; Tam, Joseph

2017-12-01

Obesity-related structural and functional changes in the kidney develop early in the course of obesity and occur independently of hypertension, diabetes, and dyslipidemia. Activating the renal cannabinoid-1 receptor (CB 1 R) induces nephropathy, whereas CB 1 R blockade improves kidney function. Whether these effects are mediated via a specific cell type within the kidney remains unknown. Here, we show that specific deletion of CB 1 R in the renal proximal tubule cells did not protect the mice from obesity, but markedly attenuated the obesity-induced lipid accumulation in the kidney and renal dysfunction, injury, inflammation, and fibrosis. These effects associated with increased activation of liver kinase B1 and the energy sensor AMP-activated protein kinase, as well as enhanced fatty acid β -oxidation. Collectively, these findings indicate that renal proximal tubule cell CB 1 R contributes to the pathogenesis of obesity-induced renal lipotoxicity and nephropathy by regulating the liver kinase B1/AMP-activated protein kinase signaling pathway. Copyright © 2017 by the American Society of Nephrology.

Evaluation of Temporal Changes in Urine-based Metabolomic and Kidney Injury Markers to Detect Compound Induced Acute Kidney Tubular Toxicity in Beagle Dogs.

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Wagoner, M P; Yang, Y; McDuffie, J E; Klapczynski, M; Buck, W; Cheatham, L; Eisinger, D; Sace, F; Lynch, K M; Sonee, M; Ma, J-Y; Chen, Y; Marshall, K; Damour, M; Stephen, L; Dragan, Y P; Fikes, J; Snook, S; Kinter, L B

2017-01-01

Urinary protein biomarkers and metabolomic markers have been leveraged to detect acute Drug Induced Kidney Injury (DIKI) in rats; however, the utility of these indicators to enable early detection of DIKI in canine models has not been well documented. Therefore, we evaluated temporal changes in biomarkers and metabolites in urine from male and female beagle dogs. Gentamicin- induced kidney lesions in male dogs were characterized by moderate to severe tubular epithelial cell degeneration/necrosis, epithelial cell regeneration and dilation; and a unique urinebased metabolomic fingerprint. These metabolite changes included time and treatment-dependent increases in lactate, taurine, glucose, lactate, alanine, and citrate as well as 9 other known metabolites. As early as 3 days post dose, gentamicin induced increases in urinary albumin, clusterin, neutrophil gelatinase associated protein (NGAL) and total protein concentrations. Urinary albumin, clusterin, and NGAL showed earlier and more robust elevations than traditional kidney safety biomarkers, blood urea nitrogen and serum creatinine. Elevations in urinary kidney injury molecule 1 (KIM-1) were less reliable for detection of gentamicin nephrotoxicity in dogs based on values generated utilizing multiple first-generation, canine-specific KIM-1 immunoassays. The metabolic fingerprint was further evaluated in male and female dogs that received Compound A which induced slightly reversible renal tubular alterations characterized as degeneration/necrosis and concurrent significant increases in urinary taurine amongst other markers. These data support further investigations to demonstrate the value of urinary metabolites, albumin, clusterin, NGAL and taurine as promising markers to enable early detection of DIKI in dogs. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

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.

Urtica dioica extract attenuates depressive like behavior and associative memory dysfunction in dexamethasone induced diabetic mice.

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Patel, Sita Sharan; Udayabanu, Malairaman

2014-03-01

Evidences suggest that glucocorticoids results in depression and is a risk factor for type 2 diabetes. Further diabetes induces oxidative stress and hippocampal dysfunction resulting in cognitive decline. Traditionally Urtica dioica has been used for diabetes mellitus and cognitive dysfunction. The present study investigated the effect of the hydroalcoholic extract of Urtica dioica leaves (50 and 100 mg/kg, p.o.) in dexamethasone (1 mg/kg, i.m.) induced diabetes and its associated complications such as depressive like behavior and cognitive dysfunction. We observed that mice administered with chronic dexamethasone resulted in hypercortisolemia, oxidative stress, depressive like behavior, cognitive impairment, hyperglycemia with reduced body weight, increased water intake and decreased hippocampal glucose transporter-4 (GLUT4) mRNA expression. Urtica dioica significantly reduced hyperglycemia, plasma corticosterone, oxidative stress and depressive like behavior as well as improved associative memory and hippocampal GLUT4 mRNA expression comparable to rosiglitazone (5 mg/kg, p.o.). Further, Urtica dioica insignificantly improved spatial memory and serum insulin. In conclusion, Urtica dioica reversed dexamethasone induced hyperglycemia and its associated complications such as depressive like behavior and cognitive dysfunction.

Luteolin ameliorates cisplatin-induced nephrotoxicity in mice through inhibition of platinum accumulation, inflammation and apoptosis in the kidney

International Nuclear Information System (INIS)

Domitrović, Robert; Cvijanović, Olga; Pugel, Ester Pernjak; Zagorac, Gordana Blagojević; Mahmutefendić, Hana; Škoda, Marko

2013-01-01

The aim of this study was to investigate the effects of flavone luteolin against cisplatin (CP)-induced kidney injury in mice. Luteolin at doses of 10 mg/kg was administered intraperitoneally (ip) once daily for 3 days following single CP (10 or 20 mg/kg) ip injection. Mice were sacrificed 24 h after the last dose of luteolin. The CP treatment significantly increased serum creatinine and blood urea nitrogen and induced pathohistological changes in the kidneys. Renal oxidative/nitrosative stress was evidenced by decreased glutathione (GSH) levels and increased 3-nitrotyrosine (3-NT) and 4-hydroxynonenal (4-HNE) formation as well as cytochrome P450 2E1 (CYP2E1) expression. The CP administration triggered inflammatory response in mice kidneys through activation of nuclear factor-kappaB (NF-κB) and overexpression of tumor necrosis factor-alpha (TNF-α) and cyclooxygenase-2 (COX-2). Simultaneously, the increase in renal p53 and caspase-3 expression indicated apoptosis of tubular cells. The administration of luteolin significantly reduced histological and biochemical changes induced by CP, decreased platinum (Pt) levels and suppressed oxidative/nitrosative stress, inflammation and apoptosis in the kidneys. These results suggest that luteolin is an effective nephroprotective agent, with potential to reduce Pt accumulation in the kidneys and ameliorate CP-induced nephrotoxicity

Curcumin and folic acid abrogated methotrexate induced vascular endothelial dysfunction.

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Sankrityayan, Himanshu; Majumdar, Anuradha S

2016-01-01

Methotrexate, an antifolate drug widely used in rheumatoid arthritis, psoriasis, and cancer, is known to cause vascular endothelial dysfunction by causing hyperhomocysteinemia, direct injury to endothelium or by increasing the oxidative stress (raising levels of 7,8-dihydrobiopterin). Curcumin is a naturally occurring polyphenol with strong antioxidant and anti-inflammatory action and therapeutic spectra similar to that of methotrexate. This study was performed to evaluate the effects of curcumin on methotrexate induced vascular endothelial dysfunction and also compare its effect with that produced by folic acid (0.072 μg·g(-1)·day(-1), p.o., 2 weeks) per se and in combination. Male Wistar rats were exposed to methotrexate (0.35 mg·kg(-1)·day(-1), i.p.) for 2 weeks to induce endothelial dysfunction. Methotrexate exposure led to shedding of endothelium, decreased vascular reactivity, increased oxidative stress, decreased serum nitrite levels, and increase in aortic collagen deposition. Curcumin (200 mg·kg(-1)·day(-1) and 400 mg·kg(-1)·day(-1), p.o.) for 4 weeks prevented the increase in oxidative stress, decrease in serum nitrite, aortic collagen deposition, and also vascular reactivity. The effects were comparable with those produced by folic acid therapy. The study shows that curcumin, when concomitantly administered with methotrexate, abrogated its vascular side effects by preventing an increase in oxidative stress and abating any reduction in physiological nitric oxide levels.

Agonist-induced desensitization of human β3-adrenoceptors expressed in human embryonic kidney cells

NARCIS (Netherlands)

Michel-Reher, Martina B.; Michel, Martin C.

2013-01-01

β3-Adrenoceptors are resistant to agonist-induced desensitization in some cell types but susceptible in others including transfected human embryonic kidney (HEK) cells. Therefore, we have studied cellular and molecular changes involved in agonist-induced β3-adrenoceptor desensitization in HEK cells.

Histopathology of kidney induced by LICAM (C) therapy in baboons after inhalation of plutonium-tributyl phosphate complex

International Nuclear Information System (INIS)

Fritsch, P.; Lepage, M.; Duserre, C.; Metivier, H.; Gerasimo, P.

1989-01-01

The histological changes induced in baboon kidneys after administration of LICAM C and/or DTPA to remove Pu after inhalation of large doses of 239 Pu-TBP have been characterised. Treatment with LICAM C alone was most effective at removing Pu from the body but increased its retention in the kidneys. It also induced specific kidney lesions confined to the proximal tubules, i.e. vacuole formation in the basal part of the tubular cells. No vacuolar lesions were observed after treatment with DTPA alone. Combined treatment with LICAM C and DTPA was less effective than with LICAM C alone but more effective than with DTPA alone. After this combined treatment, in which the smallest cumulated dose of LICAM C was used, the kidney Pu burden decreased compared to the burden after treatment with LICAM C alone, but the specific lesions in the proximal tubules were still sometimes observed. The vacuole formation induced by LICAM C seemed to be reversible and the number of vacuoles was closely correlated with the dose of LICAM C administered. (author)

Methotrexate-induced Pancytopenia in Two Patients with Renal Dysfunction

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Yusuf OĞUZ; Tayfun EYİLETEN; Murat KARAMAN; Seyid Ahmet AY; Mahmut İlker YILMAZ

2011-01-01

Methotrexate (MTX) is cleared primarily by renal excretion. The excretion of MTX is delayed in subjects with renal dysfunction and elevated plasma MTX concentrations develop which lead to bone marrow toxicities and possible pancytopenia. In this case report, we presented two advanced age patients with MTX-induced pancytopenia. The first patient on hemodialysis was diagnosed with seronegative arthritis while the second patient with congestive heart failure was diagnosed with rheumatoid arthrit...

Somatic mutations in stilbene estrogen-induced Syrian hamster kidney tumors identified by DNA fingerprinting

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Roy Deodutta

2004-01-01

Full Text Available Abstract Kidney tumors from stilbene estrogen (diethylstilbestrol-treated Syrian hamsters were screened for somatic genetic alterations by Random Amplified Polymorphic DNA-polymerase chain-reaction (RAPD-PCR fingerprinting. Fingerprints from tumor tissue were generated by single arbitrary primers and compared with fingerprints for normal tissue from the same animal, as well as normal and tumor tissues from different animals. Sixty one of the arbitrary primers amplified 365 loci that contain approximately 476 kbp of the hamster genome. Among these amplified DNA fragments, 44 loci exhibited either qualitative or quantitative differences between the tumor tissues and normal kidney tissues. RAPD-PCR loci showing decreased and increased intensities in tumor tissue DNA relative to control DNA indicate that loci have undergone allelic losses and gains, respectively, in the stilbene estrogen-induced tumor cell genome. The presence or absence of the amplified DNA fragments indicate homozygous insertions or deletions in the kidney tumor DNA compared to the age-matched normal kidney tissue DNA. Seven of 44 mutated loci also were present in the kidney tissues adjacent to tumors (free of macroscopic tumors. The presence of mutated loci in uninvolved (non-tumor surrounding tissue adjacent to tumors from stilbene estrogen-treated hamsters suggests that these mutations occurred in the early stages of carcinogenesis. The cloning and sequencing of RAPD amplified loci revealed that one mutated locus had significant sequence similarity with the hamster Cyp1A1 gene. The results show the ability of RAPD-PCR to detect and isolate, in a single step, DNA sequences representing genetic alterations in stilbene estrogen-induced cancer cells, including losses of heterozygosity, and homozygous deletion and insertion mutations. RAPD-PCR provides an alternative molecular approach for studying cancer cytogenetics in stilbene estrogen-induced tumors in humans and experimental

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

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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.

Myeloperoxidase amplified high glucose-induced endothelial dysfunction in vasculature: Role of NADPH oxidase and hypochlorous acid.

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Tian, Rong; Ding, Yun; Peng, Yi-Yuan; Lu, Naihao

2017-03-11

Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-derived reactive oxygen species (ROS) such as superoxide and hydrogen peroxide (H 2 O 2 ), have emerged as important molecules in the pathogenesis of diabetic endothelial dysfunction. Additionally, neutrophils-derived myeloperoxidase (MPO) and MPO-catalyzed hypochlorous acid (HOCl) play important roles in the vascular injury. However, it is unknown whether MPO can use vascular-derived ROS to induce diabetic endothelial dysfunction. In the present study, we demonstrated that NADPH oxidase was the main source of ROS formation in high glucose-cultured human umbilical vein endothelial cells (HUVECs), and played a critical role in high glucose-induced endothelial dysfunction such as cell apoptosis, loss of cell viability and reduction of nitric oxide (NO). However, the addition of MPO could amplify the high glucose-induced endothelial dysfunction which was inhibited by the presence of apocynin (NADPH oxidase inhibitor), catalase (H 2 O 2 scavenger), or methionine (HOCl scavenger), demonstrating the contribution of NADPH oxidase-H 2 O 2 -MPO-HOCl pathway in the MPO/high glucose-induced vascular injury. In high glucose-incubated rat aortas, MPO also exacerbated the NADPH oxidase-induced impairment of endothelium-dependent relaxation. Consistent with these in vitro data, in diabetic rat aortas, both MPO expresion and NADPH oxidase activity were increased while the endothelial function was simultaneously impaired. The results suggested that vascular-bound MPO could amplify high glucose-induced vascular injury in diabetes. MPO-NADPH oxidase-HOCl may represent an important pathogenic pathway in diabetic vascular diseases. Copyright © 2017 Elsevier Inc. All rights reserved.

Sodium hypochlorite-induced acute kidney injury

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Brandon W Peck

2014-01-01

Full Text Available Sodium hypochlorite (bleach is commonly used as an irrigant during dental proce-dures as well as a topical antiseptic agent. Although it is generally safe when applied topically, reports of accidental injection of sodium hypochlorite into tissue have been reported. Local necrosis, pain and nerve damage have been described as a result of exposure, but sodium hypo-chlorite has never been implicated as a cause of an acute kidney injury (AKI. In this report, we describe the first case of accidental sodium hypochlorite injection into the infraorbital tissue during a dental procedure that precipitated the AKI. We speculate that oxidative species induced by sodium hypochlorite caused AKI secondary to the renal tubular injury, causing mild acute tubular necrosis.

Nephroprotective effects of Colpomenia sinuosa (Derbes & Solier against carbon tetrachloride induced kidney injury in Wistar rats

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Lekameera Ramarajan

2012-05-01

Full Text Available Objective: To establish the protective effect of seaweed Colpomenia sinuosa against carbon tetra chloride (CCl4 induced oxidative stress and resultant dysfunction of rat kidney. Methods: Seven to eight weeks old male Wistar rats (150-220g were exposed to CCl4 (1.5 ml/kg injection then treated with seaweed Colpomenia sinuosa (100 mg/kg body weight in 0.3% CMC solution. Blood was collected at the 5th day of experimental period to estimate the Total count (TC, Hemoglobin (HB, Total protein (TP, Glucose, Albumin, Cholesterol, TGL and Urea. Results: The results shows significantly decreased (P<0.01 level of TC, the cholesterol and urea levels shows significantly increased (P<0.05 in CCl4 treated groups when compared to control groups. These levels were found to be normalized by oral feeding of C. sinuosa. Then the rats were sacrificed and kidneys taken for enzyme analyses and histological examination. In the CCl4 treated group significantly increased activities in TBARS, SOD, CAT, GPX, GSH (P<0.05 when compared to control group. These increased activities were found to near normal in the CCl 4 + C. sinuosa treated group and Seaweed C. sinuosa treated alone group did not change any enzyme activity. Exposure to CCl4 resulted hydrobhic changes in epithelium and Hypercellulartity of glomerulus was seen in the CCl 4 + drug treated group. Conclusions: These results suggest that the nephroprotective effect of C. sinuosa can be attributed to its enhancing effects on antioxidant defense system and lead to prevent the damage by exposure of CCl4 toxicity.

Protective role of ginseng against gentamicin induced changes in kidney of albino mice

International Nuclear Information System (INIS)

Hafeez, M.; Saeed, F.

2011-01-01

Background: Use of gentamicin is now limited due to its toxic effects, mainly on kidney and vestibular system. Herbal products including ginseng has been reported to possess protective effects against drugs induced nephrotoxicity in experimental animals. The current investigation was designed to evaluate the effects of ginseng on gentamicin induced nephrotoxicity. Methods: Eighteen male albino mice of 6-8 weeks age, were divided into 3 groups. Group-A served as control and was given normal mouse diet; Group-B was given 80 mg/Kg/day of gentamicin intraperitoneally dissolved in 1 ml of distilled water for fifteen days. Group-C was given 80 mg/Kg/day of gentamicin intraperitoneally dissolved in 1 ml of distilled water along with 100 mg/Kg/day of ginseng orally dissolved in 1 ml of distilled water, also for fifteen days. At the end of the experiment, blood was drawn from each animal by cardiac puncture for renal function tests. Each animal was then sacrificed and kidneys removed for routine histological studies. Results: In group B, weight of the animals and kidneys decreased and there was significant increase in mean serum urea, creatinine and intraluminal diameter (p<0.001) of proximal convoluted tubules as compared to the controls (group-A). Moderate to severe necrotic and degenerative changes in proximal convoluted tubules were seen in this group. When the Ginseng and gentamicin were given together (group-C), a statistically significant improvement in the mean body and kidney weight along with improvement in renal function tests and tubular diameter were seen (p<0.001). Conclusion: It appears that Ginseng has some protective role against gentamicin induced nephrotoxicity. (author)

Protective properties of sesamin against fluoride-induced oxidative stress and apoptosis in kidney of carp (Cyprinus carpio) via JNK signaling pathway.

Science.gov (United States)

Cao, Jinling; Chen, Jianjie; Xie, Lingtian; Wang, Jundong; Feng, Cuiping; Song, Jing

2015-10-01

Sesamin, a major lignan derived from sesame seeds, has been reported to have many benefits and medicinal properties. However, its protective effects against fluoride-induced injury in kidney of fish have not been clarified. Previously we found that fluoride exposure caused damage and apoptosis in the kidneys of the common carp, Cyprinus carpio. In this study, the effects of sesamin on renal oxidative stress and apoptosis in fluoride-exposed fish were determined. The results showed that sesamin alleviated significantly fluoride-induced renal damage and apoptosis of carp in a dose-dependent manner, indicated by the histopathological examination and ultrastructural observation. Moreover, treatment with sesamin also inhibited significantly fluoride-induced remarkable enhancement of reactive oxygen species (ROS) production and oxidative stress, such as the increase of lipid peroxidation level and the depletion of intracellular reduced glutathione (GSH) level in kidney. To explore the underlying mechanisms of sesamin action, we found that activities of caspase-3 were notably inhibited by treatment with sesamin in the kidney of fluoride-exposed fish. Sesamin decreased the levels of p-JNK protein in kidney, which in turn inactivated pro-apoptotic signaling events by restoring the balance between mitochondrial pro- and anti-apoptotic Bcl-2 and Bax proteins and by decreasing the release of mitochondrial cytochrome c in kidney of fluoride-exposed fish. JNK was also involved in the mitochondrial extrinsic apoptotic pathways of sesamin effects against fluoride-induced renal injury by regulating the levels of p-c-Jun, necrosis factor-alpha (TNF-α) and Bak proteins. These findings indicated that sesamin could protect kidney against fluoride-induced apoptosis by the oxidative stress downstream-mediated change in the inactivation of JNK signaling pathway. Taken together, sesamin plays an important role in maintaining renal health and preventing kidney from toxic damage induced by

Mitochondrial Dysfunction in Chemotherapy-Induced Peripheral Neuropathy (CIPN

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Annalisa Canta

2015-06-01

Full Text Available The mitochondrial dysfunction has a critical role in several disorders including chemotherapy-induced peripheral neuropathies (CIPN. This is due to a related dysregulation of pathways involving calcium signalling, reactive oxygen species and apoptosis. Vincristine is able to affect calcium movement through the Dorsal Root Ganglia (DRG neuronal mitochondrial membrane, altering its homeostasis and leading to abnormal neuronal excitability. Paclitaxel induces the opening of the mitochondrial permeability transition pore in axons followed by mitochondrial membrane potential loss, increased reactive oxygen species generation, ATP level reduction, calcium release and mitochondrial swelling. Cisplatin and oxaliplatin form adducts with mitochondrial DNA producing inhibition of replication, disruption of transcription and morphological abnormalities within mitochondria in DRG neurons, leading to a gradual energy failure. Bortezomib is able to modify mitochondrial calcium homeostasis and mitochondrial respiratory chain. Moreover, the expression of a certain number of genes, including those controlling mitochondrial functions, was altered in patients with bortezomib-induced peripheral neuropathy.

Mitochondrial Dysfunction in Chemotherapy-Induced Peripheral Neuropathy (CIPN)

Science.gov (United States)

Canta, Annalisa; Pozzi, Eleonora; Carozzi, Valentina Alda

2015-01-01

The mitochondrial dysfunction has a critical role in several disorders including chemotherapy-induced peripheral neuropathies (CIPN). This is due to a related dysregulation of pathways involving calcium signalling, reactive oxygen species and apoptosis. Vincristine is able to affect calcium movement through the Dorsal Root Ganglia (DRG) neuronal mitochondrial membrane, altering its homeostasis and leading to abnormal neuronal excitability. Paclitaxel induces the opening of the mitochondrial permeability transition pore in axons followed by mitochondrial membrane potential loss, increased reactive oxygen species generation, ATP level reduction, calcium release and mitochondrial swelling. Cisplatin and oxaliplatin form adducts with mitochondrial DNA producing inhibition of replication, disruption of transcription and morphological abnormalities within mitochondria in DRG neurons, leading to a gradual energy failure. Bortezomib is able to modify mitochondrial calcium homeostasis and mitochondrial respiratory chain. Moreover, the expression of a certain number of genes, including those controlling mitochondrial functions, was altered in patients with bortezomib-induced peripheral neuropathy. PMID:29056658

Prevalence estimates of chronic kidney disease in Canada: results of a nationally representative survey

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Arora, Paul; Vasa, Priya; Brenner, Darren; Iglar, Karl; McFarlane, Phil; Morrison, Howard; Badawi, Alaa

2013-01-01

Background: Chronic kidney disease is an important risk factor for death and cardiovascular-related morbidity, but estimates to date of its prevalence in Canada have generally been extrapolated from the prevalence of end-stage renal disease. We used direct measures of kidney function collected from a nationally representative survey population to estimate the prevalence of chronic kidney disease among Canadian adults. Methods: We examined data for 3689 adult participants of cycle 1 of the Canadian Health Measures Survey (2007–2009) for the presence of chronic kidney disease. We also calculated the age-standardized prevalence of cardiovascular risk factors by chronic kidney disease group. We cross-tabulated the estimated glomerular filtration rate (eGFR) with albuminuria status. Results: The prevalence of chronic kidney disease during the period 2007–2009 was 12.5%, representing about 3 million Canadian adults. The estimated prevalence of stage 3–5 disease was 3.1% (0.73 million adults) and albuminuria 10.3% (2.4 million adults). The prevalence of diabetes, hypertension and hypertriglyceridemia were all significantly higher among adults with chronic kidney disease than among those without it. The prevalence of albuminuria was high, even among those whose eGFR was 90 mL/min per 1.73 m2 or greater (10.1%) and those without diabetes or hypertension (9.3%). Awareness of kidney dysfunction among adults with stage 3–5 chronic kidney disease was low (12.0%). Interpretation: The prevalence of kidney dysfunction was substantial in the survey population, including individuals without hypertension or diabetes, conditions most likely to prompt screening for kidney dysfunction. These findings highlight the potential for missed opportunities for early intervention and secondary prevention of chronic kidney disease. PMID:23649413

Direct peritoneal resuscitation improves obesity-induced hepatic dysfunction after trauma.

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Matheson, Paul J; Franklin, Glen A; Hurt, Ryan T; Downard, Cynthia D; Smith, Jason W; Garrison, Richard N

2012-04-01

The metabolic syndrome and associated fatty liver disease are thought to contribute to poor outcomes in trauma patients. Experimentally, obesity compromises liver blood flow. We sought to correlate the effect of obesity, injury severity, and liver dysfunction with trauma outcomes. We hypothesized that obesity-related liver dysfunction could be mitigated with the novel technique of adjunctive direct peritoneal resuscitation (DPR). This study has clinical and experimental arms. The clinical study was a case-controlled retrospective analysis of ICU trauma patients (n = 72 obese, n = 187 nonobese). The experimental study was a hemorrhagic shock model in obese rats to assess the effect of DPR on liver blood flow, liver function, and inflammatory mediators. In trauma patients, univariate and multivariate analyses demonstrated increasing mortality (p trauma outcomes regardless of injury severity. Obesity-related liver and renal dysfunction is aggravated by injury severity. In an obese rat model of resuscitated hemorrhagic shock, the addition of DPR abrogates trauma-induced liver, renal, and inflammatory responses. We conclude that the addition of DPR to the clinical resuscitation regimen will benefit the obese trauma patient. Published by Elsevier Inc.

Concomitant Persistent Left Superior Vena Cava and Horseshoe Kidney

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Faraz Jaffer

2015-01-01

Full Text Available Persistent left superior vena cava (PLSVC and horseshoe kidney (HSK are common congenital abnormalities; however presence of both in the same person is extremely rare. A patient with hepatitis C cirrhosis awaiting transplant presented with worsening liver dysfunction, diagnosed with acute renal failure secondary to hepatorenal syndrome, and required X-ray fluoroscopy guided tunneled venous catheter placement for hemodialysis. Review of imaging studies demonstrated coexistence of PLSVC and HSK. PLSVC in adulthood is usually incidental with the most common drainage pattern being without physiologic dysfunction. Isolated horseshoe kidney is still the most common of renal fusion anomalies; however etiology of coexistent PLSVC remains unknown.

The influence of oxazaphosphorine agents on kidney function in rats

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Łukasz Dobrek

2017-01-01

Conclusions: CP caused more advanced kidney dysfunction and some indices suggested the development of prerenal acute kidney injury. In the CP-treated group some particularly marked urinary and plasma uric acid disturbances suggested compensation of increased oxidative stress as uric acid is considered to exert also antioxidant properties.

Physiological Expression of AMPKγ2RG Mutation Causes Wolff-Parkinson-White Syndrome and Induces Kidney Injury in Mice.

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Yang, Xiaodong; Mudgett, John; Bou-About, Ghina; Champy, Marie-France; Jacobs, Hugues; Monassier, Laurent; Pavlovic, Guillaume; Sorg, Tania; Herault, Yann; Petit-Demoulière, Benoit; Lu, Ku; Feng, Wen; Wang, Hongwu; Ma, Li-Jun; Askew, Roger; Erion, Mark D; Kelley, David E; Myers, Robert W; Li, Cai; Guan, Hong-Ping

2016-11-04

Mutations of the AMP-activated kinase gamma 2 subunit (AMPKγ2), N488I (AMPKγ2 NI ) and R531G (AMPKγ2 RG ), are associated with Wolff-Parkinson-White (WPW) syndrome, a cardiac disorder characterized by ventricular pre-excitation in humans. Cardiac-specific transgenic overexpression of human AMPKγ2 NI or AMPKγ2 RG leads to constitutive AMPK activation and the WPW phenotype in mice. However, overexpression of these mutant proteins also caused profound, non-physiological increase in cardiac glycogen, which might abnormally alter the true phenotype. To investigate whether physiological levels of AMPKγ2 NI or AMPKγ2 RG mutation cause WPW syndrome and metabolic changes in other organs, we generated two knock-in mouse lines on the C57BL/6N background harboring mutations of human AMPKγ2 NI and AMPKγ2 RG , respectively. Similar to the reported phenotypes of mice overexpressing AMPKγ2 NI or AMPKγ2 RG in the heart, both lines developed WPW syndrome and cardiac hypertrophy; however, these effects were independent of cardiac glycogen accumulation. Compared with AMPKγ2 WT mice, AMPKγ2 NI and AMPKγ2 RG mice exhibited reduced body weight, fat mass, and liver steatosis when fed with a high fat diet (HFD). Surprisingly, AMPKγ2 RG but not AMPKγ2 NI mice fed with an HFD exhibited severe kidney injury characterized by glycogen accumulation, inflammation, apoptosis, cyst formation, and impaired renal function. These results demonstrate that expression of AMPKγ2 NI and AMPKγ2 RG mutations at physiological levels can induce beneficial metabolic effects but that this is accompanied by WPW syndrome. Our data also reveal an unexpected effect of AMPKγ2 RG in the kidney, linking lifelong constitutive activation of AMPK to a potential risk for kidney dysfunction in the context of an HFD. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Physiological Expression of AMPKγ2RG Mutation Causes Wolff-Parkinson-White Syndrome and Induces Kidney Injury in Mice*

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Yang, Xiaodong; Mudgett, John; Bou-About, Ghina; Champy, Marie-France; Jacobs, Hugues; Monassier, Laurent; Pavlovic, Guillaume; Sorg, Tania; Herault, Yann; Petit-Demoulière, Benoit; Lu, Ku; Feng, Wen; Wang, Hongwu; Ma, Li-Jun; Askew, Roger; Erion, Mark D.; Kelley, David E.; Myers, Robert W.; Li, Cai

2016-01-01

Mutations of the AMP-activated kinase gamma 2 subunit (AMPKγ2), N488I (AMPKγ2NI) and R531G (AMPKγ2RG), are associated with Wolff-Parkinson-White (WPW) syndrome, a cardiac disorder characterized by ventricular pre-excitation in humans. Cardiac-specific transgenic overexpression of human AMPKγ2NI or AMPKγ2RG leads to constitutive AMPK activation and the WPW phenotype in mice. However, overexpression of these mutant proteins also caused profound, non-physiological increase in cardiac glycogen, which might abnormally alter the true phenotype. To investigate whether physiological levels of AMPKγ2NI or AMPKγ2RG mutation cause WPW syndrome and metabolic changes in other organs, we generated two knock-in mouse lines on the C57BL/6N background harboring mutations of human AMPKγ2NI and AMPKγ2RG, respectively. Similar to the reported phenotypes of mice overexpressing AMPKγ2NI or AMPKγ2RG in the heart, both lines developed WPW syndrome and cardiac hypertrophy; however, these effects were independent of cardiac glycogen accumulation. Compared with AMPKγ2WT mice, AMPKγ2NI and AMPKγ2RG mice exhibited reduced body weight, fat mass, and liver steatosis when fed with a high fat diet (HFD). Surprisingly, AMPKγ2RG but not AMPKγ2NI mice fed with an HFD exhibited severe kidney injury characterized by glycogen accumulation, inflammation, apoptosis, cyst formation, and impaired renal function. These results demonstrate that expression of AMPKγ2NI and AMPKγ2RG mutations at physiological levels can induce beneficial metabolic effects but that this is accompanied by WPW syndrome. Our data also reveal an unexpected effect of AMPKγ2RG in the kidney, linking lifelong constitutive activation of AMPK to a potential risk for kidney dysfunction in the context of an HFD. PMID:27621313

Tumor-Induced CD8+ T-Cell Dysfunction in Lung Cancer Patients

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Heriberto Prado-Garcia

2012-01-01

Full Text Available Lung cancer is the leading cause of cancer deaths worldwide and one of the most common types of cancers. The limited success of chemotherapy and radiotherapy regimes have highlighted the need to develop new therapies like antitumor immunotherapy. CD8+ T-cells represent a major arm of the cell-mediated anti-tumor response and a promising target for developing T-cell-based immunotherapies against lung cancer. Lung tumors, however, have been considered to possess poor immunogenicity; even so, lung tumor-specific CD8+ T-cell clones can be established that possess cytotoxicity against autologous tumor cells. This paper will focus on the alterations induced in CD8+ T-cells by lung cancer. Although memory CD8+ T-cells infiltrate lung tumors, in both tumor-infiltrating lymphocytes (TILs and malignant pleural effusions, these cells are dysfunctional and the effector subset is reduced. We propose that chronic presence of lung tumors induces dysfunctions in CD8+ T-cells and sensitizes them to activation-induced cell death, which may be associated with the poor clinical responses observed in immunotherapeutic trials. Getting a deeper knowledge of the evasion mechanisms lung cancer induce in CD8+ T-cells should lead to further understanding of lung cancer biology, overcome tumor evasion mechanisms, and design improved immunotherapeutic treatments for lung cancer.

MALATHION INDUCED HISTOLOGICAL MODIFICATIONS IN GILLS AND KIDNEY OF CARASSIUS AURATUS GIBELIO

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ANDREA CRISTINA STAICU

2008-05-01

Full Text Available Malathion is an organophosphorous insecticide, used in agriculture and a possible source of environmental poisoning. During malathion metabolization, mitochondria generates reactive oxygen species, responsible for significant structural changes. In this study, gills and kidney histological changes in Carassius auratus gibelio exposed to 0.05 mg/l malathion were investigated. In kidney, the effects were dramatic. The 24 -72 hours exposure to malathion induced cytoplasm vacuolization and changes in cell and nuclear volumes. In addition, necrotic renal tubules appeared, nuclear malformations of epithelial cells, anisokary, nuclei pycnosis and nuclei hypertrophy, were noticed. Epithelial ruptures, secondary lamellae fusion and hyperplasia of branchial epithelium, vascular congestion were the main changes noticed soon after pollutant exposure. We suggest that structural changes in gill and kidney could be used as good response to aquatic pollution with organophosphorous insecticides.

Resveratrol attenuates methylglyoxal-induced mitochondrial dysfunction and apoptosis by Sestrin2 induction

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Seo, Kyuhwa; Seo, Suho; Han, Jae Yun; Ki, Sung Hwan; Shin, Sang Mi, E-mail: smshin@chosun.ac.kr

2014-10-15

Methylglyoxal is found in high levels in the blood and other tissues of diabetic patients and exerts deleterious effects on cells and tissues. Previously, we reported that resveratrol, a polyphenol in grapes, induced the expression of Sestrin2 (SESN2), a novel antioxidant protein, and inhibited hepatic lipogenesis. This study investigated whether resveratrol protects cells from the methylglyoxal-induced toxicity via SESN2 induction. Methylglyoxal significantly induced cell death in HepG2 cells. However, cells pretreated with resveratrol were rescued from methylglyoxal-induced apoptosis. Resveratrol attenuated glutathione (GSH) depletion and ROS production promoted by methylglyoxal. Moreover, mitochondrial damage was observed by methylglyoxal treatment, but resveratrol restored mitochondrial function, as evidenced by the observed lack of mitochondrial permeability transition and increased ADP/ATP ratio. Resveratrol treatment inhibited SESN2 depletion elicited by methylglyoxal. SESN2 overexpression repressed methylglyoxal-induced mitochondrial dysfunction and apoptosis. Likewise, rotenone-induced cytotoxicity was not observed in SESN2 overexpressed cells. Furthermore, siRNA knockdown of SESN2 reduced the ability of resveratrol to prevent methylglyoxal-induced mitochondrial permeability transition. In addition, when mice were exposed to methylglyoxal after infection of Ad-SESN2, the plasma levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and GSH depletion by methylglyoxal in liver was reduced in Ad-SESN2 infected mice. Our results demonstrated that resveratrol is capable of protecting cells from methylglyoxal-induced mitochondrial dysfunction and oxidative stress via SESN2 induction. - Highlights: • Resveratrol decreased methylglyoxal-induced apoptosis. • Resveratrol attenuated GSH depletion and ROS production promoted by methylglyoxal. • Resveratrol restored the mitochondrial function by Sestrin2 induction. • Induction of Sestrin2

Resveratrol attenuates methylglyoxal-induced mitochondrial dysfunction and apoptosis by Sestrin2 induction

International Nuclear Information System (INIS)

Seo, Kyuhwa; Seo, Suho; Han, Jae Yun; Ki, Sung Hwan; Shin, Sang Mi

2014-01-01

Methylglyoxal is found in high levels in the blood and other tissues of diabetic patients and exerts deleterious effects on cells and tissues. Previously, we reported that resveratrol, a polyphenol in grapes, induced the expression of Sestrin2 (SESN2), a novel antioxidant protein, and inhibited hepatic lipogenesis. This study investigated whether resveratrol protects cells from the methylglyoxal-induced toxicity via SESN2 induction. Methylglyoxal significantly induced cell death in HepG2 cells. However, cells pretreated with resveratrol were rescued from methylglyoxal-induced apoptosis. Resveratrol attenuated glutathione (GSH) depletion and ROS production promoted by methylglyoxal. Moreover, mitochondrial damage was observed by methylglyoxal treatment, but resveratrol restored mitochondrial function, as evidenced by the observed lack of mitochondrial permeability transition and increased ADP/ATP ratio. Resveratrol treatment inhibited SESN2 depletion elicited by methylglyoxal. SESN2 overexpression repressed methylglyoxal-induced mitochondrial dysfunction and apoptosis. Likewise, rotenone-induced cytotoxicity was not observed in SESN2 overexpressed cells. Furthermore, siRNA knockdown of SESN2 reduced the ability of resveratrol to prevent methylglyoxal-induced mitochondrial permeability transition. In addition, when mice were exposed to methylglyoxal after infection of Ad-SESN2, the plasma levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and GSH depletion by methylglyoxal in liver was reduced in Ad-SESN2 infected mice. Our results demonstrated that resveratrol is capable of protecting cells from methylglyoxal-induced mitochondrial dysfunction and oxidative stress via SESN2 induction. - Highlights: • Resveratrol decreased methylglyoxal-induced apoptosis. • Resveratrol attenuated GSH depletion and ROS production promoted by methylglyoxal. • Resveratrol restored the mitochondrial function by Sestrin2 induction. • Induction of Sestrin2

Use of unripe plantain (Musa paradisiaca) in the management of diabetes and hepatic dysfunction in streptozotocin induced diabetes in rats.

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Eleazu, Chinedum O; Okafor, Polycarp

2015-03-01

This study aims to investigate the effect of unripe plantain (Musa paradisiaca) on markers of hepatic dysfunction in streptozotocin induced diabetic rats. Blood glucose; relative liver weight (RLW); relative kidney weight (RKW); relative heart weight (RHW); relative pancreatic weight (RPW); serum and hepatic serum aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP); serum amylase, lipase, total, and conjugated bilirubin; and chemical analysis of the test feed were determined using standard techniques. The diabetic rats had significant alteration (P 0.05) in the RHW of the rats in the three groups, as well as significant decreases (P 0.05) in the amylase levels of the rats fed unripe plantain compared with the nondiabetic rats. The test and standard rat feeds contained considerable amount of proteins, carbohydrates, fats, phenols, and crude fiber. Amelioration of acute pancreatitis by unripe plantain could play a key role in its management of diabetes and related complications.

Nitrite-induced acute kidney injury with secondary hyperparathyroidism: Case report and literature review.

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Peng, Tao; Hu, Zhao; Yang, Xiangdong; Gao, Yanxia; Ma, Chengjun

2018-02-01

Acute kidney injury (AKI) with hyperparathyroidism caused by nitrite was rare, and renal function and parathyroid hormone (PTH) decreased to normal range after therapy. Acute kidney injury was diagnosed in a 40-year-old male with hyperparathyroidism and cyanosis of his hands and both forearms. The patient ate some recently pickled vegetables, and he experienced nausea, vomiting and diarrhoea without oliguria or anuria; Additionally, his hands and both forearms had a typical blue ash appearance. After admission, the laboratory findings indicated theincreasing serum creatinine (Scr) and parathyroid hormone (PTH). He was diagnosed as acute kidney injury with hyperparathyroidism caused by nitrite. The patient stopped eating the pickled vegetables and was given rehydration, added calories and other supportive therapy without any glucocorticoids. According to his clinical manifestations, laboratory findings and imaging results, the patient was diagnosed with acute kidney injury with secondary hyperparathyroidism. He was given symptomatic supportive care therapy. After one week, the serum creatinine, parathyroid hormone (PTH), hypercalcemia, hyperphosphatemia, proteinuria, and urine red blood cell values decreased to normal range. Nitrite-induced acute kidney injury with secondary hyperparathyroidism was relatively rare. After therapy, the function of the kidney and parathyroid returned to normal. This case suggests that detailed collection of medical history, physical examination and correct symptomatic treatment is very important.

Thyroid function, reduced kidney function and incident chronic kidney disease in a community-based population: the Atherosclerosis Risk in Communities study.

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Schultheiss, Ulla T; Daya, Natalie; Grams, Morgan E; Seufert, Jochen; Steffes, Michael; Coresh, Josef; Selvin, Elizabeth; Köttgen, Anna

2017-11-01

Reduced kidney function is a common public health problem that increases risk for a wide variety of adverse outcomes, making the identification of potentially modifiable factors associated with the development of incident chronic kidney disease (CKD) important. Alterations in the hypothalamic-pituitary-thyroid axis have been linked to reduced kidney function, but the association of thyroid function with the development of incident CKD is largely uncharacterized. Concentrations of thyroid stimulating hormone (TSH), free thyroxine (FT4), triiodothyronine (T3) and thyroid peroxidase antibody (TPOAb) were quantified in 12 785 black and white participants of the ongoing community-based prospective Atherosclerosis Risk in Communities study. Thyroid markers and clinical categories of thyroid dysfunction (euthyroidism, combined subclinical and overt hypothyroidism, combined subclinical and overt hyperthyroidism) were also evaluated for their association with reduced kidney function (estimated glomerular filtration rate kidney function at study baseline. The clinical entities hypothyroidism and hyperthyroidism were also associated with higher odds of baseline reduced kidney function, but this was not significant. However, none of the markers of thyroid function nor different clinical categories of thyroid dysfunction (hypothyroidism, hyperthyroidism or TPOAb positivity) were associated with incident CKD in adjusted analyses. Elevated TSH, FT4 and reduced T3 concentrations were associated with reduced kidney function cross-sectionally. The lack of association with the development of incident CKD suggests that altered thyroid function in the general population is not causally related to CKD development, but screening for thyroidal status may be especially relevant in persons with reduced kidney function. © The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Evaluation of chronic kidney disease in chronic heart failure: From biomarkers to arterial renal resistances

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Iacoviello, Massimo; Leone, Marta; Antoncecchi, Valeria; Ciccone, Marco Matteo

2015-01-01

Chronic kidney disease and its worsening are recurring conditions in chronic heart failure (CHF) which are independently associated with poor patient outcome. The heart and kidney share many pathophysiological mechanisms which can determine dysfunction in each organ. Cardiorenal syndrome is the condition in which these two organs negatively affect each other, therefore an accurate evaluation of renal function in the clinical setting of CHF is essential. This review aims to revise the parameters currently used to evaluate renal dysfunction in CHF with particular reference to the usefulness and the limitations of biomarkers in evaluating glomerular dysfunction and tubular damage. Moreover, it is reported the possible utility of renal arterial resistance index (a parameter associated with abnormalities in renal vascular bed) for a better assesment of kidney disfunction. PMID:25610846

Mitochondrial Dysfunction in Lyssavirus-Induced Apoptosis▿ †

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Gholami, Alireza; Kassis, Raïd; Real, Eléonore; Delmas, Olivier; Guadagnini, Stéphanie; Larrous, Florence; Obach, Dorothée; Prevost, Marie-Christine; Jacob, Yves; Bourhy, Hervé

2008-01-01

Lyssaviruses are highly neurotropic viruses associated with neuronal apoptosis. Previous observations have indicated that the matrix proteins (M) of some lyssaviruses induce strong neuronal apoptosis. However, the molecular mechanism(s) involved in this phenomenon is still unknown. We show that for Mokola virus (MOK), a lyssavirus of low pathogenicity, the M (M-MOK) targets mitochondria, disrupts the mitochondrial morphology, and induces apoptosis. Our analysis of truncated M-MOK mutants suggests that the information required for efficient mitochondrial targeting and dysfunction, as well as caspase-9 activation and apoptosis, is held between residues 46 and 110 of M-MOK. We used a yeast two-hybrid approach, a coimmunoprecipitation assay, and confocal microscopy to demonstrate that M-MOK physically associates with the subunit I of the cytochrome c (cyt-c) oxidase (CcO) of the mitochondrial respiratory chain; this is in contrast to the M of the highly pathogenic Thailand lyssavirus (M-THA). M-MOK expression induces a significant decrease in CcO activity, which is not the case with M-THA. M-MOK mutations (K77R and N81E) resulting in a similar sequence to M-THA at positions 77 and 81 annul cyt-c release and apoptosis and restore CcO activity. As expected, the reverse mutations, R77K and E81N, introduced in M-THA induce a phenotype similar to that due to M-MOK. These features indicate a novel mechanism for energy depletion during lyssavirus-induced apoptosis. PMID:18321977

MR imaging of adult glomerulocystic kidney disease

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Egashira, K.; Nakata, H.; Hashimoto, O.; Kaizu, K.; University of Occupational and Environmental Health School of Medicine, Kitakyushu

1991-01-01

A 59-year-old man with hypertension and severe renal dysfunction was diagnosed as having adult glomerulocystic kidney disease. MR imaging of the kidney showed a diffuse reduction of the intensity of the renal cortex with a loss of normal cortico-medullary differentiation of T1-weighted images. Numerous small cortical cysts were also demonstrated. These MR findings complemented the results of the biopsy and were useful for making a definitive diagnosis. (orig.)

Stress induced right ventricular dysfunction: An indication of reversible right ventricular ischaemia

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Underwood, S.R.; Walton, S.; Emanuel, R.W.; Swanton, R.H.; Campos Costa, D.; Laming, P.J.; Ell, P.J.

1987-01-01

Stress induced changes in left ventricular ejection fraction are widely used in the detection and assessment of coronary artery disease. This study demonstrates that right ventricular dysfunction may also occur, and assesses its significance in terms of coronary artery anatomy. This study involved 14 normal subjects and 26 with coronary artery disease investigated by equilibrium radionuclide ventriculography, at rest and during maximal dynamic exercise. Mean normal resting right ventricular ejection fraction (RVEF) was 0.40 (SD 0.118), and all normal subjects increased RVEF with stress (mean ΔRVEF+0.13 SD 0.099). Mean ΔRVEF in the subjects with coronary artery disease was significantly lower at 0.00 (SD 0.080), but there was overlap between the two groups. The largest falls in RVEF were seen if the right coronary artery was occluded without retrograde filling. In this subgroup with the most severely compromised right ventricular perfusion (nine subjects), RVEF always fell with stress, and mean ΔRVEF was -0.08 (SD 0.050). There was no significant correlation between ΔLVEF and ΔRVEF, implying that the right ventricular dysfunction was due to right ventricular ischaemia, rather than secondary to left ventricular dysfunction. Stress induced right ventricular ischaemia can therefore be detected readily by radionuclide ventriculography. (orig.)

Cigarette Smoke-Induced Cell Death Causes Persistent Olfactory Dysfunction in Aged Mice

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Rumi Ueha

2018-06-01

Full Text Available Introduction: Exposure to cigarette smoke is a cause of olfactory dysfunction. We previously reported that in young mice, cigarette smoke damaged olfactory progenitors and decreased mature olfactory receptor neurons (ORNs, then, mature ORNs gradually recovered after smoking cessation. However, in aged populations, the target cells in ORNs by cigarette smoke, the underlying molecular mechanisms by which cigarette smoke impairs the regenerative ORNs, and the degree of ORN regeneration after smoking cessation remain unclear.Objectives: To explore the effects of cigarette smoke on the ORN cell system using an aged mouse model of smoking, and to investigate the extent to which smoke-induced damage to ORNs recovers following cessation of exposure to cigarette smoke in aged mice.Methods: We intranasally administered a cigarette smoke solution (CSS to 16-month-old male mice over 24 days, then examined ORN existence, cell survival, changes of inflammatory cytokines in the olfactory epithelium (OE, and olfaction using histological analyses, gene analyses and olfactory habituation/dishabituation tests.Results: CSS administration reduced the number of mature ORNs in the OE and induced olfactory dysfunction. These changes coincided with an increase in the number of apoptotic cells and Tumor necrosis factor (TNF expression and a decrease in Il6 expression. Notably, the reduction in mature ORNs did not recover even on day 28 after cessation of treatment with CSS, resulting in persistent olfactory dysfunction.Conclusion: In aged mice, by increasing ORN death, CSS exposure could eventually overwhelm the regenerative capacity of the OE, resulting in continued reduction in the number of mature ORNs and olfactory dysfunction.

Lithium induces microcysts and polyuria in adolescent rat kidney independent of cyclooxygenase‐2

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Kjaersgaard, Gitte; Madsen, Kirsten; Marcussen, Niels; Jensen, Boye L.

2014-01-01

Abstract In patients, chronic treatment with lithium leads to renal microcysts and nephrogenic diabetes insipidus (NDI). It was hypothesized that renal cyclooxygenase‐2 (COX‐2) activity promotes microcyst formation and NDI. Kidney microcysts were induced in male adolescent rats by feeding dams with lithium (50 mmol/kg chow) from postnatal days 7–34. Lithium treatment induced somatic growth retardation, renal microcysts and dilatations in cortical collecting duct; it increased cortical cell proliferation and inactive pGSK‐3β abundance; it lowered aquaporin‐2 (AQP2) protein abundance and induced polyuria with decreased ability to concentrate the urine; and it increased COX‐2 protein level in thick ascending limb. Concomitant treatment with lithium and a specific COX‐2 inhibitor, parecoxib (5 mg/kg per day, P10–P34), did not prevent lithium‐induced microcysts and polyuria, but improved urine concentrating ability transiently after a 1‐desamino‐8‐D‐arginine vasopressin challenge. COX‐2 inhibition did not reduce cortical lithium‐induced cell proliferation and phosphorylation of glycogen synthase kinase‐3β (GSK‐3β). COX‐1 protein abundance increased in rat kidney cortex in response to lithium. COX‐1 immunoreactivity was found in microcyst epithelium in rat kidney. A human nephrectomy specimen from a patient treated for 28 years with lithium displayed multiple, COX‐1‐immunopositive, microcysts. In chronic lithium‐treated adolescent rats, COX‐2 is not colocalized with microcystic epithelium, mitotic activity, and inactive pGSK‐3β in collecting duct; a blocker of COX‐2 does not prevent cell proliferation, cyst formation, or GSK‐3β inactivation. It is concluded that COX‐2 activity is not the primary cause for microcysts and polyuria in a NaCl‐substituted rat model of lithium nephropathy. COX‐1 is a relevant candidate to affect the injured epithelium. PMID:24744881

Disappearance of the telomere dysfunction-induced stress response in fully senescent cells.

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Bakkenist, Christopher J; Drissi, Rachid; Wu, Jing; Kastan, Michael B; Dome, Jeffrey S

2004-06-01

Replicative senescence is a natural barrier to cellular proliferation that is triggered by telomere erosion and dysfunction. Here, we demonstrate that ATM activation and H2AX-gamma nuclear focus formation are sensitive markers of telomere dysfunction in primary human fibroblasts. Whereas the activated form of ATM and H2AX-gamma foci were rarely observed in early-passage cells, they were readily detected in late-passage cells. The ectopic expression of telomerase in late-passage cells abrogated ATM activation and H2AX-gamma focus formation, suggesting that these stress responses were the consequence of telomere dysfunction. ATM activation was induced in quiescent fibroblasts by inhibition of TRF2 binding to telomeres, indicating that telomere uncapping is sufficient to initiate the telomere signaling response; breakage of chromosomes with telomeric associations is not required for this activation. Although ATM activation and H2AX-gamma foci were readily observed in late-passage cells, they disappeared once cells became fully senescent, indicating that constitutive signaling from dysfunctional telomeres is not required for the maintenance of senescence.

Bardoxolone methyl (BARD) ameliorates aristolochic acid (AA)-induced acute kidney injury through Nrf2 pathway.

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Wu, Juan; Liu, Xinhui; Fan, Jinjin; Chen, Wenfang; Wang, Juan; Zeng, Youjia; Feng, Xiaorang; Yu, Xueqing; Yang, Xiao

2014-04-06

Bardoxolone methyl (BARD) is an antioxidant modulator that acts through induction of the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. This study aimed to investigate the role of BARD in protecting kidneys from aristolochic acid (AA)-induced acute kidney injury (AKI). Male C57BL/6 mice received intraperitoneal (i.p.) injections of aristolochic acid I (AAI) (5mg/kg/day) for 5 days to produce acute AA nephropathy (AAN) model. BARD (10mg/kg/day, i.p.) was applied for 7 consecutive days, starting 2 days prior to AAI administration. The mice in the AA group showed AKI as evidenced by worsening kidney function evaluated by blood urea nitrogen (BUN) and serum creatinine (SCr) levels, and severe tubulointerstitial injury marked by massive tubule necrosis in kidney tissues. BARD significantly reduced BUN and SCr levels which were elevated by AAI. Additionally, AAI-induced histopathological renal damage was ameliorated by BARD. Furthermore, the expression of Nrf2 was reduced, and its repressor Kelch-like ECH-associated protein 1 (Keap1) was increased significantly, whereas heme oxygenase-1 (HO-1) was upregulated and NAD(P)H quinone oxidoreductase-1 (NQO1) was barely increased in the cytoplasm of tubules in kidneys after treatment with AAI. BARD significantly upregulated renal Nrf2, NQO1 and HO-1 expression and downregulated Keap1 expression compared with those in the AA group. Moreover, it was found that Nrf2 was expressed both in the cytoplasm and nuclear of glomeruli and tubules, whereas NQO1 and HO-1 were localized in the cytoplasm of tubules only. In conclusion, AA-induced acute renal injury was associated with impaired Nrf2 activation and expression of its downstream target genes in renal tissues. BARD prevented renal damage induced by AAI, and this renoprotective effect may be exerted by activating the Nrf2 signaling pathway and increasing expression of the downstream target genes. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Mitochondrial Reactive Oxygen Species and Kidney Hypoxia in the Development of Diabetic Nephropathy.

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Schiffer, Tomas A; Friederich-Persson, Malou

2017-01-01

The underlying mechanisms in the development of diabetic nephropathy are currently unclear and likely consist of a series of dynamic events from the early to late stages of the disease. Diabetic nephropathy is currently without curative treatments and it is acknowledged that even the earliest clinical manifestation of nephropathy is preceded by an established morphological renal injury that is in turn preceded by functional and metabolic alterations. An early manifestation of the diabetic kidney is the development of kidney hypoxia that has been acknowledged as a common pathway to nephropathy. There have been reports of altered mitochondrial function in the diabetic kidney such as altered mitophagy, mitochondrial dynamics, uncoupling, and cellular signaling through hypoxia inducible factors and AMP-kinase. These factors are also likely to be intertwined in a complex manner. In this review, we discuss how these pathways are connected to mitochondrial production of reactive oxygen species (ROS) and how they may relate to the development of kidney hypoxia in diabetic nephropathy. From available literature, it is evident that early correction and/or prevention of mitochondrial dysfunction may be pivotal in the prevention and treatment of diabetic nephropathy.

Renal Dysfunction in the Presence of Normoalbuminuria in Type 2 Diabetes

DEFF Research Database (Denmark)

Dwyer, Jamie P; Parving, Hans-Henrik; Hunsicker, Lawrence G

2012-01-01

population of patients with type 2 diabetes. Renal dysfunction was present in a large proportion of these patients without proteinuria, assessed by a single random albumin-to-creatinine ratio (ACR). We therefore undertook to characterize the nature of this association of non-proteinuric renal dysfunction...... in type 2 diabetes. METHODS: In the DEMAND (Developing Education on Microalbuminuria for Awareness of Renal and Cardiovascular Risk in Diabetes) study, a global, cross-sectional study which described the prevalence and risk factors for albuminuria in a clinic-based cohort, kidney function was assessed...... in 11,573 patients; ACR was measured using the Bayer reagent strip Multistix® 10SG. Normoalbuminuria was defined as ACR 300 mg/g. RESULTS: Among the patients with estimated kidney function determined, chronic kidney disease was noted in 17% of those with normoalbuminuria (stage 3-5), and significant...

2-Chlorohexadecanoic acid induces ER stress and mitochondrial dysfunction in brain microvascular endothelial cells

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Eva Bernhart

2018-05-01

Full Text Available Peripheral leukocytes induce blood-brain barrier (BBB dysfunction through the release of cytotoxic mediators. These include hypochlorous acid (HOCl that is formed via the myeloperoxidase-H2O2-chloride system of activated phagocytes. HOCl targets the endogenous pool of ether phospholipids (plasmalogens generating chlorinated inflammatory mediators like e.g. 2-chlorohexadecanal and its conversion product 2-chlorohexadecanoic acid (2-ClHA. In the cerebrovasculature these compounds inflict damage to brain microvascular endothelial cells (BMVEC that form the morphological basis of the BBB. To follow subcellular trafficking of 2-ClHA we synthesized a ‘clickable’ alkyne derivative (2-ClHyA that phenocopied the biological activity of the parent compound. Confocal and superresolution structured illumination microscopy revealed accumulation of 2-ClHyA in the endoplasmic reticulum (ER and mitochondria of human BMVEC (hCMEC/D3 cell line. 2-ClHA and its alkyne analogue interfered with protein palmitoylation, induced ER-stress markers, reduced the ER ATP content, and activated transcription and secretion of interleukin (IL−6 as well as IL-8. 2-ClHA disrupted the mitochondrial membrane potential and induced procaspase-3 and PARP cleavage. The protein kinase R-like ER kinase (PERK inhibitor GSK2606414 suppressed 2-ClHA-mediated activating transcription factor 4 synthesis and IL-6/8 secretion, but showed no effect on endothelial barrier dysfunction and cleavage of procaspase-3. Our data indicate that 2-ClHA induces potent lipotoxic responses in brain endothelial cells and could have implications in inflammation-induced BBB dysfunction.

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.

Drug induced acute kidney injury: an experimental animal study

International Nuclear Information System (INIS)

Khan, M.W.A.; Khan, B.T.; Qazi, R.A.; Ashraf, M.; Waqar, M.

2017-01-01

Objective: To assess the extent of drug induced nephrotoxicity in laboratory animals for determining the role and extent of iatrogenic kidney damage in patients exposed to nephrotoxic drugs in various clinical setups. Study Design: Randomized control trail. Place and Duration of study: Pharmacology department and animal house of Army Medical College from Jan 2011 to Aug 2011. Material and Methods: Thirty six mixed breed rabbits were used in this study. Animals were randomly divided into six groups consisting of six rabbits in each. Groups were named A, B, C, D, E and F. Group A was control group. Group B was given 0.9% normal saline. Group C rabbits were given acute nephrotoxic single dose of amphotericin B deoxycholate. Group D received 0.9% normal saline 10ml/kg followed by amphotericin B infusion. Group E was injected acute nephrotoxic regimen of cyclosporine and amphotericin B infusion. Group F received saline loading along with acute nephrotoxic regimen of cyclosporine and amphotericin B infusion. Results: Biochemical and histopathological analysis showed significant kidney injury in rabbits exposed to acute nephrotoxic doses of amphotericin B and cyclosporine. Toxicity was additive when the two drugs were administered simultaneously. Group of rabbits with saline loading had significantly lesser kidney damage. Conclusion: Iatrogenic acute kidney damage is a major cause of morbidity in experimental animals exposed to such nephrotoxic drugs like amphotericin B and cyclosporine, used either alone or in combination. Clinical studies are recommended to assess the extent of iatrogenic renal damage in patients and its economic burden. Efficient and cost effective protective measure may be adopted in clinical setups against such adverse effects. (author)

Curcumin Protects against Cadmium-Induced Vascular Dysfunction, Hypertension and Tissue Cadmium Accumulation in Mice

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Upa Kukongviriyapan

2014-03-01

Full Text Available Curcumin from turmeric is commonly used worldwide as a spice and has been demonstrated to possess various biological activities. This study investigated the protective effect of curcumin on a mouse model of cadmium (Cd—induced hypertension, vascular dysfunction and oxidative stress. Male ICR mice were exposed to Cd (100 mg/L in drinking water for eight weeks. Curcumin (50 or 100 mg/kg was intragastrically administered in mice every other day concurrently with Cd. Cd induced hypertension and impaired vascular responses to phenylephrine, acetylcholine and sodium nitroprusside. Curcumin reduced the toxic effects of Cd and protected vascular dysfunction by increasing vascular responsiveness and normalizing the blood pressure levels. The vascular protective effect of curcumin in Cd exposed mice is associated with up-regulation of endothelial nitric oxide synthase (eNOS protein, restoration of glutathione redox ratio and alleviation of oxidative stress as indicated by decreasing superoxide production in the aortic tissues and reducing plasma malondialdehyde, plasma protein carbonyls, and urinary nitrate/nitrite levels. Curcumin also decreased Cd accumulation in the blood and various organs of Cd-intoxicated mice. These findings suggest that curcumin, due to its antioxidant and chelating properties, is a promising protective agent against hypertension and vascular dysfunction induced by Cd.

Hospital specific factors affect quality of blood pressure treatment in chronic kidney disease

NARCIS (Netherlands)

Zuilen, A.D. van; Blankestijn, P.J.; Buren, M. van; Dam, M.A. ten; Kaasjager, K.A.; Ligtenberg, G.; Sijpkens, Y.W.; Sluiter, H.E.; Ven, P.J. van der; Vervoort, G.M.M.; Vleming, L.; Bots, M.L.; Wetzels, J.F.M.

2011-01-01

BACKGROUND: Blood pressure (BP) is the most important modifiable risk factor for cardiovascular (CV) disease and progression of kidney dysfunction in patients with chronic kidney disease. Despite extensive antihypertensive treatment possibilities, adequate control is notoriously hard to achieve.

Intermittent hypercapnia induces long-lasting ventilatory plasticity to enhance CO2 responsiveness to overcome dysfunction

Science.gov (United States)

Mosher, Bryan Patrick

The ability of the brain to detect (central CO2 chemosensitivity) and respond to (central CO2 chemoresponsiveness) changes in tissue CO2/pH, is a homeostatic process essential for mammalian life. Dysfunction of the serotonin (5-HT) mechanisms compromises ventilatory CO 2 chemosensitivity/responsiveness and may enhance vulnerability to pathologies such as the Sudden Infant Death Syndrome (SIDS). The laboratory of Dr. Michael Harris has shown medullary raphe contributions to central chemosensitivity involving both 5-HT- and gamma-aminobutyric acid (GABA)-mediated mechanisms. I tested the hypothesis that postnatal exposure to mild intermittent hypercapnia (IHc) induces respiratory plasticity, due in part to strengthening of bicuculline- and saclofen-sensitive mechanisms (GABAA and GABAB receptor antagonists respectively). Rats were exposed to IHc-pretreatment (8 cycles of 5 % CO2) for 5 days beginning at postnatal day 12 (P12). I subsequently assessed CO2 responsiveness using an in situ perfused brainstem preparation. Hypercapnic responses were determined with and without pharmacological manipulation. In addition, IHc-pretreatment effectiveness was tested for its ability to overcome dysfunction in the CO2 responsiveness induced by a dietary tryptophan restriction. This dysfunctional CO2 responsiveness has been suggested to arise from a chronic, partial 5-HT reduction imparted by the dietary restriction. Results show IHc-pretreatment induced plasticity sufficient for CO2 responsiveness despite removal of otherwise critical ketanserin-sensitive mechanisms. CO2 responsiveness following IHc-pretreatment was absent if ketanserin was combined with bicuculline and saclofen, indicating that the plasticity was dependent upon bicuculline- and saclofen-sensitive mechanisms. IHc--induced plasticity was also capable of overcoming the ventilatory defects associated with maternal dietary restriction. Duration of IHc-induced plasticity was also investigated and found to last far into

Overexpressed cyclophilin B suppresses aldosterone-induced proximal tubular cell injury both in vitro and in vivo.

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Wang, Bin; Lin, Lilu; Wang, Haidong; Guo, Honglei; Gu, Yong; Ding, Wei

2016-10-25

The renin-angiotensin-aldosterone system (RAAS) is overactivated in patients with chronic kidney disease. Oxidative stress and endoplasmic reticulum stress (ERS) are two major mechanisms responsible for aldosterone-induced kidney injury. Cyclophilin (CYP) B is a chaperone protein that accelerates the rate of protein folding through its peptidyl-prolyl cis-trans isomerase (PPIase) activity. We report that overexpression of wild-type CYPB attenuated aldosterone-induced oxidative stress (evidenced by reduced production of reactive oxygen species and improved mitochondrial dysfunction), ERS (indicated by reduced expression of the ERS markers glucose-regulated protein 78 [GRP78] and C/-EBP homologous protein [CHOP]), and tubular cell apoptosis in comparison with aldosterone-induced human kidney-2 (HK-2) cells. The in vivo study also yielded similar results. Hence, CYPB performs a crucial function in protecting cells against aldosterone-induced oxidative stress, ERS, and tubular cell injury via its PPIase activity.

Fullerenol cytotoxicity in kidney cells is associated with cytoskeleton disruption, autophagic vacuole accumulation, and mitochondrial dysfunction

International Nuclear Information System (INIS)

Johnson-Lyles, Denise N.; Peifley, Kimberly; Lockett, Stephen; Neun, Barry W.; Hansen, Matthew; Clogston, Jeffrey; Stern, Stephan T.; McNeil, Scott E.

2010-01-01

Water soluble fullerenes, such as the hydroxylated fullerene, fullerenol (C 60 OH x ), are currently under development for diagnostic and therapeutic biomedical applications in the field of nanotechnology. These molecules have been shown to undergo urinary clearance, yet there is limited data available on their renal biocompatibility. Here we examine the biological responses of renal proximal tubule cells (LLC-PK1) exposed to fullerenol. Fullerenol was found to be cytotoxic in the millimolar range, with viability assessed by the sulforhodamine B and trypan blue assays. Fullerenol-induced cell death was associated with cytoskeleton disruption and autophagic vacuole accumulation. Interaction with the autophagy pathway was evaluated in vitro by Lysotracker Red dye uptake, LC3-II marker expression and TEM. Fullerenol treatment also resulted in coincident loss of cellular mitochondrial membrane potential and ATP depletion, as measured by the Mitotracker Red dye and the luciferin-luciferase assays, respectively. Fullerenol-induced ATP depletion and loss of mitochondrial potential were partially ameliorated by co-treatment with the autophagy inhibitor, 3-methyladenine. In vitro fullerenol treatment did not result in appreciable oxidative stress, as measured by lipid peroxide and glutathione content. Based on these data, it is hypothesized that cytoskeleton disruption may be an initiating event in fullerenol cytotoxicity, leading to subsequent autophagy dysfunction and loss of mitochondrial capacity. As nanoparticle-induced cytoskeleton disruption, autophagic vacuole accumulation and mitochondrial dysfunction are commonly reported in the literature, the proposed mechanism may be relevant for a variety of nanomaterials.

A case of tacrolimus-induced encephalopathy after kidney transplantation

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Myoung Uk Kim

2011-01-01

Full Text Available We present a case of tacrolimus-induced encephalopathy after successful kidney transplantation. An 11-year-old girl presented with sudden onset of neurologic symptoms, hypertension, and psychiatric symptoms, with normal kidney function, after kidney transplantation. The symptoms improved after cessation of tacrolimus. Magnetic resonance imaging (MRI showed acute infarction of the middle cerebral artery (MCA territory in the right frontal lobe. Three days later, she had normal mental function and maintained normal blood pressure with left hemiparesis. Follow-up MRI was performed on D19, showing new infarct lesions at both cerebral hemispheres. Ten days later, MRI showed further improvement, but brain single photon emission computed tomography (SPECT showed mild reduction of uptake in both the anterior cingulate gyrus and the left thalamus. One month after onset of symptoms, angiography showed complete resolution of stenosis. However, presenting as a mild fine motor disability of both hands and mild dysarthria, what had been atrophy at both centrum semiovale at 4 months now showed progression to encephalomalacia. There are two points of interest in this case. First, encephalopathy occurred after administration of tacrolimus and improved after discontinuation of the drug. Second, the development of right-side hemiplegia could not be explained by conventional MRI; but through diffusion tensor imaging (DTI and diffusion tensor tractography (DTT of white matter tract, visualization was possible.

In vitro and in vivo studies of Allium sativum extract against deltamethrin-induced oxidative stress in rats brain and kidney.

Science.gov (United States)

Ncir, Marwa; Saoudi, Mongi; Sellami, Hanen; Rahmouni, Fatma; Lahyani, Amina; Makni Ayadi, Fatma; El Feki, Abdelfattah; Allagui, Mohamed Salah

2017-09-18

The present study investigated the in vitro and the in vivo antioxidant capacities of Allium sativum (garlic) extract against deltamethrin-induced oxidative damage in rat's brain and kidney. The in vitro result showed that highest extraction yield was achieved with methanol (20.08%). Among the tested extracts, the methanol extract exhibited the highest total phenolic, flavonoids contents and antioxidant activity. The in vivo results showed that deltamethrin treatment caused an increase of the acetylcholinesterase level (AChE) in brain and plasma, the brain and kidney conjugated dienes and lipid peroxidation (LPO) levels as compared to control group. The antioxidant enzymes results showed that deltamethrin treatment induced a significantly decrease (p < 0.01) in brain and kidney antioxidant enzymes as catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) to control group. The co-administration of garlic extract reduced the toxic effects in brain and kidney tissues induced by deltamethrin.

Albumin extravasation in bicuculline-induced blood-brain barrier dysfunction

International Nuclear Information System (INIS)

Persson, L.I.; Rosengren, L.E.; Johansson, B.B.

1980-01-01

The extravasation of endogeneous rat albumin and exogeneous 125 I-labeled human serum albumin was compared in rats subjected to bicuculline-induced blood-brain barrier dysfunction. The correlation between rocket immunoelectrophoretic assays of endogeneous rat albumin and 125 I-labeled human serum albumin, assayed by gamma scintillation counting, was good irrespective of whether 125 I-labeled albumin was studied in whole brain tissue or in brain homogenates. The ratio of brain to serum albumin was similar with the two assay methods. (author)

Cannabis-induced Moto-Cognitive Dysfunction in Wistar Rats: Ameliorative Efficacy of Nigella Sativa.

Science.gov (United States)

Imam, Aminu; Ajao, Moyosore Saliu; Amin, Abdulbasit; Abdulmajeed, Wahab Imam; Ibrahim, Abdulmumin; Olajide, Olayemi Joseph; Ajibola, Musa Iyiola; Alli-Oluwafuyi, Abdulmusawir; Balogun, Wasiu Gbolahan

2016-09-01

Cannabis is a widely used illicit drug with various threats of personality syndrome, and Nigella sativa has been widely implicated as having therapeutic efficacy in many neurological diseases. The present study investigates the ameliorative efficacy of Nigella sativa oil (NSO) on cannabis-induced moto-cognitive defects. Scopolamine (1 mg/kg i.p.) was given to induce dementia as a standard base line for cannabis (20 mg/kg)-induced cognitive impairment, followed by an oral administration of NSO (1 ml/kg) for 14 consecutive days. The Morris water maze (MWM) paradigm was used to assess the memory index, the elevated plus maze was used for anxiety-like behaviour, and the open field test was used for locomotor activities; thereafter, the rats were sacrificed and their brains were removed for histopathologic studies. Cannabis-like Scopolamine caused memory impairment, delayed latency in the MWM, and anxiety-like behaviour, coupled with alterations in the cerebello-hippocampal neurons. The post-treatment of rats with NSO mitigated cannabis-induced cognitive dysfunction as with scopolamine and impaired anxiety-like behaviour by increasing open arm entry, line crossing, and histological changes. The observed ameliorative effects of NSO make it a promising agent against moto-cognitive dysfunction and cerebelo-hippocampal alterations induced by cannabis.

Neuroprotective effects of oleuropein against cognitive dysfunction induced by colchicine in hippocampal CA1 area in rats.

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Pourkhodadad, Soheila; Alirezaei, Masoud; Moghaddasi, Mehrnoush; Ahmadvand, Hassan; Karami, Manizheh; Delfan, Bahram; Khanipour, Zahra

2016-09-01

Alzheimer's disease is a progressive neurodegenerative disorder with decline in memory. The role of oxidative stress is well known in the pathogenesis of the disease. The purpose of this study was to evaluate pretreatment effects of oleuropein on oxidative status and cognitive dysfunction induced by colchicine in the hippocampal CA1 area. Male Wistar rats were pretreated orally once daily for 10 days with oleuropein at doses of 10, 15 and 20 mg/kg. Thereafter, colchicine (15 μg/rat) was administered into the CA1 area of the hippocampus to induce cognitive dysfunction. The Morris water maze was used to assess learning and memory. Biochemical parameters such as glutathione peroxidase and catalase activities, nitric oxide and malondialdehyde concentrations were measured to evaluate the antioxidant status in the rat hippocampus. Our results indicated that colchicine significantly impaired spatial memory and induced oxidative stress; in contrast, oleuropein pretreatment significantly improved learning and memory retention, and attenuated the oxidative damage. The results clearly indicate that oleuropein has neuroprotective effects against colchicine-induced cognitive dysfunction and oxidative damage in rats.

Ginger extract diminishes chronic fructose consumption-induced kidney injury through suppression of renal overexpression of proinflammatory cytokines in rats.

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Yang, Ming; Liu, Changjin; Jiang, Jian; Zuo, Guowei; Lin, Xuemei; Yamahara, Johji; Wang, Jianwei; Li, Yuhao

2014-05-27

The metabolic syndrome is associated with an increased risk of development and progression of chronic kidney disease. Renal inflammation is well known to play an important role in the initiation and progression of tubulointerstitial injury of the kidneys. Ginger, one of the most commonly used spices and medicinal plants, has been demonstrated to improve diet-induced metabolic abnormalities. However, the efficacy of ginger on the metabolic syndrome-associated kidney injury remains unknown. This study aimed to investigate the impact of ginger on fructose consumption-induced adverse effects in the kidneys. The fructose control rats were treated with 10% fructose in drinking water over 5 weeks. The fructose consumption in ginger-treated rats was adjusted to match that of fructose control group. The ethanolic extract of ginger was co-administered (once daily by oral gavage). The indexes of lipid and glucose homeostasis were determined enzymatically, by ELISA and/or histologically. Gene expression was analyzed by Real-Time PCR. In addition to improve hyperinsulinemia and hypertriglyceridemia, supplement with ginger extract (50 mg/kg) attenuated liquid fructose-induced kidney injury as characterized by focal cast formation, slough and dilation of tubular epithelial cells in the cortex of the kidneys in rats. Furthermore, ginger also diminished excessive renal interstitial collagen deposit. By Real-Time PCR, renal gene expression profiles revealed that ginger suppressed fructose-stimulated monocyte chemoattractant protein-1 and its receptor chemokine (C-C motif) receptor-2. In accord, overexpression of two important macrophage accumulation markers CD68 and F4/80 was downregulated. Moreover, overexpressed tumor necrosis factor-alpha, interleukin-6, transforming growth factor-beta1 and plasminogen activator inhibitor (PAI)-1 were downregulated. Ginger treatment also restored the downregulated ratio of urokinase-type plasminogen activator to PAI-1. The present results

The molecular mechanism of leptin secretion and expression induced by aristolochic acid in kidney fibroblast.

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Tsung-Chieh Lin

Full Text Available BACKGROUND: Leptin is a peptide hormone playing pivotal role in regulating food intake and energy expenditure. Growing evidence has suggested the pro-inflammatory and fibrogenic properties of leptin. In addition, patients with renal fibrosis have higher level of plasma leptin, which was due to the increased leptin production. Aristolochic acid (AA is a botanical toxin characterized to associate with the development of renal fibrosis including tubulointerstitial fibrosis. However, whether leptin is upregulated to participate in AA-induced kidney fibrosis remain completely unknown. METHODOLOGY/PRINCIPAL FINDINGS: In this study, leptin expression was increased by sublethal dose of AA in kidney fibroblast NRK49f determined by enzyme-linked immunosorbent assay and Western blot. Data from real-time reverse transcriptase-polymerase chain reaction revealed that leptin was upregulated by AA at transcriptional level. DNA binding activity of CCAAT enhancer binding protein α (C/EBP α, one of the transcription factors for leptin gene, was enhanced in DNA affinity precipitation assay and chromatin immunoprecipitation experiments. Knockdown of C/EBP α expression by small interfering RNA markedly reduced AA-induced leptin expression. Moreover, AA promoted Akt interaction with p-PDK1, and increased phosphorylated activation of Akt. Akt knockdown, and inhibition of Akt signaling by LY294002 and mTOR inhibitor rapamycin reduced leptin expression. Furthermore, treatment of LY294002 or rapamycin significantly suppressed AA-induced C/EBP α DNA-binding activity. These results suggest that Akt and C/EBP α activation were involved in AA-regulated leptin expression. CONCLUSIONS/SIGNIFICANCE: Our findings demonstrate the first that AA could induce secretion and expression of fibrogenic leptin in kidney fibroblasts, which reveal potential involvement of leptin in the progression of kidney fibrosis in aristolochic acid nephropathy.

Structural transition of kidney cystatin in dimethylnitrosamine-induced renal cancer in rats: identification as a novel biomarker for kidney cancer and prognosis.

Science.gov (United States)

Shamsi, Anas; Ahmed, Azaj; Bano, Bilqees

2017-04-01

In our study, renal cancer is induced in rats making use of dimethylnitrosamine (DMN). G1 - Group 1 were control rats and G2 - Group 2 rats were given a single intra-peritoneal injection of DMN of 50 mg/kg body weight resulting in 100% incidences of renal tumors after 12 months. SEM and histopathology confirmed the presence of renal cancer in the DMN-treated rats. Making use of ammonium sulfate precipitation and gel filtration chromatography on Sephacryl S-100HR column, a thiol protease inhibitor was isolated from kidney of control rats known as Rat kidney Cystatin (RKC) as well as from kidney of cancerous rat called as Cancerous Rat Kidney Cystatin (CRKC). Both these inhibitors were characterized, and interestingly, it was found that CRKC showed greater anti-papain activity and also it was stable in a broad pH and temperature range thus implying that CRKC is more stable as compared to RKC. UV and fluorescence spectroscopy point out in structural difference between RKC and CRKC which was further confirmed by Circular dichroism (CD) and FTIR spectroscopy. Our study clearly showed that kidney cystatin is structurally modified in the case of renal cancer and performs its role in a more efficacious manner.

76 FR 36931 - National Institute of Diabetes and Digestive and Kidney Diseases; Notice of Closed Meetings

Science.gov (United States)

2011-06-23

... Diabetes and Digestive and Kidney Diseases Special Emphasis Panel; Liver Disease and Transplantation... Diabetes and Digestive and Kidney Diseases; Notice of Closed Meetings Pursuant to section 10(d) of the... of Diabetes and Digestive and Kidney Diseases Special Emphasis Panel; Urinary Tract Dysfunction P01...

The Role of Drug Transporters in the Kidney: Lessons from Tenofovir

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Darren Michael Moss

2014-11-01

Full Text Available Tenofovir disoproxil fumarate, the prodrug of nucleotide reverse transcriptase inhibitor tenofovir, shows high efficacy and relatively low toxicity in HIV patients. However, long-term kidney toxicity is now acknowledged as a modest but significant risk for tenofovir-containing regimens, and continuous use of tenofovir in HIV therapy is currently under question by practitioners and researchers. Co-morbidities (hepatitis C, diabetes, low body weight, older age, concomitant administration of potentially nephrotoxic drugs, low CD4 count, and duration of therapy are all risk factors associated with tenofovir-associated tubular dysfunction. Tenofovir is predominantly eliminated via the proximal tubules of the kidney, therefore drug transporters expressed in renal proximal tubule cells are believed to influence tenofovir plasma concentration and toxicity in the kidney. We review here the current evidence that the actions, pharmacogenetics and drug interactions of drug transporters are relevant factors for tenofovir-associated tubular dysfunction. The use of creatinine and novel biomarkers for kidney damage, and the role that drug transporters play in biomarker disposition, is discussed. The lessons learnt from investigating the role of transporters in tenofovir kidney elimination and toxicity can be utilised for future drug development and clinical management programs.

Astaxanthin Attenuates Homocysteine-Induced Cardiotoxicity in Vitro and in Vivo by Inhibiting Mitochondrial Dysfunction and Oxidative Damage

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Cun-dong Fan

2017-12-01

Full Text Available Homocysteine (Hcy as an independent risk factor contributes to the occurrence and development of human cardiovascular diseases (CVD. Induction of oxidative stress and apoptosis was commonly accepted as the major mechanism in Hcy-induced cardiotoxicity. Astaxanthin (ATX as one of the most powerful antioxidants exhibits novel cardioprotective potential against Hcy-induced endothelial dysfunction. However, the protective effect and mechanism of ATX against Hcy-induced cardiotoxicity in cardiomyocytes have not been elucidated yet. Herein, H9c2 rat cardiomyocytes and Hcy-injured animal model were employed in the present study. The MTT, flow cytometry analysis (FCM, TUNEL-DAPI and western blotting results all demonstrated that ATX significantly alleviated Hcy-induced cytotoxicity in H9c2 cells through inhibition of mitochondria-mediated apoptosis. The JC-1 and Mito-tracker staining both revealed that ATX pre-treatment blocked Hcy-induced mitochondrial dysfunction by regulating Bcl-2 family expression. Moreover, DCFH-DA and Mito-SOX staining showed that ATX effectively attenuated Hcy-induced oxidative damage via scavenging intracellular reactive oxygen species (ROS. Importantly, the ELISA and immunohistochemical results indicated that Hcy-induced cardiotoxicity in vivo was also significantly inhibited by ATX through inhibition of oxidative damage and apoptosis, and improvement of the angiogenesis. Taken together, our results demonstrated that ATX suppressed Hcy-induced cardiotoxicity in vitro and in vivo by inhibiting mitochondrial dysfunction and oxidative damage. Our findings validated the strategy of using ATX may be a highly efficient way to combat Hcy-mediated human CVD.

Astaxanthin Attenuates Homocysteine-Induced Cardiotoxicity in Vitro and in Vivo by Inhibiting Mitochondrial Dysfunction and Oxidative Damage.

Science.gov (United States)

Fan, Cun-Dong; Sun, Jing-Yi; Fu, Xiao-Ting; Hou, Ya-Jun; Li, Yuan; Yang, Ming-Feng; Fu, Xiao-Yan; Sun, Bao-Liang

2017-01-01

Homocysteine (Hcy) as an independent risk factor contributes to the occurrence and development of human cardiovascular diseases (CVD). Induction of oxidative stress and apoptosis was commonly accepted as the major mechanism in Hcy-induced cardiotoxicity. Astaxanthin (ATX) as one of the most powerful antioxidants exhibits novel cardioprotective potential against Hcy-induced endothelial dysfunction. However, the protective effect and mechanism of ATX against Hcy-induced cardiotoxicity in cardiomyocytes have not been elucidated yet. Herein, H9c2 rat cardiomyocytes and Hcy-injured animal model were employed in the present study. The MTT, flow cytometry analysis (FCM), TUNEL-DAPI and western blotting results all demonstrated that ATX significantly alleviated Hcy-induced cytotoxicity in H9c2 cells through inhibition of mitochondria-mediated apoptosis. The JC-1 and Mito-tracker staining both revealed that ATX pre-treatment blocked Hcy-induced mitochondrial dysfunction by regulating Bcl-2 family expression. Moreover, DCFH-DA and Mito-SOX staining showed that ATX effectively attenuated Hcy-induced oxidative damage via scavenging intracellular reactive oxygen species (ROS). Importantly, the ELISA and immunohistochemical results indicated that Hcy-induced cardiotoxicity in vivo was also significantly inhibited by ATX through inhibition of oxidative damage and apoptosis, and improvement of the angiogenesis. Taken together, our results demonstrated that ATX suppressed Hcy-induced cardiotoxicity in vitro and in vivo by inhibiting mitochondrial dysfunction and oxidative damage. Our findings validated the strategy of using ATX may be a highly efficient way to combat Hcy-mediated human CVD.

Modulatory effect of Mangifera indica against carbon tetrachloride induced kidney damage in rats.

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Awodele, Olufunsho; Adeneye, Adejuwon Adewale; Aiyeola, Sheriff Aboyade; Benebo, Adokiye Senibo

2015-12-01

There is little scientific evidence on the local use of Mangifera indica in kidney diseases. This study investigated the reno-modulatory roles of the aqueous stem bark extract of Mangifera indica (MIASE) against CCl4-induced renal damage. Rats were treated intragastrically with 125, 250 and 500 mg/kg/day MIASE for 7 days before and after the administration of CCl4 (3 ml/kg of 30% CCl4, i.p.). Serum levels of electrolytes (Na+, K+, Cl(-), HCO3(-)), urea and creatinine were determined. Renal tissue reduced glutathione (GSH), malondialdehyde (MDA), catalase (CAT), superoxide (SOD) activities were also assessed. The histopathological changes in kidneys were determined using standard methods. In CCl4 treated rats the results showed significant (pMangifera indica may present a great prospect for drug development in the management of kidney disease with lipid peroxidation as its etiology.

Ameliorating effects of Raphanus sativus leaves on sodium arsenite-induced perturbation of blood indices in Swiss albino mice

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Sayada Dilruba

2017-10-01

Conclusions: Results of this study suggest the protective or ameliorating effects of RSL on Sa-induced perturbation of blood indices are related to the hepatic, cardiovascular and kidney dysfunction. Therefore, RSL may be useful to reduce arsenic toxicity in human in the future.

Grape Seed oil as Anti hepatic and Anti renal Dysfunction agent in Paracetamol Administrated Rats

International Nuclear Information System (INIS)

Farag, M.F.; Osman, N.N.; Darwish, M.M.

2010-01-01

The protection conferred by dietary grape seed oil (GSO) against paracetamol (PCL)-induced liver and kidney dysfunction have been evaluated in adult male albino Wistar rats. The animals (180-200 g) were randomly divided into four groups of seven rats each. Group l: normal control, group II: animals received GSO (3.7 g Kg-1 body wt/day orally), group III: animals received PCL (4 g Kg-1 body wt/day orally) and group IV: animals received PCL plus GSO. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AP), gamma glutamyl transferase (GGT), urea (U), creatinine (Cr) and albumin (A) levels in serum and blood urea nitrogen (BUN) were measured. In addition, the levels of thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) and the activity of superoxide dismutase (SOD) and catalase (CAT) in the liver and kidney homogenates were chosen for assessing. The PCL induced a significant elevation in the serum AST, ALT, AP and GGT. Moreover, a significant increase in serum U, Cr, A and BUN were evident. Furthermore, a significant rise in TBARS, while a significant declined activity of SOD and CAT and GSH content in liver and kidney homogenates were also observed. Oral administration of GSO resulted in a significant reduction in liver and kidney markers in serum, BUN as well hepatic and renal TBARS accompanied by a significant improvement in the tissue antioxidants and A, when compared with PCL damaged rats. It was suggested that GSO has potent hepatic and renal protective effects against the oxidative damage induced in rats due to PCL treatment, perhaps by its antioxidative effects hence eliminating the deleterious effects of PCL.

Ambulatory blood pressure monitoring is recommended in the clinical management of children with a solitary functioning kidney

NARCIS (Netherlands)

Westland, R.; Schreuder, M.F.; Lof, D.F. van der; Vermeulen, A.; Meer, I.M. van der; Bokenkamp, A.; Wijk, J.A. van

2014-01-01

BACKGROUND: Children with a solitary functioning kidney are at increased risk of developing chronic kidney disease. Hypertension may be an early indicator of renal dysfunction in these patients. We determined blood pressure (BP) profiles of children with a solitary functioning kidney by using

Cardiac-Specific Overexpression of Catalase Attenuates Lipopolysaccharide-Induced Myocardial Contractile Dysfunction: Role of Autophagy

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Turdi, Subat; Han, Xuefeng; Huff, Anna F.; Roe, Nathan D.; Hu, Nan; Gao, Feng; Ren, Jun

2012-01-01

Lipopolysaccharide (LPS) from Gram-negative bacteria is a major initiator of sepsis, leading to cardiovascular collapse. Accumulating evidence has indicated a role of reactive oxygen species (ROS) in cardiovascular complication in sepsis. This study was designed to examine the effect of cardiac-specific overexpression of catalase in LPS-induced cardiac contractile dysfunction and the underlying mechanism(s) with a focus on autophagy. Catalase transgenic and wild-type FVB mice were challenged with LPS (6 mg/kg) and cardiac function was evaluated. Levels of oxidative stress, autophagy, apoptosis and protein damage were examined using fluorescence microscopy, Western blot, TUNEL assay, caspase-3 activity and carbonyl formation. Kaplan-Meier curve was constructed for survival following LPS treatment. Our results revealed a lower mortality in catalase mice compared with FVB mice following LPS challenge. LPS injection led to depressed cardiac contractile capacity as evidenced by echocardiography and cardiomyocyte contractile function, the effect of which was ablated by catalase overexpression. LPS treatment induced elevated TNF-α level, autophagy, apoptosis (TUNEL, caspase-3 activation, cleaved caspase-3), production of ROS and O2−, and protein carbonyl formation, the effects of which were significantly attenuated by catalase overexpression. Electron microscopy revealed focal myocardial damage characterized by mitochondrial injury following LPS treatment, which was less severe in catalase mice. Interestingly, LPS-induced cardiomyocyte contractile dysfunction was prevented by antioxidant NAC and the autophagy inhibitor 3-methyladenine. Taken together, our data revealed that catalase protects against LPS-induced cardiac dysfunction and mortality, which may be associated with inhibition of oxidative stress and autophagy. PMID:22902401

Single-dose-dexketoprofen-induced acute kidney injury due to massive rhabdomyolysis.

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Sav, Tansu; Unal, Aydin; Erden, Abdulsamet; Gunal, Ali Ihsan

2012-10-01

A 70-year-old male patient was admitted complaining of weakness and pain in his arms and lower limbs. His serum creatine kinase and serum creatinine were markedly elevated (36,248 IU/L and 2.8 mg/dL, respectively). He had taken dexketoprofen trometamol because of a common cold, which had developed the previous night. Acute kidney injury caused by dexketoprofen-induced rhabdomyolysis was diagnosed by ruling out other possible causes, such as dermato/polymyositis, myxedema, brucellosis, and hepatitis. Dexketoprofen administration was stopped. As diuresis did not restore spontaneously, the patient was treated with I.V. alkaline solutions and mannitol. Hemodialysis was performed because of anuria and severe metabolic acidosis. The patient's renal function later recovered. In conclusion, dexketoprofen may be a potential risk factor for acute kidney injury and rhabdomyolysis.

Therapeutic Effects of Procainamide on Endotoxin-Induced Rhabdomyolysis in Rats.

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Chih-Chin Shih

Full Text Available Overt systemic inflammatory response is a predisposing mechanism for infection-induced skeletal muscle damage and rhabdomyolysis. Aberrant DNA methylation plays a crucial role in the pathophysiology of excessive inflammatory response. The antiarrhythmic drug procainamide is a non-nucleoside inhibitor of DNA methyltransferase 1 (DNMT1 used to alleviate DNA hypermethylation. Therefore, we evaluated the effects of procainamide on the syndromes and complications of rhabdomyolysis rats induced by lipopolysaccharide (LPS. Rhabdomyolysis animal model was established by intravenous infusion of LPS (5 mg/kg accompanied by procainamide therapy (50 mg/kg. During the experimental period, the changes of hemodynamics, muscle injury index, kidney function, blood gas, blood electrolytes, blood glucose, and plasma interleukin-6 (IL-6 levels were examined. Kidneys and lungs were exercised to analyze superoxide production, neutrophil infiltration, and DNMTs expression. The rats in this model showed similar clinical syndromes and complications of rhabdomyolysis including high levels of plasma creatine kinase, acute kidney injury, hyperkalemia, hypocalcemia, metabolic acidosis, hypotension, tachycardia, and hypoglycemia. The increases of lung DNMT1 expression and plasma IL-6 concentration were also observed in rhabdomyolysis animals induced by LPS. Treatment with procainamide not only inhibited the overexpression of DNMT1 but also diminished the overproduction of IL-6 in rhabdomyolysis rats. In addition, procainamide improved muscle damage, renal dysfunction, electrolytes disturbance, metabolic acidosis, hypotension, and hypoglycemia in the rats with rhabdomyolysis. Moreover, another DNMT inhibitor hydralazine mitigated hypoglycemia, muscle damage, and renal dysfunction in rhabdomyolysis rats. These findings reveal that therapeutic effects of procainamide could be based on the suppression of DNMT1 and pro-inflammatory cytokine in endotoxin-induced rhabdomyolysis.

Therapeutic Effects of Procainamide on Endotoxin-Induced Rhabdomyolysis in Rats.

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Shih, Chih-Chin; Hii, Hiong-Ping; Tsao, Cheng-Ming; Chen, Shiu-Jen; Ka, Shuk-Man; Liao, Mei-Hui; Wu, Chin-Chen

2016-01-01

Overt systemic inflammatory response is a predisposing mechanism for infection-induced skeletal muscle damage and rhabdomyolysis. Aberrant DNA methylation plays a crucial role in the pathophysiology of excessive inflammatory response. The antiarrhythmic drug procainamide is a non-nucleoside inhibitor of DNA methyltransferase 1 (DNMT1) used to alleviate DNA hypermethylation. Therefore, we evaluated the effects of procainamide on the syndromes and complications of rhabdomyolysis rats induced by lipopolysaccharide (LPS). Rhabdomyolysis animal model was established by intravenous infusion of LPS (5 mg/kg) accompanied by procainamide therapy (50 mg/kg). During the experimental period, the changes of hemodynamics, muscle injury index, kidney function, blood gas, blood electrolytes, blood glucose, and plasma interleukin-6 (IL-6) levels were examined. Kidneys and lungs were exercised to analyze superoxide production, neutrophil infiltration, and DNMTs expression. The rats in this model showed similar clinical syndromes and complications of rhabdomyolysis including high levels of plasma creatine kinase, acute kidney injury, hyperkalemia, hypocalcemia, metabolic acidosis, hypotension, tachycardia, and hypoglycemia. The increases of lung DNMT1 expression and plasma IL-6 concentration were also observed in rhabdomyolysis animals induced by LPS. Treatment with procainamide not only inhibited the overexpression of DNMT1 but also diminished the overproduction of IL-6 in rhabdomyolysis rats. In addition, procainamide improved muscle damage, renal dysfunction, electrolytes disturbance, metabolic acidosis, hypotension, and hypoglycemia in the rats with rhabdomyolysis. Moreover, another DNMT inhibitor hydralazine mitigated hypoglycemia, muscle damage, and renal dysfunction in rhabdomyolysis rats. These findings reveal that therapeutic effects of procainamide could be based on the suppression of DNMT1 and pro-inflammatory cytokine in endotoxin-induced rhabdomyolysis.

Alda-1 Protects Against Acrolein-Induced Acute Lung Injury and Endothelial Barrier Dysfunction.

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Lu, Qing; Mundy, Miles; Chambers, Eboni; Lange, Thilo; Newton, Julie; Borgas, Diana; Yao, Hongwei; Choudhary, Gaurav; Basak, Rajshekhar; Oldham, Mahogany; Rounds, Sharon

2017-12-01

Inhalation of acrolein, a highly reactive aldehyde, causes lung edema. The underlying mechanism is poorly understood and there is no effective treatment. In this study, we demonstrated that acrolein not only dose-dependently induced lung edema but also promoted LPS-induced acute lung injury. Importantly, acrolein-induced lung injury was prevented and rescued by Alda-1, an activator of mitochondrial aldehyde dehydrogenase 2. Acrolein also dose-dependently increased monolayer permeability, disrupted adherens junctions and focal adhesion complexes, and caused intercellular gap formation in primary cultured lung microvascular endothelial cells (LMVECs). These effects were attenuated by Alda-1 and the antioxidant N-acetylcysteine, but not by the NADPH inhibitor apocynin. Furthermore, acrolein inhibited AMP-activated protein kinase (AMPK) and increased mitochondrial reactive oxygen species levels in LMVECs-effects that were associated with impaired mitochondrial respiration. AMPK total protein levels were also reduced in lung tissue of mice and LMVECs exposed to acrolein. Activation of AMPK with 5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside blunted an acrolein-induced increase in endothelial monolayer permeability, but not mitochondrial oxidative stress or inhibition of mitochondrial respiration. Our results suggest that acrolein-induced mitochondrial dysfunction may not contribute to endothelial barrier dysfunction. We speculate that detoxification of acrolein by Alda-1 and activation of AMPK may be novel approaches to prevent and treat acrolein-associated acute lung injury, which may occur after smoke inhalation.

Lung Oxidative Stress, DNA Damage, Apoptosis, and Fibrosis in Adenine-Induced Chronic Kidney Disease in Mice

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Abderrahim Nemmar

2017-11-01

Full Text Available It is well-established that there is a crosstalk between the lung and the kidney, and several studies have reported association between chronic kidney disease (CKD and pulmonary pathophysiological changes. Experimentally, CKD can be caused in mice by dietary intake of adenine. Nevertheless, the consequence of such intervention on the lung received only scant attention. Here, we assessed the pulmonary effects of adenine (0.2% w/w in feed for 4 weeks-induced CKD in mice by assessing various physiological histological and biochemical endpoints. Adenine treatment induced a significant increase in urine output, urea and creatinine concentrations, and it decreased the body weight and creatinine clearance. It also increased proteinuria and the urinary levels of kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin. Compared with control group, the histopathological evaluation of lungs from adenine-treated mice showed polymorphonuclear leukocytes infiltration in alveolar and bronchial walls, injury, and fibrosis. Moreover, adenine caused a significant increase in lung lipid peroxidation and reactive oxygen species and decreased the antioxidant catalase. Adenine also induced DNA damage assessed by COMET assay. Similarly, adenine caused apoptosis in the lung characterized by a significant increase of cleaved caspase-3. Moreover, adenine induced a significant increase in the expression of nuclear factor erythroid 2–related factor 2 (Nrf2 in the lung. We conclude that administration of adenine in mice induced CKD is accompanied by lung oxidative stress, DNA damage, apoptosis, and Nrf2 expression and fibrosis.

The Prevalence of Kidney Dysfunction and Associated Risk Factors ...

African Journals Online (AJOL)

Journal Home > Vol 44, No 3 (2017) > ... use of a kidney disease screening algorithm to guide choice of a cART regimen in the absence of serum creatinine. Despite ... Hypertension OR=2.63, (95% CI 1.11, 6.12) was the only factor found to be ...

Early superoxide scavenging accelerates renal microvascular rarefaction and damage in the stenotic kidney.

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Kelsen, Silvia; He, Xiaochen; Chade, Alejandro R

2012-08-15

Renal artery stenosis (RAS), the main cause of chronic renovascular disease (RVD), is associated with significant oxidative stress. Chronic RVD induces renal injury partly by promoting renal microvascular (MV) damage and blunting MV repair in the stenotic kidney. We tested the hypothesis that superoxide anion plays a pivotal role in MV dysfunction, reduction of MV density, and progression of renal injury in the stenotic kidney. RAS was induced in 14 domestic pigs and observed for 6 wk. Seven RAS pigs were chronically treated with the superoxide dismutase mimetic tempol (RAS+T) to reduce oxidative stress. Single-kidney hemodynamics and function were quantified in vivo using multidetector computer tomography (CT) and renal MV density was quantified ex vivo using micro-CT. Expression of angiogenic, inflammatory, and apoptotic factors was measured in renal tissue, and renal apoptosis and fibrosis were quantified in tissue sections. The degree of RAS and blood pressure were similarly increased in RAS and RAS+T. Renal blood flow (RBF) and glomerular filtration rate (GFR) were reduced in the stenotic kidney (280.1 ± 36.8 and 34.2 ± 3.1 ml/min, P < 0.05 vs. control). RAS+T kidneys showed preserved GFR (58.5 ± 6.3 ml/min, P = not significant vs. control) but a similar decreases in RBF (293.6 ± 85.2 ml/min) and further decreases in MV density compared with RAS. These changes were accompanied by blunted angiogenic signaling and increased apoptosis and fibrosis in the stenotic kidney of RAS+T compared with RAS. The current study shows that tempol administration provided limited protection to the stenotic kidney. Despite preserved GFR, renal perfusion was not improved by tempol, and MV density was further reduced compared with untreated RAS, associated with increased renal apoptosis and fibrosis. These results suggest that a tight balance of the renal redox status is necessary for a normal MV repair response to injury, at least at the early stage of RVD, and raise caution

Induced Pluripotent Stem Cells-Derived Mesenchymal Stem Cells Attenuate Cigarette Smoke-Induced Cardiac Remodeling and Dysfunction

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Yingmin Liang

2017-07-01

Full Text Available The strong relationship between cigarette smoking and cardiovascular disease (CVD has been well-documented, but the mechanisms by which smoking increases CVD risk appear to be multifactorial and incompletely understood. Mesenchymal stem cells (MSCs are regarded as an important candidate for cell-based therapy in CVD. We hypothesized that MSCs derived from induced pluripotent stem cell (iPSC-MSCs or bone marrow (BM-MSCs might alleviate cigarette smoke (CS-induced cardiac injury. This study aimed to investigate the effects of BM-MSCs or iPSC-MSCs on CS-induced changes in serum and cardiac lipid profiles, oxidative stress and inflammation as well as cardiac function in a rat model of passive smoking. Male Sprague-Dawley rats were randomly selected for exposure to either sham air (SA as control or 4% CS for 1 h per day for 56 days. On day 29 and 43, human adult BM-MSCs, iPSC-MSCs or PBS were administered intravenously to CS-exposed rats. Results from echocardiography, serum and cardiac lipid profiles, cardiac antioxidant capacity, cardiac pro- and anti-inflammatory cytokines and cardiac morphological changes were evaluated at the end of treatment. iPSC-MSC-treated group showed a greater effect in the improvement of CS-induced cardiac dysfunction over BM-MSCs-treated group as shown by increased percentage left ventricular ejection fraction and percentage fractional shortening, in line with the greater reversal of cardiac lipid abnormality. In addition, iPSC-MSCs administration attenuated CS-induced elevation of cardiac pro-inflammatory cytokines as well as restoration of anti-inflammatory cytokines and anti-oxidative markers, leading to ameliorate cardiac morphological abnormalities. These data suggest that iPSC-MSCs on one hand may restore CS-induced cardiac lipid abnormality and on the other hand may attenuate cardiac oxidative stress and inflammation via inhibition of CS-induced NF-κB activation, leading to improvement of cardiac remodeling and

Dietary management of chronic kidney disease: protein restriction and beyond.

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Goraya, Nimrit; Wesson, Donald E

2012-11-01

More kidney protective strategies are needed to reduce the burden of complete kidney failure from chronic kidney disease (CKD). Clinicians sometimes use protein restriction as kidney protection despite its demonstrated lack of effectiveness in the only large-scale study. Small-scale studies support that dietary acid reduction is kidney-protective, including when done with base-inducing foods like fruits and vegetables. We review these studies in light of current kidney-protective recommendations. Animal models of CKD show that acid-inducing dietary protein exacerbates and base-inducing protein ameliorates nephropathy progression, and that increased intake of acid-inducing but not base-inducing dietary protein exacerbates progression. Clinical studies show that dietary acid reduction with Na-based alkali reduces kidney injury and slows nephropathy progression in patients with CKD and reduced glomerular filtration rate (GFR); base-inducing fruits and vegetables reduce kidney injury in patients with reduced GFR; and base-inducing fruits and vegetables improve metabolic acidosis in CKD. Protein type rather than amount might more importantly affect nephropathy progression. Base-inducing foods might be another way to reduce dietary acid, a strategy shown in small studies to slow nephropathy progression. Further studies will determine if CKD patients should be given base-inducing food as part of their management.

Cardio-renal syndromes: a systematic approach for consensus definition and classification.

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Ronco, Claudio; Ronco, Federico

2012-03-01

The "Cardio-Renal Syndrome" (CRS) is a disorder of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other. The general definition has been expanded to five subtypes reflecting the primacy of organ dysfunction and the time-frame of the syndrome: CRS type I: acute worsening of heart function (AHF-ACS) leading to kidney injury and/or dysfunction. CRS type II: chronic abnormalities in heart function (CHF-CHD) leading to kidney injury or dysfunction. CRS type III: acute worsening of kidney function (AKI) leading to heart injury and/or dysfunction. CRS type IV: chronic kidney disease (CKD) leading to heart injury, disease and/or dysfunction. CRS type V: systemic conditions leading to simultaneous injury and/or dysfunction of heart and kidney. Different pathophysiological mechanisms are involved in the combined dysfunction of heart and kidney in these five types of the syndrome.

Andrographolide induced acute kidney injury: analysis of 26 cases reported in Chinese Literature.

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Zhang, Wu-Xing; Zhang, Zhi-Min; Zhang, Zhi-Qiang; Wang, Yang; Zhou, Wei

2014-01-01

Some Chinese herbs have been known for their kidney toxicity. Andrographolide, the primary component of a traditional medicinal herb, Andrographis paniculata, is widely used in China for the treatment of upper and lower respiratory tract infection, and dysentery etc. The aim of the study was to identify and summarize any case of kidney injury attributed to its use in the Chinese literature. A systemic analysis of the Chinese literature from January 1978 to August 2013 was conducted of case reports of andrographolide induced acute kidney injury (AKI). We identified 26 cases of andrographolide induced AKI (22 males and four females), with an average age of 31.3 years (range: 21 months to 47 years). 100-750 mg (58% 500 mg) of andrographolide was administered in 100-500 mL 5% glucose solution or normal saline by intravenous drip once a day. The adverse event appeared after one to six doses (19 [73.1%] patients got only one dose; cumulative dose 690 ± 670 mg) of andrographolide was given, or 0-96 h (median 1 h) after andrographolide was given. The symptoms included flank pain in 23 cases (88.5%), decreased urine volume in five cases (19.2%), and nausea or vomiting in six cases (23.1%). Laboratory tests showed maximum creatinine 352.8 ± 184.1 (158-889) μmol/L and blood urea nitrogen 12.1 ± 7.6 (4.0-40.6) mmol/L. Urine analysis showed proteinuria in 10 (38.5%) cases and occult blood in eight (30.8%) cases. Kidney biopsy was carried out in two cases and both revealed acute tubular necrosis. Management of this adverse event included withdrawal of the culprit drug, conservative therapy, and renal replacement therapy (six cases, 23.1%). All the patients recovered and were discharged with a normal or close to normal serum creatinine. Their average length of hospital stay was 12.1 ± 4.8 days. Acute kidney injury may occur shortly after intravenous infusion of andrographolide, with symptoms including flank pain, decreased urine output, and

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

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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.

Clinico-pathological features of kidney disease in diabetic cases.

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Furuichi, Kengo; Shimizu, Miho; Okada, Hirokazu; Narita, Ichiei; Wada, Takashi

2018-03-21

Diabetic kidney disease is the major cause of end-stage kidney disease in developed countries. However, the onset of kidney disorder and the progression pattern of kidney dysfunction and proteinuria greatly vary cases by cases. Therefore, risk classification with clinical data and pathological findings is important. Recent clinico-pathological study with kidney biopsy samples from diabetic patients revealed that pathological changes of diabetic nephropathy are characteristic and have special impacts on prognosis in each clinical stage. Moreover, comparison of the clinico-pathological findings of diabetic nephropathy with hypertensive nephrosclerosis revealed that there are few differences in their pathological findings in cases with low albuminuria and preserved estimated glomerular filtration rate (eGFR). Because it is so difficult to clearly distinguish pure kidney lesions caused by diabetes and kidney lesions due to effects other than diabetes, it is vital that these overlapped pathological findings be confirmed on kidney biopsy in cases of early stage diabetes. Further research is warranted regarding the pathogenesis of diabetic nephropathy and indication of kidney biopsy in diabetic cases.

4-Phenylbutyrate inhibits tunicamycin-induced acute kidney injury via CHOP/GADD153 repression.

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Rachel E Carlisle

Full Text Available Different forms of acute kidney injury (AKI have been associated with endoplasmic reticulum (ER stress; these include AKI caused by acetaminophen, antibiotics, cisplatin, and radiocontrast. Tunicamycin (TM is a nucleoside antibiotic known to induce ER stress and is a commonly used inducer of AKI. 4-phenylbutyrate (4-PBA is an FDA approved substance used in children who suffer from urea cycle disorders. 4-PBA acts as an ER stress inhibitor by aiding in protein folding at the molecular level and preventing misfolded protein aggregation. The main objective of this study was to determine if 4-PBA could protect from AKI induced by ER stress, as typified by the TM-model, and what mechanism(s of 4-PBA's action were responsible for protection. C57BL/6 mice were treated with saline, TM or TM plus 4-PBA. 4-PBA partially protected the anatomic segment most susceptible to damage, the outer medullary stripe, from TM-induced AKI. In vitro work showed that 4-PBA protected human proximal tubular cells from apoptosis and TM-induced CHOP expression, an ER stress inducible proapoptotic gene. Further, immunofluorescent staining in the animal model found similar protection by 4-PBA from CHOP nuclear translocation in the tubular epithelium of the medulla. This was accompanied by a reduction in apoptosis and GRP78 expression. CHOP(-/- mice were protected from TM-induced AKI. The protective effects of 4-PBA extended to the ultrastructural integrity of proximal tubule cells in the outer medulla. When taken together, these results indicate that 4-PBA acts as an ER stress inhibitor, to partially protect the kidney from TM-induced AKI through the repression of ER stress-induced CHOP expression.

Long distance run induced hydration and kidney function changes in marathoners

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Luiz Guilherme Cruz Gonçalves

2015-09-01

Full Text Available AbstractThe aim of the study was to verify the hydration status and the kidney function in marathoners during the training season and after a marathon race. Nine male runners were investigated during 12 weeks of training. Urine was collected in four moments; in the beginning (C1 and during (C2 the training program, before (C3 and after (C4 the competition. Urine pH was measured using reagent tapes, urine density with a refractometer, protein excretion by Bradford assay and erythrocytes and leucocytes by microscopy. Changes were observed when C-4 was compared to the other collection times for all variables investigated. It is possible to conclude that physical exertion induced important changes in the hydration status and glomerular membrane selectivity to macromolecules, modifying the kidney function of the marathoners in C4.

Synthetic marijuana and acute kidney injury: an unforeseen association.

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Kazory, Amir; Aiyer, Ravi

2013-06-01

Synthetic cannabinoids (SCs) have emerged as drugs of abuse with increasing popularity among young adults. The potential renal complication related to the abuse of SC was not recognized until recently. Here, we present a case of severe acute kidney injury (AKI) that developed after inhalation of SC in an otherwise healthy young patient. A kidney biopsy revealed severe acute tubular necrosis, and supportive management resulted in the recovery of the kidney function. Herein, we briefly summarize the only two previous reports (a total of 21 cases) on the association between SC abuse and renal dysfunction and identify the common aspects in all observations.

Functional recovery in the irradiated kidney following removal of the contralateral unirradiated kidney

International Nuclear Information System (INIS)

Robbins, M.E.C.; Hopewell, J.W.; Golding, S.J.

1986-01-01

Radiation-induced damage to one kidney in the pig causes a fall in total renal function; this would be recognised and lead to a compensatory response in the unirradiated kidney. The presence of the unirradiated contralateral kidney may effectively prevent the irradiated kidney from expressing any potential for repair and/or recovery of function. If this were true then the question would obviously arise, does the irradiated kidney retain some capacity for recovery? In order to answer this question, the contralateral unirradiated kidney was removed from pigs 26 weeks after the irradiation of the other kidney. The subsequent response of the irradiated kidney to nephrectomy was assessed in terms of the changes in renal size and haemodynamics, i.e. GFR and effective renal plasma flow (ERPF). (Auth.)

Cardiac-specific overexpression of catalase attenuates lipopolysaccharide-induced myocardial contractile dysfunction: role of autophagy.

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Turdi, Subat; Han, Xuefeng; Huff, Anna F; Roe, Nathan D; Hu, Nan; Gao, Feng; Ren, Jun

2012-09-15

Lipopolysaccharide (LPS) from gram-negative bacteria is a major initiator of sepsis, leading to cardiovascular collapse. Accumulating evidence has indicated a role of reactive oxygen species (ROS) in cardiovascular complications in sepsis. This study was designed to examine the effect of cardiac-specific overexpression of catalase in LPS-induced cardiac contractile dysfunction and the underlying mechanism(s) with a focus on autophagy. Catalase transgenic and wild-type FVB mice were challenged with LPS (6 mg/kg) and cardiac function was evaluated. Levels of oxidative stress, autophagy, apoptosis, and protein damage were examined using fluorescence microscopy, Western blot, TUNEL assay, caspase-3 activity, and carbonyl formation. A Kaplan-Meier curve was constructed for survival after LPS treatment. Our results revealed a lower mortality in catalase mice compared with FVB mice after LPS challenge. LPS injection led to depressed cardiac contractile capacity as evidenced by echocardiography and cardiomyocyte contractile function, the effect of which was ablated by catalase overexpression. LPS treatment induced elevated TNF-α level, autophagy, apoptosis (TUNEL, caspase-3 activation, cleaved caspase-3), production of ROS and O(2)(-), and protein carbonyl formation, the effects of which were significantly attenuated by catalase overexpression. Electron microscopy revealed focal myocardial damage characterized by mitochondrial injury after LPS treatment, which was less severe in catalase mice. Interestingly, LPS-induced cardiomyocyte contractile dysfunction was prevented by the antioxidant N-acetylcysteine and the autophagy inhibitor 3-methyladenine. Taken together, our data revealed that catalase protects against LPS-induced cardiac dysfunction and mortality, which may be associated with inhibition of oxidative stress and autophagy. Copyright © 2012 Elsevier Inc. All rights reserved.

Mesenchymal stem cells correct haemodynamic dysfunction associated with liver injury after extended resection in a pig model.

Science.gov (United States)

Tautenhahn, Hans-Michael; Brückner, Sandra; Uder, Christiane; Erler, Silvio; Hempel, Madlen; von Bergen, Martin; Brach, Janine; Winkler, Sandra; Pankow, Franziska; Gittel, Claudia; Baunack, Manja; Lange, Undine; Broschewitz, Johannes; Dollinger, Matthias; Bartels, Michael; Pietsch, Uta; Amann, Kerstin; Christ, Bruno

2017-06-01

In patients, acute kidney injury (AKI) is often due to haemodynamic impairment associated with hepatic decompensation following extended liver surgery. Mesenchymal stem cells (MSCs) supported tissue protection in a variety of acute and chronic diseases, and might hence ameliorate AKI induced by extended liver resection. Here, 70% liver resection was performed in male pigs. MSCs were infused through a central venous catheter and haemodynamic parameters as well as markers of acute kidney damage were monitored under intensive care conditions for 24 h post-surgery. Cytokine profiles were established to anticipate the MSCs' potential mode of action. After extended liver resection, hyperdynamic circulation, associated with hyponatraemia, hyperkalaemia, an increase in serum aldosterone and low urine production developed. These signs of hepatorenal dysfunction and haemodynamic impairment were corrected by MSC treatment. MSCs elevated PDGF levels in the serum, possibly contributing to circulatory homeostasis. Another 14 cytokines were increased in the kidney, most of which are known to support tissue regeneration. In conclusion, MSCs supported kidney and liver function after extended liver resection. They probably acted through paracrine mechanisms improving haemodynamics and tissue homeostasis. They might thus provide a promising strategy to prevent acute kidney injury in the context of post-surgery acute liver failure.

Assessment of cisplatin-induced kidney injury using an integrated rodent platform

Energy Technology Data Exchange (ETDEWEB)

Chen, Yafei [Global Safety Assessment, AstraZeneca R and D Waltham, MA 02451 (United States); Brott, David [Patient Safety, AstraZeneca R and D Wilmington, DE 19850 (United States); Luo, Wenli [Discovery Statistics, AstraZeneca R and D Waltham, MA 02451 (United States); Gangl, Eric [DMPK, AstraZeneca R and D Waltham, MA 02451 (United States); Kamendi, Harriet; Barthlow, Herbert; Lengel, David; Fikes, James; Kinter, Lewis [Global Safety Assessment, AstraZeneca R and D Waltham, MA 02451 (United States); Valentin, Jean-Pierre [Global Safety Assessment, AstraZeneca R and D Alderley Park, Macclesfield, SK10 4TG (United Kingdom); Bialecki, Russell, E-mail: russell.bialecki@astrazeneca.com [Global Safety Assessment, AstraZeneca R and D Waltham, MA 02451 (United States)

2013-05-01

Current diagnosis of drug-induced kidney injury (DIKI) primarily relies on detection of elevated plasma creatinine (Cr) or blood urea nitrogen (BUN) levels; however, both are indices of overall kidney function and changes are delayed with respect to onset of nephron injury. Our aim was to investigate whether early changes in new urinary DIKI biomarkers predict plasma Cr, BUN, renal hemodynamic and kidney morphological changes associated with kidney injury following a single dose of cisplatin (CDDP) using an integrated platform in rodent. Conscious surgically prepared male Han Wistar rats were given a single intraperitoneal dose of CDDP (15 mg/kg). Glomerular filtration rate (GFR), effective renal plasma flow (ERPF), urinalysis, DIKI biomarkers, CDDP pharmacokinetics, blood pressures, heart rate, body temperature and electroencephalogram (EEG) were measured in the same vehicle- or CDDP-treated animals over 72 h. Plasma chemistry (including Cr and BUN) and renal tissues were examined at study termination. Cisplatin caused progressive reductions of GFR, ERPF, heart rate and body temperature from day 1 (0–24 h). DIKI biomarkers including alpha-glutathione S-transferase (α-GST) significantly increased as early as 6 h post-dose, which preceded significant declines of GFR and ERPF (24 h), increased plasma Cr and BUN (72 h), and associated with renal acute tubular necrosis at 72 h post-dose. The present study adds to the current understanding of CDDP action by demonstrating that early increases in urinary excretion of α-GST predict DIKI risk following acute exposure to CDDP in rats, before changes in traditional DIKI markers are evident. - Highlights: ► CDDP causes direct damage to kidneys without affecting EEG or CVS function. ► α-GST and albumin detect DIKI earlier when compared with traditional indices. ► Integrated “cardiovascular-EEG-renal” model to better understand DIKI mechanisms ► Promotes 3R's principles in drug discovery and development.

Assessment of cisplatin-induced kidney injury using an integrated rodent platform

International Nuclear Information System (INIS)

Chen, Yafei; Brott, David; Luo, Wenli; Gangl, Eric; Kamendi, Harriet; Barthlow, Herbert; Lengel, David; Fikes, James; Kinter, Lewis; Valentin, Jean-Pierre; Bialecki, Russell

2013-01-01

Current diagnosis of drug-induced kidney injury (DIKI) primarily relies on detection of elevated plasma creatinine (Cr) or blood urea nitrogen (BUN) levels; however, both are indices of overall kidney function and changes are delayed with respect to onset of nephron injury. Our aim was to investigate whether early changes in new urinary DIKI biomarkers predict plasma Cr, BUN, renal hemodynamic and kidney morphological changes associated with kidney injury following a single dose of cisplatin (CDDP) using an integrated platform in rodent. Conscious surgically prepared male Han Wistar rats were given a single intraperitoneal dose of CDDP (15 mg/kg). Glomerular filtration rate (GFR), effective renal plasma flow (ERPF), urinalysis, DIKI biomarkers, CDDP pharmacokinetics, blood pressures, heart rate, body temperature and electroencephalogram (EEG) were measured in the same vehicle- or CDDP-treated animals over 72 h. Plasma chemistry (including Cr and BUN) and renal tissues were examined at study termination. Cisplatin caused progressive reductions of GFR, ERPF, heart rate and body temperature from day 1 (0–24 h). DIKI biomarkers including alpha-glutathione S-transferase (α-GST) significantly increased as early as 6 h post-dose, which preceded significant declines of GFR and ERPF (24 h), increased plasma Cr and BUN (72 h), and associated with renal acute tubular necrosis at 72 h post-dose. The present study adds to the current understanding of CDDP action by demonstrating that early increases in urinary excretion of α-GST predict DIKI risk following acute exposure to CDDP in rats, before changes in traditional DIKI markers are evident. - Highlights: ► CDDP causes direct damage to kidneys without affecting EEG or CVS function. ► α-GST and albumin detect DIKI earlier when compared with traditional indices. ► Integrated “cardiovascular-EEG-renal” model to better understand DIKI mechanisms ► Promotes 3R's principles in drug discovery and development

Acetylcholine serves as a derepressor in Loperamide-induced Opioid-Induced Bowel Dysfunction (OIBD) in zebrafish

OpenAIRE

Shi, Yanyan; Zhang, Yu; Zhao, Fangying; Ruan, Hua; Huang, Honghui; Luo, Lingfei; Li, Li

2014-01-01

The mechanisms underlying gut development, especially peristalsis, are widely studied topics. However, the causes of gut peristalsis-related diseases, especially Opioid-Induced Bowel Dysfunction (OIBD) disorder, have not been well defined. Therefore, our study used zebrafish, a popular model for studying both gut development and peristalsis, and DCFH-DA, a dye that clearly labels the live fish gut lumen, to characterize the formation process of gut lumen as well as the gut movement style in v...

Resolvin D1 Protects Lipopolysaccharide-induced Acute Kidney Injury by Down-regulating Nuclear Factor-kappa B Signal and Inhibiting Apoptosis

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Yu-Liang Zhao

2016-01-01

Conclusion: In LPS-induced AKI, RvD1 could decrease TNF-α level, ameliorate kidney pathological injury, protect kidney function, and improve animal survival by down-regulating NF-κB inflammatory signal as well as inhibiting renal cell apoptosis.

Autophagy Limits Endotoxemic Acute Kidney Injury and Alters Renal Tubular Epithelial Cell Cytokine Expression.

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Jeremy S Leventhal

Full Text Available Sepsis related acute kidney injury (AKI is a common in-hospital complication with a dismal prognosis. Our incomplete understanding of disease pathogenesis has prevented the identification of hypothesis-driven preventive or therapeutic interventions. Increasing evidence in ischemia-reperfusion and nephrotoxic mouse models of AKI support the theory that autophagy protects renal tubular epithelial cells (RTEC from injury. However, the role of RTEC autophagy in septic AKI remains unclear. We observed that lipopolysaccharide (LPS, a mediator of gram-negative bacterial sepsis, induces RTEC autophagy in vivo and in vitro through TLR4-initiated signaling. We modeled septic AKI through intraperitoneal LPS injection in mice in which autophagy-related protein 7 was specifically knocked out in the renal proximal tubules (ATG7KO. Compared to control littermates, ATG7KO mice developed more severe renal dysfunction (24hr BUN 100.1mg/dl +/- 14.8 vs 54.6mg/dl +/- 11.3 and parenchymal injury. After injection with LPS, analysis of kidney lysates identified higher IL-6 expression and increased STAT3 activation in kidney lysates from ATG7KO mice compared to controls. In vitro experiments confirmed an altered response to LPS in RTEC with genetic or pharmacological impairment of autophagy. In conclusion, RTEC autophagy protects against endotoxin induced injury and regulates downstream effects of RTEC TLR4 signaling.

Artesunate Protects Against the Organ Injury and Dysfunction Induced by Severe Hemorrhage and Resuscitation.

Science.gov (United States)

Sordi, Regina; Nandra, Kiran K; Chiazza, Fausto; Johnson, Florence L; Cabrera, Claudia P; Torrance, Hew D; Yamada, Noriaki; Patel, Nimesh S A; Barnes, Michael R; Brohi, Karim; Collino, Massimo; Thiemermann, Christoph

2017-02-01

To evaluate the effects of artesunate on organ injury and dysfunction associated with hemorrhagic shock (HS) in the rat. HS is still a common cause of death in severely injured patients and is characterized by impairment of organ perfusion, systemic inflammatory response, and multiple organ failure. There is no specific therapy that reduces organ injury/dysfunction. Artesunate exhibits pharmacological actions beyond its antimalarial activity, such as anticancer, antiviral, and anti-inflammatory effects. Rats were submitted to HS. Mean arterial pressure was reduced to 30 mm Hg for 90 minutes, followed by resuscitation. Rats were randomly treated with artesunate (2.4 or 4.8 mg/kg i.v.) or vehicle upon resuscitation. Four hours later, parameters of organ injury and dysfunction were assessed. Artesunate attenuated the multiple organ injury and dysfunction caused by HS. Pathway analysis of RNA sequencing provided good evidence to support an effect of artesunate on the Akt-survival pathway, leading to downregulation of interleukin-1 receptor-associated kinase 1. Using Western blot analysis, we confirmed that treatment of HS rats with artesunate enhanced the phosphorylation (activation) of Protein kinase B (Akt) and endothelial nitric oxide synthase and the phosphorylation (inhibition) of glycogen synthase kinase-3β (GSK-3β). Moreover, artesunate attenuated the HS-induced activation of nuclear factor kappa B and reduced the expression of proinflammatory proteins (inducible nitric oxide synthase, tumor necrosis factor-α, and interleukin 6). Artesunate attenuated the organ injury/dysfunction associated with HS by a mechanism that involves the activation of the Akt-endothelial nitric oxide synthase survival pathway, and the inhibition of glycogen synthase kinase-3β and nuclear factor kappa B. A phase II clinical trial evaluating the effects of good manufacturing practice-artesunate in patients with trauma and severe hemorrhage is planned.

Emerging therapies for patients with symptoms of opioid-induced bowel dysfunction

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Leppert W

2015-04-01

Full Text Available Wojciech Leppert Chair and Department of Palliative Medicine, Poznan University of Medical Sciences, Poznan, Poland Abstract: Opioid-induced bowel dysfunction (OIBD comprises gastrointestinal (GI symptoms, including dry mouth, nausea, vomiting, gastric stasis, bloating, abdominal pain, and opioid-induced constipation, which significantly impair patients’ quality of life and may lead to undertreatment of pain. Traditional laxatives are often prescribed for OIBD symptoms, although they display limited efficacy and exert adverse effects. Other strategies include prokinetics and change of opioids or their administration route. However, these approaches do not address underlying causes of OIBD associated with opioid effects on mostly peripheral opioid receptors located in the GI tract. Targeted management of OIBD comprises purely peripherally acting opioid receptor antagonists and a combination of opioid receptor agonist and antagonist. Methylnaltrexone induces laxation in 50%–60% of patients with advanced diseases and OIBD who do not respond to traditional oral laxatives without inducing opioid withdrawal symptoms with similar response (45%–50% after an oral administration of naloxegol. A combination of prolonged-release oxycodone with prolonged-release naloxone (OXN in one tablet (a ratio of 2:1 provides analgesia with limited negative effect on the bowel function, as oxycodone displays high oral bioavailability and naloxone demonstrates local antagonist effect on opioid receptors in the GI tract and is totally inactivated in the liver. OXN in daily doses of up to 80 mg/40 mg provides equally effective analgesia with improved bowel function compared to oxycodone administered alone in patients with chronic non-malignant and cancer-related pain. OIBD is a common complication of long-term opioid therapy and may lead to quality of life deterioration and undertreatment of pain. Thus, a complex assessment and management that addresses underlying

Drug dosing in chronic kidney disease.

Science.gov (United States)

Gabardi, Steven; Abramson, Stuart

2005-05-01

Patients with chronic kidney disease (CKD) are at high risk for adverse drug reactions and drug-drug interactions. Drug dosing in these patients often proves to be a difficult task. Renal dysfunction-induced changes in human pathophysiology regularly results may alter medication pharmacodynamics and handling. Several pharmacokinetic parameters are adversely affected by CKD, secondary to a reduced oral absorption and glomerular filtration; altered tubular secretion; and reabsorption and changes in intestinal, hepatic, and renal metabolism. In general, drug dosing can be accomplished by multiple methods; however, the most common recommendations are often to reduce the dose or expand the dosing interval, or use both methods simultaneously. Some medications need to be avoided all together in CKD either because of lack of efficacy or increased risk of toxicity. Nevertheless, specific recommendations are available for dosing of certain medications and are an important resource, because most are based on clinical or pharmacokinetic trials.

Livolin Forte Ameliorates Cadmium-Induced Kidney Injury in Wistar Rats

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Akomolafe Rufus O.

2016-06-01

Full Text Available The kidney, which is an integral part of the drug excretion system, was reported as one of the targets of cadmium toxicity. Early events of cadmium toxicity in the cell include a decrease in cell membrane fluidity, breakdown of its integrity, and impairment of its repair mechanisms. Phosphatidylcholine and vitamin E have a marked fluidizing effect on cellular membranes. We hypothesized that Livolin forte (LIV could attenuate kidney damage induced by cadmium in rats. Twenty-five adult male Wistar rats were divided into five groups of five rats each: group I (control group received 0.3 ml/kg/day of propylene glycol for six weeks; group II was given 5 mg/kg/day of cadmium (Cd i.p for 5 consecutive days; group III rats were treated in a similar way as group II but were allowed a recovery period of 4 weeks; group IV was treated with LIV (5.2 mg/kg/day for a period of 4 weeks after inducing renal injury with Cd similarly to group II; and group V was allowed a recovery period of 2 weeks after a 4-week LIV treatment (5.2 mg/kg/day following Cd administration. A significant increase in plasma creatinine, urea, uric acid, and TBARS were observed in groups II and III compared to the control rats. Significant reductions in total protein, glucose, and GSH activity were also recorded. The urine concentrations of creatinine, urea, and uric acid in groups II and III were significantly lower than the control group. Th is finding was accompanied by a significant decrease in creatinine and urea clearance. Post-treatment with LIV caused significant decreases in plasma creatinine, urea, uric acid, and TBARS. Significant increases in total protein, glucose, and GSH activity of groups IV and V were observed compared to group II. A significant increase in urine concentrations of creatinine, urea, and uric acid and significant decreases in total protein, glucose, and GSH activity were observed in groups IV and V compared to group II. Photomicrographs of the rat kidneys

Rosmarinic Acid Alleviates the Endothelial Dysfunction Induced by Hydrogen Peroxide in Rat Aortic Rings via Activation of AMPK

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Hui Zhou

2017-01-01

Full Text Available Endothelial dysfunction is the key player in the development and progression of vascular events. Oxidative stress is involved in endothelial injury. Rosmarinic acid (RA is a natural polyphenol with antioxidative, antiapoptotic, and anti-inflammatory properties. The present study investigates the protective effect of RA on endothelial dysfunction induced by hydrogen peroxide (H2O2. Compared with endothelium-denuded aortic rings, the endothelium significantly alleviated the decrease of vasoconstrictive reactivity to PE and KCl induced by H2O2. H2O2 pretreatment significantly injured the vasodilative reactivity to ACh in endothelium-intact aortic rings in a concentration-dependent manner. RA individual pretreatment had no obvious effect on the vasoconstrictive reaction to PE and KCl, while its cotreatment obviously mitigated the endothelium-dependent relaxation impairments and the oxidative stress induced by H2O2. The RA cotreatment reversed the downregulation of AMPK and eNOS phosphorylation induced by H2O2 in HAEC cells. The pretreatment with the inhibitors of AMPK (compound C and eNOS (L-NAME wiped off RA’s beneficial effects. All these results demonstrated that RA attenuated the endothelial dysfunction induced by oxidative stress by activating the AMPK/eNOS pathway.

Inhibition of CYP2E1 attenuates chronic alcohol intake-induced myocardial contractile dysfunction and apoptosis.

Science.gov (United States)

Zhang, Rong-Huai; Gao, Jian-Yuan; Guo, Hai-Tao; Scott, Glenda I; Eason, Anna R; Wang, Xiao-Ming; Ren, Jun

2013-01-01

Alcohol intake is associated with myocardial contractile dysfunction and apoptosis although the precise mechanism is unclear. This study was designed to examine the effect of the cytochrome P450 enzyme CYP2E1 inhibition on ethanol-induced cardiac dysfunction. Adult male mice were fed a 4% ethanol liquid or pair-fed control diet for 6weeks. Following 2weeks of diet feeding, a cohort of mice started to receive the CYP2E1 inhibitor diallyl sulfide (100mg/kg/d, i.p.) for the remaining feeding duration. Cardiac function was assessed using echocardiographic and IonOptix systems. Western blot analysis was used to evaluate CYP2E1, heme oxygenase-1 (HO-1), iNOS, the intracellular Ca(2+) regulatory proteins sarco(endo)plasmic reticulum Ca(2+)-ATPase, Na(+)Ca(2+) exchanger and phospholamban, pro-apoptotic protein cleaved caspase-3, Bax, c-Jun-NH(2)-terminal kinase (JNK) and apoptosis signal-regulating kinase (ASK-1). Ethanol led to elevated levels of CYP2E1, iNOS and phospholamban, decreased levels of HO-1 and Na(+)Ca(2+) exchanger, cardiac contractile and intracellular Ca(2+) defects, cardiac fibrosis, overt O(2)(-) production, and apoptosis accompanied with increased phosphorylation of JNK and ASK-1, the effects were significantly attenuated or ablated by diallyl sulfide. Inhibitors of JNK and ASK-1 but not HO-1 inducer or iNOS inhibitor obliterated ethanol-induced cardiomyocyte contractile dysfunction, substantiating a role for JNK and ASK-1 signaling in ethanol-induced myocardial injury. Taken together, these findings suggest that ethanol metabolism through CYP2E1 may contribute to the pathogenesis of alcoholic cardiomyopathy including myocardial contractile dysfunction, oxidative stress and apoptosis, possibly through activation of JNK and ASK-1 signaling. Copyright © 2012 Elsevier B.V. All rights reserved.

T1-mapping for assessment of ischemia-induced acute kidney injury and prediction of chronic kidney disease in mice

Energy Technology Data Exchange (ETDEWEB)

Hueper, Katja; Gutberlet, Marcel; Wacker, Frank; Hartung, Dagmar [Hannover Medical School, Department of Radiology, Hannover (Germany); Hannover Medical School, REBIRTH Cluster of Excellence, Hannover (Germany); Peperhove, Matti; Tewes, Susanne; Barrmeyer, Amelie [Hannover Medical School, Department of Radiology, Hannover (Germany); Rong, Song [Hannover Medical School, Department of Nephrology, Hannover (Germany); Zunyi Medical College, Laboratory of Organ Transplantation, Zunyi (China); Gerstenberg, Jessica; Haller, Herman; Gueler, Faikah [Hannover Medical School, Department of Nephrology, Hannover (Germany); Mengel, Michael [University of Alberta, Department of Laboratory Medicine and Pathology, Edmonton (Canada); Meier, Martin [Hannover Medical School, REBIRTH Cluster of Excellence, Hannover (Germany); Hannover Medical School, Institute for Animal Science, Hannover (Germany); Chen, Rongjun [Hannover Medical School, Department of Nephrology, Hannover (Germany); Zhejiang University, The Kidney Disease Center of the First Affiliated Hospital, Hangzhou (China)

2014-09-15

To investigate whether T1-mapping allows assessment of acute kidney injury (AKI) and prediction of chronic kidney disease (CKD) in mice. AKI was induced in C57Bl/6N mice by clamping of the right renal pedicle for 35 min (moderate AKI, n = 26) or 45 min (severe AKI, n = 23). Sham animals served as controls (n = 9). Renal histology was assessed in the acute (day 1 + day 7; d1 + d7) and chronic phase (d28) after AKI. Furthermore, longitudinal MRI-examinations (prior to until d28 after surgery) were performed using a 7-Tesla magnet. T1-maps were calculated from a fat-saturated echoplanar inversion recovery sequence, and mean and relative T1-relaxation times were determined. Renal histology showed severe tubular injury at d1 + d7 in both AKI groups, whereas, at d28, only animals with prolonged 45-min ischemia showed persistent signs of AKI. Following both AKI severities T1-values significantly increased and peaked at d7. T1-times in the contralateral kidney without AKI remained stable. At d7 relative T1-values in the outer stripe of the outer medulla were significantly higher after severe than after moderate AKI (138 ± 2 % vs. 121 ± 3 %, p = 0.001). T1-elevation persisted until d28 only after severe AKI. Already at d7 T1 in the outer stripe of the outer medulla correlated with kidney volume loss indicating CKD (r = 0.83). T1-mapping non-invasively detects AKI severity in mice and predicts further outcome. (orig.)

T1-mapping for assessment of ischemia-induced acute kidney injury and prediction of chronic kidney disease in mice

International Nuclear Information System (INIS)

Hueper, Katja; Gutberlet, Marcel; Wacker, Frank; Hartung, Dagmar; Peperhove, Matti; Tewes, Susanne; Barrmeyer, Amelie; Rong, Song; Gerstenberg, Jessica; Haller, Herman; Gueler, Faikah; Mengel, Michael; Meier, Martin; Chen, Rongjun

2014-01-01

To investigate whether T1-mapping allows assessment of acute kidney injury (AKI) and prediction of chronic kidney disease (CKD) in mice. AKI was induced in C57Bl/6N mice by clamping of the right renal pedicle for 35 min (moderate AKI, n = 26) or 45 min (severe AKI, n = 23). Sham animals served as controls (n = 9). Renal histology was assessed in the acute (day 1 + day 7; d1 + d7) and chronic phase (d28) after AKI. Furthermore, longitudinal MRI-examinations (prior to until d28 after surgery) were performed using a 7-Tesla magnet. T1-maps were calculated from a fat-saturated echoplanar inversion recovery sequence, and mean and relative T1-relaxation times were determined. Renal histology showed severe tubular injury at d1 + d7 in both AKI groups, whereas, at d28, only animals with prolonged 45-min ischemia showed persistent signs of AKI. Following both AKI severities T1-values significantly increased and peaked at d7. T1-times in the contralateral kidney without AKI remained stable. At d7 relative T1-values in the outer stripe of the outer medulla were significantly higher after severe than after moderate AKI (138 ± 2 % vs. 121 ± 3 %, p = 0.001). T1-elevation persisted until d28 only after severe AKI. Already at d7 T1 in the outer stripe of the outer medulla correlated with kidney volume loss indicating CKD (r = 0.83). T1-mapping non-invasively detects AKI severity in mice and predicts further outcome. (orig.)

Protective effects of exercise training on endothelial dysfunction induced by total sleep deprivation in healthy subjects.

Science.gov (United States)

Sauvet, Fabien; Arnal, Pierrick J; Tardo-Dino, Pierre Emmanuel; Drogou, Catherine; Van Beers, Pascal; Bougard, Clément; Rabat, Arnaud; Dispersyn, Garance; Malgoyre, Alexandra; Leger, Damien; Gomez-Merino, Danielle; Chennaoui, Mounir

2017-04-01

Sleep loss is a risk factor for cardiovascular events mediated through endothelial dysfunction. To determine if 7weeks of exercise training can limit cardiovascular dysfunction induced by total sleep deprivation (TSD) in healthy young men. 16 subjects were examined during 40-h TSD, both before and after 7weeks of interval exercise training. Vasodilatation induced by ACh, insulin and heat (42°C) and pulse wave velocity (PWV), blood pressure and heart rate (HR) were assessed before TSD (controlday), during TSD, and after one night of sleep recovery. Biomarkers of endothelial activation, inflammation, and hormones were measured from morning blood samples. Before training, ACh-, insulin- and heat-induced vasodilatations were significantly decreased during TSD and recovery as compared with the control day, with no difference after training. Training prevented the decrease of ACh-induced vasodilation related to TSD after sleep recovery, as well as the PWV increase after TSD. A global lowering effect of training was found on HR values during TSD, but not on blood pressure. Training induces the decrease of TNF-α concentration after TSD and prevents the increase of MCP-1 after sleep recovery. Before training, IL-6 concentrations increased. Cortisol and testosterone decreased after TSD as compared with the control day, while insulin and E-selectin increased after sleep recovery. No effect of TSD or training was found on CRP and sICAM-1. In healthy young men, a moderate to high-intensity interval training is effective at improving aerobic fitness and limiting vascular dysfunction induced by TSD, possibly through pro-inflammatory cytokine responses.(ClinicalTrial:NCT02820649). Copyright © 2017 Elsevier B.V. All rights reserved.

Ergosterol peroxide from Cordyceps cicadae ameliorates TGF-β1-induced activation of kidney fibroblasts.

Science.gov (United States)

Zhu, Rong; Zheng, Rong; Deng, Yueyi; Chen, Yiping; Zhang, Shuwei

2014-02-15

Chronic kidney disease is a growing public health problem with an urgent need for new pharmacological agents. Ergosterol peroxide (EP) is the major sterol produced by Cordyceps cicadae Shing (C. cicadae), a widely used traditional Chinese medicine. C. cicadae has been used to treat many kinds of diseases and has a potential benefit on renoprotection. This study aimed to investigate the anti-fibrotic effects of EP as well as the underlying mechanisms. A normal rat kidney fibroblast cell line (NRK-49F) was stimulated to undergo fibroblast activation by transforming growth factor-β1 (TGF-β1) and EP treatment was applied to explore its potential anti-fibrotic effects. Cell proliferation was investigated using MTT analysis. Fibrosis-associated protein expression was analyzed using immunohistochemistry and/or Western blotting. EP treatment attenuated TGF-β1-induced renal fibroblast proliferation, expression of cytoskeleton protein and CTGF, as well as ECM production. Additionally, EP blocked TGF-β1-stimulated phosphorylation of ERK1/2, p38 and JNK pathway. Moreover, the TGF-β1-induced expression of fibronectin was attenuated by either inhibition of MAPKs or by EP treatment. In conclusion, our findings demonstrate that EP is able to suppress TGF-β1-induced fibroblasts activation in NRK-49F. This new information provides a line of theoretical evidence supporting the use of C. cicadae in the intervention of kidney disease and suggests that EP has the potential to be developed as a therapeutic agent to prevent renal fibrosis. Copyright © 2013 Elsevier GmbH. All rights reserved.

Functional evaluation of transplanted kidneys by Gd-DTPA enhanced turbo FLASH MR imaging

International Nuclear Information System (INIS)

Nakashima, Rumi; Yamashita, Yasuyuki; Tomiguchi, Seiji; Tsuji, Akinori; Takahashi, Mutsumasa

1996-01-01

We evaluated the usefulness of dynamic turbo FLASH MR imaging in the differential diagnosis of complications after renal transplantation in 17 patients (10 from living relatives and 7 from cadavers). Coronal turbo FLASH dynamic images were obtained every 5 sec for 5 min after an intravenous bolus injection of Gd-DTPA. Corticomedullary differentiation (CMD) on spin echo coronal T 1 -weighted images and MR renogram patterns of the renal cortex and medulla were obtained for quantitative analysis of the Gd-DTPA-enhanced dynamic turbo-FLASH images. The signal intensity ratio of the medulla to cortex after Gd-DTPA enhancement was compared among four groups: normal (n=9), acute tubular necrosis (ATN) or cyclosporine A (CyA) tubulopathy (n=6), acute rejection (AR) in the living related donor kidney (n=4), and AR in the cadaveric kidney (n=5). Although loss of CMD was seen in severe renal dysfunction in the transplanted kidneys, there was considerable overlap among the four groups. On dynamic study, there was significant differences in the signal intensity ratio of the medulla to cortex between normally functioning kidneys or ATN/CyA tubulopathy and AR (p<0.01). In patients with severe renal dysfunction, the arterial cortical peak was indistinct. In conclusion, MR renograms obtained from dynamic turbo FLASH MR imaging played a significant role in evaluating dysfunction of the renal transplant. (author)

Ketamine Causes Mitochondrial Dysfunction in Human Induced Pluripotent Stem Cell-Derived Neurons

Science.gov (United States)

Ito, Hiroyuki; Uchida, Tokujiro; Makita, Koshi

2015-01-01

Purpose Ketamine toxicity has been demonstrated in nonhuman mammalian neurons. To study the toxic effect of ketamine on human neurons, an experimental model of cultured neurons from human induced pluripotent stem cells (iPSCs) was examined, and the mechanism of its toxicity was investigated. Methods Human iPSC-derived dopaminergic neurons were treated with 0, 20, 100 or 500 μM ketamine for 6 and 24 h. Ketamine toxicity was evaluated by quantification of caspase 3/7 activity, reactive oxygen species (ROS) production, mitochondrial membrane potential, ATP concentration, neurotransmitter reuptake activity and NADH/NAD+ ratio. Mitochondrial morphological change was analyzed by transmission electron microscopy and confocal microscopy. Results Twenty-four-hour exposure of iPSC-derived neurons to 500 μM ketamine resulted in a 40% increase in caspase 3/7 activity (P ketamine (100 μM) decreased the ATP level (22%, P ketamine concentration, which suggests that mitochondrial dysfunction preceded ROS generation and caspase activation. Conclusions We established an in vitro model for assessing the neurotoxicity of ketamine in iPSC-derived neurons. The present data indicate that the initial mitochondrial dysfunction and autophagy may be related to its inhibitory effect on the mitochondrial electron transport system, which underlies ketamine-induced neural toxicity. Higher ketamine concentration can induce ROS generation and apoptosis in human neurons. PMID:26020236

Tributyltin chloride induces renal dysfunction by inflammation and oxidative stress in female rats.

Science.gov (United States)

Coutinho, João V S; Freitas-Lima, Leandro C; Freitas, Frederico F C T; Freitas, Flávia P S; Podratz, Priscila L; Magnago, Rafaella P L; Porto, Marcella L; Meyrelles, Silvana S; Vasquez, Elisardo C; Brandão, Poliane A A; Carneiro, Maria T W D; Paiva-Melo, Francisca D; Miranda-Alves, Leandro; Silva, Ian V; Gava, Agata L; Graceli, Jones B

2016-10-17

Tributyltin chloride (TBT) is an organometallic pollutant that is used as a biocide in antifouling paints. TBT induces several toxic and endocrine-disrupting effects. However, studies evaluating the effects of TBT on renal function are rare. This study demonstrates that TBT exposure is responsible for improper renal function as well as the development of abnormal morphophysiology in mammalian kidneys. Female rats were treated with TBT, and their renal morphophysiology was assessed. Morphophysiological abnormalities such as decreased glomerular filtration rate and increased proteinuria levels were observed in TBT rats. In addition, increases in inflammation, collagen deposition and α-smooth muscle actin (α-SMA) protein expression were observed in TBT kidneys. A disrupted cellular redox balance and apoptosis in kidney tissue were also observed in TBT rats. TBT rats demonstrated reduced serum estrogen levels and estrogen receptor-α (ERα) protein expression in renal cortex. Together, these data provide in vivo evidence that TBT is toxic to normal renal function and that these effects may be associated with renal histopathology complications, such as inflammation and fibrosis. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

The protective effect of hydroalcoholic extract of Ginger (Zingiber officinale Rosc.) against iron-induced functional and histological damages in rat liver and kidney.

Science.gov (United States)

Gholampour, Firouzeh; Behzadi Ghiasabadi, Fatemeh; Owji, Seyed Mohammad; Vatanparast, Jaafar

2017-01-01

Iron overload in the body is related with toxic effects and threatens the health. The aim of this study was to evaluate the protective role of hydroalcoholic extract of ginger ( Zingiber officinale ) against ferrous sulfate-induced hepatic and renal functional disorders and histological damages in rats. The rats were divided into four groups (n=7): Sham, Sham + G.E (ginger extract, 400 mg/kg/day for 14 days), FS (ferrous sulfate, 30 mg/kg/day for 14 days), FS+G.E (ferrous sulfate, 30 mg/kg/day for 14 days; ginger extract, 400 mg/kg/day for 11 days from the fourth day of ferrous sulfate injection). After 24 hr, blood, urine and tissue samples were collected. Compared with Sham and Sham + G.E groups, administration of ferrous sulfate resulted in liver and kidney dysfunction as evidenced by significantly higher levels of serum hepatic markers and bilirubin, and lower levels of serum albumin, total protein, triglyceride, cholesterol and glucose, as well as lower creatinine clearance and higher fractional excretion of sodium (p<0.001). This was accompanied by increased malondialdehyde levels and histological damages (p<0.001). In the FS + G.E, ginger extract significantly (p<0.01) reversed the levels of serum hepatic markers, renal functional markers and lipid peroxidation marker. Furthermore, it restored the levels of serum total protein, albumin, glucose, triglycerides and cholesterol and decreased bilirubin concentration in the blood. All these changes were corroborated by histological observations of liver and kidney. In conclusion, ginger extract appears to exert protective effects against ferrous sulfate-induced hepatic and renal toxicity by reducing lipid peroxidation and chelating iron.

Importance of mitochondrial calcium uniporter in high glucose-induced endothelial cell dysfunction.

Science.gov (United States)

Chen, Wei; Yang, Jie; Chen, Shuhua; Xiang, Hong; Liu, Hengdao; Lin, Dan; Zhao, Shaoli; Peng, Hui; Chen, Pan; Chen, Alex F; Lu, Hongwei

2017-11-01

Mitochondrial Ca 2+ overload is implicated in hyperglycaemia-induced endothelial cell dysfunction, but the key molecular events responsible remain unclear. We examined the involvement of mitochondrial calcium uniporter, which mediates mitochondrial Ca 2+ uptake, in endothelial cell dysfunction resulting from high-glucose treatment. Human umbilical vein endothelial cells were exposed to various glucose concentrations and to high glucose (30 mM) following mitochondrial calcium uniporter inhibition or activation with ruthenium red and spermine, respectively. Subsequently, mitochondrial calcium uniporter and mitochondrial calcium uniporter regulator 1 messenger RNA and protein expression was measured by real-time polymerase chain reaction and western blotting. Ca 2+ concentrations were analysed by laser confocal microscopy, and cytoplasmic and mitochondrial oxidative stress was detected using 2',7'-dichlorofluorescein diacetate and MitoSOX Red, respectively. Apoptosis was assessed by annexin V-fluorescein isothiocyanate/propidium iodide staining, and a wound-healing assay was performed using an in vitro model. High glucose markedly upregulated mitochondrial calcium uniporter and mitochondrial calcium uniporter regulator 1 messenger RNA expression, as well as protein production, in a dose- and time-dependent manner with a maximum effect demonstrated at 72 h and 30 mM glucose concentration. Moreover, high-glucose treatment significantly raised both mitochondrial and cytoplasmic Ca 2+ and reactive oxygen species levels, increased apoptosis and compromised wound healing (all p calcium uniporter, respectively. Mitochondrial calcium uniporter plays an important role in hyperglycaemia-induced endothelial cell dysfunction and may constitute a therapeutic target to reduce vascular complications in diabetes.

Protective effects of Spirulina maxima on hyperlipidemia and oxidative-stress induced by lead acetate in the liver and kidney.

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Ponce-Canchihuamán, Johny C; Pérez-Méndez, Oscar; Hernández-Muñoz, Rolando; Torres-Durán, Patricia V; Juárez-Oropeza, Marco A

2010-03-31

Oxidative damage has been proposed as a possible mechanism involved in lead toxicity, specially affecting the liver and kidney. Previous studies have shown the antioxidant effect of Spirulina maxima in several experimental models of oxidative stress. The current study was carried out to evaluate the antioxidant activity of Spirulina maxima against lead acetate-induced hyperlipidemia and oxidative damage in the liver and kidney of male rats. Control animals were fed on a standard diet and did not receive lead acetate (Control group). Experimental animals were fed on a standard laboratory diet with or without Spirulina maxima 5% in the standard laboratory diet and treated with three doses of lead acetate (25 mg each/weekly, intraperitoneal injection) (lead acetate with Spirulina, and lead acetate without Spirulina groups). The results showed that Spirulina maxima prevented the lead acetate-induced significant changes on plasma and liver lipid levels and on the antioxidant status of the liver and kidney. On the other hand, Spirulina maxima succeeded to improve the biochemical parameters of the liver and kidney towards the normal values of the Control group. It was concluded that Spirulina maxima has protective effects on lead acetate-induced damage, and that the effects are associated with the antioxidant effect of Spirulina.

Assessment of mitochondrial dysfunction-related, drug-induced hepatotoxicity in primary rat hepatocytes

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Liu, Cong; Sekine, Shuichi; Ito, Kousei

2016-01-01

Evidence that mitochondrial dysfunction plays a central role in drug-induced liver injury is rapidly accumulating. In contrast to physiological conditions, in which almost all adenosine triphosphate (ATP) in hepatocytes is generated in mitochondria via aerobic respiration, the high glucose content and limited oxygen supply of conventional culture systems force primary hepatocytes to generate most ATP via cytosolic glycolysis. Thus, such anaerobically poised cells are resistant to xenobiotics that impair mitochondrial function, and are not suitable to identify drugs with mitochondrial liabilities. In this study, primary rat hepatocytes were cultured in galactose-based medium, instead of the conventional glucose-based medium, and in hyperoxia to improve the reliance of energy generation on aerobic respiration. Activation of mitochondria was verified by diminished cellular lactate release and increased oxygen consumption. These conditions improved sensitivity to the mitochondrial complex I inhibitor rotenone. Since oxidative stress is also a general cause of mitochondrial impairment, cells were exposed to test compounds in the presence of transferrin to increase the generation of reactive oxygen species via increased uptake of iron. Finally, 14 compounds with reported mitochondrial liabilities were tested to validate this new drug-induced mitochondrial toxicity assay. Overall, the culture of primary rat hepatocytes in galactose, hyperoxia and transferrin is a useful model for the identification of mitochondrial dysfunction-related drug-induced hepatotoxicity. - Highlights: • Drug-induced mitochondrial toxicity was evaluated using primary rat hepatocytes. • Galactose and hyperoxia could activate OXPHOS in primary rat hepatocytes. • Cells with enhanced OXPHOS exhibit improved sensitivity to mitochondrial toxins. • Transferrin potentiate mitochondrial toxicity via increased ROS production.

Assessment of mitochondrial dysfunction-related, drug-induced hepatotoxicity in primary rat hepatocytes

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Liu, Cong; Sekine, Shuichi, E-mail: ssekine@faculty.chiba-u.jp; Ito, Kousei

2016-07-01

Evidence that mitochondrial dysfunction plays a central role in drug-induced liver injury is rapidly accumulating. In contrast to physiological conditions, in which almost all adenosine triphosphate (ATP) in hepatocytes is generated in mitochondria via aerobic respiration, the high glucose content and limited oxygen supply of conventional culture systems force primary hepatocytes to generate most ATP via cytosolic glycolysis. Thus, such anaerobically poised cells are resistant to xenobiotics that impair mitochondrial function, and are not suitable to identify drugs with mitochondrial liabilities. In this study, primary rat hepatocytes were cultured in galactose-based medium, instead of the conventional glucose-based medium, and in hyperoxia to improve the reliance of energy generation on aerobic respiration. Activation of mitochondria was verified by diminished cellular lactate release and increased oxygen consumption. These conditions improved sensitivity to the mitochondrial complex I inhibitor rotenone. Since oxidative stress is also a general cause of mitochondrial impairment, cells were exposed to test compounds in the presence of transferrin to increase the generation of reactive oxygen species via increased uptake of iron. Finally, 14 compounds with reported mitochondrial liabilities were tested to validate this new drug-induced mitochondrial toxicity assay. Overall, the culture of primary rat hepatocytes in galactose, hyperoxia and transferrin is a useful model for the identification of mitochondrial dysfunction-related drug-induced hepatotoxicity. - Highlights: • Drug-induced mitochondrial toxicity was evaluated using primary rat hepatocytes. • Galactose and hyperoxia could activate OXPHOS in primary rat hepatocytes. • Cells with enhanced OXPHOS exhibit improved sensitivity to mitochondrial toxins. • Transferrin potentiate mitochondrial toxicity via increased ROS production.

Haemodynamic-guided fluid administration for the prevention of contrast-induced acute kidney injury: the POSEIDON randomised controlled trial.

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Brar, Somjot S; Aharonian, Vicken; Mansukhani, Prakash; Moore, Naing; Shen, Albert Y-J; Jorgensen, Michael; Dua, Aman; Short, Lindsay; Kane, Kevin

2014-05-24

The administration of intravenous fluid remains the cornerstone treatment for the prevention of contrast-induced acute kidney injury. However, no well-defined protocols exist to guide fluid administration in this treatment. We aimed to establish the efficacy of a new fluid protocol to prevent contrast-induced acute kidney injury. In this randomised, parallel-group, comparator-controlled, single-blind phase 3 trial, we assessed the efficacy of a new fluid protocol based on the left ventricular end-diastolic pressure for the prevention of contrast-induced acute kidney injury in patients undergoing cardiac catheterisation. The primary outcome was the occurrence of contrast-induced acute kidney injury, which was defined as a greater than 25% or greater than 0·5 mg/dL increase in serum creatinine concentration. Between Oct 10, 2010, and July 17, 2012, 396 patients aged 18 years or older undergoing cardiac catheterisation with an estimated glomerular filtration rate of 60 mL/min per 1·73 m(2) or less and one or more of several risk factors (diabetes mellitus, history of congestive heart failure, hypertension, or age older than 75 years) were randomly allocated in a 1:1 ratio to left ventricular end-diastolic pressure-guided volume expansion (n=196) or the control group (n=200) who received a standard fluid administration protocol. Four computer-generated concealed randomisation schedules, each with permuted block sizes of 4, were used for randomisation, and participants were allocated to the next sequential randomisation number by sealed opaque envelopes. Patients and laboratory personnel were masked to treatment assignment, but the physicians who did the procedures were not masked. Both groups received intravenous 0·9% sodium chloride at 3 mL/kg for 1 h before cardiac catheterisation. Analyses were by intention to treat. Adverse events were assessed at 30 days and 6 months and all such events were classified by staff who were masked to treatment assignment. This

Rho-Kinase Inhibition Ameliorates Dasatinib-Induced Endothelial Dysfunction and Pulmonary Hypertension

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Csilla Fazakas

2018-05-01

Full Text Available The multi-kinase inhibitor dasatinib is used for treatment of imatinib-resistant chronic myeloid leukemia, but is prone to induce microvascular dysfunction. In lung this can manifest as capillary leakage with pleural effusion, pulmonary edema or even pulmonary arterial hypertension. To understand how dasatinib causes endothelial dysfunction we examined the effects of clinically relevant concentrations of dasatinib on both human pulmonary arterial macro- and microvascular endothelial cells (ECs. The effects of dasatinib was compared to imatinib and nilotinib, two other clinically used BCR/Abl kinase inhibitors that do not inhibit Src. Real three-dimensional morphology and high resolution stiffness mapping revealed softening of both macro- and microvascular ECs upon dasatinib treatment, which was not observed in response to imatinib. In a dose-dependent manner, dasatinib decreased transendothelial electrical resistance/impedance and caused a permeability increase as well as disruption of tight adherens junctions in both cell types. In isolated perfused and ventilated rat lungs, dasatinib increased mean pulmonary arterial pressure, which was accompanied by a gain in lung weight. The Rho-kinase inhibitor Y27632 partly reversed the dasatinib-induced changes in vitro and ex vivo, presumably by acting downstream of Src. Co-administration of the Rho-kinase inhibitor Y27632 completely blunted the increased pulmonary pressure in response to dasatinib. In conclusion, a dasatinib-induced permeability increase in human pulmonary arterial macro- and microvascular ECs might explain many of the adverse effects of dasatinib in patients. Rho-kinase inhibition might be suitable to ameliorate these effects.

Renal oxygenation and hemodynamics in acute kidney injury and chronic kidney disease

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Singh, Prabhleen; Ricksten, Sven-Erik; Bragadottir, Gudrun; Redfors, Bengt; Nordquist, Lina

2013-01-01

Summary 1. Acute kidney injury (AKI) puts a major burden on health systems that may arise from multiple initiating insults, including ischemia-reperfusion injury, cardiovascular surgery, radio-contrast administration as well as sepsis. Similarly, the incidence and prevalence of chronic kidney disease (CKD) continues to increase with significant morbidity and mortality. Moreover, an increasing number of AKI patients survive to develop CKD and end-stage kidney disease (ESRD). 2. Although the mechanisms for development of AKI and progression of CKD remain poorly understood, initial impairment of oxygen balance is likely to constitute a common pathway, causing renal tissue hypoxia and ATP starvation that will in turn induce extracellular matrix production, collagen deposition and fibrosis. Thus, possible future strategies for one or both conditions may involve dopamine, loop-diuretics, inducible nitric oxide synthase inhibitors and atrial natriuretic peptide, substances that target kidney oxygen consumption and regulators of renal oxygenation such as nitric oxide and heme oxygenase-1. PMID:23360244

Voiding dysfunction in children aged five to 15 years

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Karaklajić Dragana

2004-01-01

Full Text Available Voiding dysfunction in children was analyzed in 91 patients in a period from January 1st to October 1st 1998. Most of the patients had functional voiding disorder (92.31%, and only 7.69% manifested monosymptomatic night enuresis. The number of girls was bigger in the group of patients with voiding dysfunction while the boys were predominant in the group with mono-symptomatic nocturnal enuresis. More than a half of children with functional voiding disorder had repeated urinal infections (58.23%, incontinence (93.49%, need for urgent voiding (68.13%, and vesicoureteral reflux (47.61%. The most common type of voiding dysfunction was urge syndrome/urge incontinence. The incidence of dysfunctional voiding disorder was more often in children with scaring changes of kidney which were diagnosed by static scintigraphy.

Prevention of chemotherapy-induced nephrotoxicity in children with cancer

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Fatemeh Ghane Sharbaf

2017-01-01

Full Text Available Children with cancer treated with cytotoxic drugs are frequently at risk of developing renal dysfunction. The cytotoxic drugs that are widely used for cancer treatment in children are cisplatin (CPL, ifosfamide (IFO, carboplatin, and methotrexate (MTX. Mechanisms of anticancer drug-induced renal disorders are different and include acute kidney injury (AKI, tubulointerstitial disease, vascular damage, hemolytic uremic syndrome (HUS, and intrarenal obstruction. CPL nephrotoxicity is dose-related and is often demonstrated with hypomagnesemia, hypokalemia, and impaired renal function with rising serum creatinine and blood urea nitrogen levels. CPL, mitomycin C, and gemcitabine treatment cause vascular injury and HUS. High-dose IFO, streptozocin, and azacitidine cause renal tubular dysfunction manifested by Fanconi syndrome, rickets, and osteomalacia. AKI is a common adverse effect of MTX, interferon-alpha, and nitrosourea compound treatment. These strategies to reduce the cytotoxic drug-induced nephrotoxicity should include adequate hydration, forced diuresis, and urinary alkalization. Amifostine, sodium thiosulfate, and diethyldithiocarbamate provide protection against CPL-induced renal toxicity.

Effect of Γ-aminobutyric acid on kidney injury induced by renal ischemia-reperfusion in male and female rats: Gender-related difference.

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Vafapour, Marzieh; Nematbakhsh, Mehdi; Monajemi, Ramesh; Mazaheri, Safoora; Talebi, Ardeshir; Talebi, Nahid; Shirdavani, Soheyla

2015-01-01

The most important cause of kidney injury is renal ischemia/reperfusion injury (IRI), which is gender-related. This study was designed to investigate the protective role of Γ-aminobutyric acid (GABA (against IRI in male and female rats. Thirty-six female and male wistar rats were assigned to six experimental groups. The IRI was induced by clamping renal vessels for 45 min then was performed reperfusion for 24 h. The group sex posed to IRI were pretreated with GABA and were compared with the control groups. Serum levels of creatinine and blood urea nitrogen, kidney weight, and kidney tissue damage score increased in the IRI alone groups, (P GABA decreased these parameters in female significantly (P GABA. Testis weight did not alter in male rats. Serum level of nitrite and kidney level of malondialdehyde (MDA) had no significant change in both female and male rats. Kidney level of nitrite increased significantly in female rats experienced IRI and serum level of MDA increased significantly in males that were exposed to IRI (P GABA could ameliorate kidney injury induced by renal IRI in a gender dependent manner.

Tyrosine Kinase Inhibitors Induced Thyroid Dysfunction: A Review of Its Incidence, Pathophysiology, Clinical Relevance, and Treatment

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Hala Ahmadieh

2013-01-01

Full Text Available Tyrosine kinase inhibitors (TKI belong to a new class of molecular multitargeted anticancer therapy which targets different growth factor receptors and hence attenuates cancer cell survival and growth. Since their introduction as adjunct treatment for renal cell carcinoma and gastrointestinal stromal tumors (GIST, a number of reports have demonstrated that TKI can induce thyroid dysfunction which was especially more common with sunitinib maleate. Many mechanisms with respect to this adverse effect of tyrosine kinase inhibitors have been proposed including their induction of thyroiditis, capillary regression in the thyroid gland, antithyroid peroxidase antibody production, and their ability to decrease iodine uptake by the thyroid gland. Of interest is the observation that TKI-induced thyroid dysfunction may actually be protective as it was shown to improve overall survival, and it was suggested that it may have a prognostic value. Followup on thyroid function tests while patients are maintained on tyrosine kinase inhibitor is strongly recommended. When thyroid dysfunction occurs, appropriate treatment should be individualized depending on patients symptoms and thyroid stimulating hormone level.

How Kidney Cell Death Induces Renal Necroinflammation.

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Mulay, Shrikant R; Kumar, Santhosh V; Lech, Maciej; Desai, Jyaysi; Anders, Hans-Joachim

2016-05-01

The nephrons of the kidney are independent functional units harboring cells of a low turnover during homeostasis. As such, physiological renal cell death is a rather rare event and dead cells are flushed away rapidly with the urinary flow. Renal cell necrosis occurs in acute kidney injuries such as thrombotic microangiopathies, necrotizing glomerulonephritis, or tubular necrosis. All of these are associated with intense intrarenal inflammation, which contributes to further renal cell loss, an autoamplifying process referred to as necroinflammation. But how does renal cell necrosis trigger inflammation? Here, we discuss the role of danger-associated molecular patterns (DAMPs), mitochondrial (mito)-DAMPs, and alarmins, as well as their respective pattern recognition receptors. The capacity of DAMPs and alarmins to trigger cytokine and chemokine release initiates the recruitment of leukocytes into the kidney that further amplify necroinflammation. Infiltrating neutrophils often undergo neutrophil extracellular trap formation associated with neutrophil death or necroptosis, which implies a release of histones, which act not only as DAMPs but also elicit direct cytotoxic effects on renal cells, namely endothelial cells. Proinflammatory macrophages and eventually cytotoxic T cells further drive kidney cell death and inflammation. Dissecting the molecular mechanisms of necroinflammation may help to identify the best therapeutic targets to limit nephron loss in kidney injury. Copyright © 2016 Elsevier Inc. All rights reserved.

Impaired Hedgehog signalling-induced endothelial dysfunction is sufficient to induce neuropathy: implication in diabetes.

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Chapouly, Candice; Yao, Qinyu; Vandierdonck, Soizic; Larrieu-Lahargue, Frederic; Mariani, John N; Gadeau, Alain-Pierre; Renault, Marie-Ange

2016-02-01

Microangiopathy, i.e. endothelial dysfunction, has long been suggested to contribute to the development of diabetic neuropathy, although this has never been fully verified. In the present paper, we have identified the role of Hedgehog (Hh) signalling in endoneurial microvessel integrity and evaluated the impact of impaired Hh signalling in endothelial cells (ECs) on nerve function. By using Desert Hedgehog (Dhh)-deficient mice, we have revealed, that in the absence of Dhh, endoneurial capillaries are abnormally dense and permeable. Furthermore, Smoothened (Smo) conditional KO mice clarified that this increased vessel permeability is specifically due to impaired Hh signalling in ECs and is associated with a down-regulation of Claudin5 (Cldn5). Moreover, impairment of Hh signalling in ECs was sufficient to induce hypoalgesia and neuropathic pain. Finally in Lepr(db/db) type 2 diabetic mice, the loss of Dhh expression observed in the nerve was shown to be associated with increased endoneurial capillary permeability and decreased Cldn5 expression. Conversely, systemic administration of the Smo agonist SAG increased Cldn5 expression, decreased endoneurial capillary permeability, and restored thermal algesia to diabetic mice, demonstrating that loss of Dhh expression is crucial in the development of diabetic neuropathy. The present work demonstrates the critical role of Dhh in maintaining blood nerve barrier integrity and demonstrates for the first time that endothelial dysfunction is sufficient to induce neuropathy. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

A H2S Donor GYY4137 Exacerbates Cisplatin-Induced Nephrotoxicity in Mice

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Mi Liu

2016-01-01

Full Text Available Accumulating evidence demonstrated that hydrogen sulfide (H2S is highly involved in inflammation, oxidative stress, and apoptosis and contributes to the pathogenesis of kidney diseases. However, the role of H2S in cisplatin nephrotoxicity is still debatable. Here we investigated the effect of GYY4137, a novel slow-releasing H2S donor, on cisplatin nephrotoxicity in mice. Male C57BL/6 mice were pretreated with GYY4137 for 72 h prior to cisplatin injection. After cisplatin treatment for 72 h, mice developed obvious renal dysfunction and kidney injury as evidenced by elevated blood urea nitrogen (BUN and histological damage. Consistently, these mice also showed increased proinflammatory cytokines such as TNF-α, IL-6, and IL-1β in circulation and/or kidney tissues. Meanwhile, circulating thiobarbituric aid-reactive substances (TBARS and renal apoptotic indices including caspase-3, Bak, and Bax were all elevated. However, application of GYY4137 further aggravated renal dysfunction and kidney structural injury in line with promoted inflammation, oxidative stress, and apoptotic response following cisplatin treatment. Taken together, our results suggested that GYY4137 exacerbated cisplatin-induced nephrotoxicity in mice possibly through promoting inflammation, oxidative stress, and apoptotic response.

Kidney tissue targeted metabolic profiling of glucocorticoid-induced osteoporosis and the proposed therapeutic effects of Rhizoma Drynariae studied using UHPLC/MS/MS.

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Huang, Yue; Liu, Xinyu; Zhao, Longshan; Li, Famei; Xiong, Zhili

2014-06-01

Traditional Chinese medicine and modern science have indicated that there is a close relationship between bone and kidney. In light of this, this project was designed to study the metabolic profiling by UHPLC/MS/MS of glucocorticoid-induced osteoporosis in kidney tissue and the possible therapeutic effects of Rhizoma Drynariae (RD), a classic traditional Chinese medicine, in improving the kidney function and strengthening bone. Twenty-one Wistar rats were divided into three groups: control group (rats before prednisolone inducing), a model group (prednisolone-induced group) and a treatment group (prednisolone-induced rats that were then administered RD ethanol extracts). By using pattern recognition analysis, a significant change in the metabolic profile of kidney tissue samples was observed in the model group and restoration of the profile was observed after the administration of RD ethanol extracts. Some significantly changed biomarkers related to osteoporosis such as sphingolipids (C16 dihydrosphingosine, C18 dihydrosphingosine, C18 phytosphingosine, C20 phytosphingosine), lysophosphatidycholines (C16:0 LPC, C18:0 LPC) and phenylalanine were identified. As a complement to the metabolic profiling of RD in plasma, these biomarkers suggest that kidney damage, cell cytotoxicity and apoptosis exist in osteoporosis rats, which is helpful in further understanding the underlying process of glucocorticoid-induced osetoporosis and the suggested therapeutic effects of RD. The method shows that tissue target metabonomics might provide a powerful tool to further understand the process of disease and the mechanism of therapeutic effect of Chinese medicines. Copyright © 2014 John Wiley & Sons, Ltd.

Obesity-induced vascular dysfunction and arterial stiffening requires endothelial cell arginase 1.

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Bhatta, Anil; Yao, Lin; Xu, Zhimin; Toque, Haroldo A; Chen, Jijun; Atawia, Reem T; Fouda, Abdelrahman Y; Bagi, Zsolt; Lucas, Rudolf; Caldwell, Ruth B; Caldwell, Robert W

2017-11-01

Elevation of arginase activity has been linked to vascular dysfunction in diabetes and hypertension by a mechanism involving decreased nitric oxide (NO) bioavailability due to L-arginine depletion. Excessive arginase activity also can drive L-arginine metabolism towards the production of ornithine, polyamines, and proline, promoting proliferation of vascular smooth muscle cells and collagen formation, leading to perivascular fibrosis. We hypothesized that there is a specific involvement of arginase 1 expression within the vascular endothelial cells in this pathology. To test this proposition, we used models of type 2 diabetes and metabolic syndrome. Studies were performed using wild type (WT), endothelial-specific arginase 1 knockout (EC-A1-/-) and littermate controls(A1con) mice fed high fat-high sucrose (HFHS) or normal diet (ND) for 6 months and isolated vessels exposed to palmitate-high glucose (PA/HG) media. Some WT mice or isolated vessels were treated with an arginase inhibitor, ABH [2-(S)-amino-6-boronohexanoic acid. In WT mice, the HFHS diet promoted increases in body weight, fasting blood glucose, and post-prandial insulin levels along with arterial stiffening and fibrosis, elevated blood pressure, decreased plasma levels of L-arginine, and elevated L-ornithine. The HFHS diet or PA/HG treatment also induced increases in vascular arginase activity along with oxidative stress, reduced vascular NO levels, and impaired endothelial-dependent vasorelaxation. All of these effects except obesity and hypercholesterolemia were prevented or significantly reduced by endothelial-specific deletion of arginase 1 or ABH treatment. Vascular dysfunctions in diet-induced obesity are prevented by deletion of arginase 1 in vascular endothelial cells or arginase inhibition. These findings indicate that upregulation of arginase 1 expression/activity in vascular endothelial cells has an integral role in diet-induced cardiovascular dysfunction and metabolic syndrome. Published

Effect of spent turmeric on kidney glycoconjugates in streptozotocin-induced diabetic rats.

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Kumar, Gurusiddaiah Suresh; Salimath, Paramahans Veerayya

2014-01-01

Curcumin known to have number of medicinal use and masked the fiber containing ukonan like active polysaccharide in turmeric and its pharmacological effect will be addressed on diabetic nephropathy particularly the glycoconjugates of extracellular components viz., glycoproteins and glycosaminoglycans - heparan sulfate (HS). Male Wistar rats were maintained on AIN-76 diet containing 10% spent turmeric and were grouped into control and STZ induced diabetes SFC/TFC and SFD/TFD, respectively. Diabetic status was monitored using blood and urine, and at the end, harvested kidneys were used to study the amelioration of glycoprotiens (collagen) and HS by enzymatic digestion, spectrophotometric, hydroxyproline and agarose electrophoretic methods. In the present study spent turmeric (10%) fed diabetic rats showed improved glomerular filtration rate (50%), kidney enlargement (60%) and other glycoconjugate metabolism in kidney. Increased collagen content in diabetic group was observed by hydroxyproline estimation (24%) and periodic acid-Schiff's (PAS) staining. Furthermore, elevated activities of enzymes involved in the synthesis and degradation of glycosaminoglycans (GAGs) were significantly lowered in spent turmeric fed diabetic group. Improvement in total GAGs (43%) and sulfate content (18%) followed by fractionation of GAGs using specific enzymes led to HS (28%) in the spent turmeric fed diabetic group, when compared to starch fed diabetic group and was further confirmed by electrophoresis of GAG. These results clearly indicate beneficial role of spent turmeric in controlling glycoconjugates such as glycoproteins and heparan sulfate related kidney complications during diabetes.

Protocatechuic aldehyde attenuates cisplatin-induced acute kidney injury by suppressing Nox-mediated oxidative stress and renal inflammation

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Li Gao

2016-12-01

Full Text Available Cisplatin is a classic chemotherapeutic agent widely used to treat different types of cancers including ovarian, head and neck, testicular and uterine cervical carcinomas. However, cisplatin induces acute kidney injury by directly triggering an excessive inflammatory response, oxidative stress and programmed cell death of renal tubular epithelial cells. All of which lead to higher mortality rates in patients. In this study we examined the protective effect of protocatechuic aldehyde (PA in vitro in cisplatin-treated tubular epithelial cells and in vivo in cisplatin nephropathy. PA is a monomer of Traditional Chinese Medicine isolated from the root of S. miltiorrhiza. Results show that PA prevented cisplatin-induced decline of renal function and histological damage, which was confirmed by attenuation of KIM1 in both mRNA and protein levels. Moreover, PA reduced renal inflammation by suppressing oxidative stress and programmed cell death in response to cisplatin, which was further evidenced by in vitro data. Of note, PA suppressed NAPDH oxidases, including Nox2 and Nox4, in a dosage-dependent manner. Moreover, silencing Nox4, but not Nox2, removed the inhibitory effect of PA on cisplatin-induced renal injury, indicating that Nox4 may play a pivotal role in mediating the protective effect of PA in cisplatin-induced acute kidney injury. Collectively, our data indicate that PA largely blocked cisplatin-induced acute kidney injury by suppressing Nox-mediated oxidative stress and renal inflammation without compromising anti-tumor activity of cisplatin. These findings suggest that PA and its derivatives may serve as potential protective agents for cancer patients with cisplatin treatment.

Effect of Nigella sativa on ischemia-reperfusion induced rat kidney damage

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Shahrzad Havakhah

2015-12-01

Full Text Available Objective(s:There are a few previously reported studies about the effect of Nigella sativa oil on renal ischemia-reperfusion injury (IRI. The aim of the present study was to test the hypothesis whether pre- or post-treatment with N. sativa hydroalcoholic extract (NSE would reduce tissue injury and oxidative damages in a clinically relevant rat model of renal IRI.    Materials and Methods: IRI was induced by clamping of bilateral renal arteries for 40 min fallowed by reperfusion for 180 min. NSE was prepared in a Soxhlet extractor and administrated with doses of 150 mg/kg or 300 mg/kg at 1 hr before ischemia induction (P-150 and 300 or at the beginning of reperfusion phase (T-150 and 300, via jugular catheter intravenously. The kidneys were then removed and subjected to biochemical analysis, comet assay or histopathological examination. Results: The kidneys of untreated IRI rats had a higher histopathological score (P

Postirradiation cardiovascular dysfunction

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Hawkins, R.N.; Cockerham, L.G.

1987-01-01

Cardiovascular dysfunction may be defined as the inability of any element of the cardiovascular system to perform adequately upon demand, leading to inadequate performance and nutritive insufficiency of various parts of the body. Exposure to supralethal doses of radiation (accidental and therapeutic) has been show to induce significant alterations in cardiovascular function in man. These findings indicate that, after irradiation, cardiovascular function is a major determinant of continued performance and even survival. For the two persons who received massive radiation doses (45 and 88 Gy, respectively) in criticality accidents, the inability to maintain systematic arterial blood pressure (AP) was the immediate cause of death. In a study of cancer patients given partial-body irradiation, two acute lethalities were attributed to myocardial infarction after an acute hypotensive episode during the first few hours postexposure. Although radiation-induced cardiovascular dysfunction has been observed in many species, its severity, duration, and even etiology may vary with the species, level of exposure, and dose rate. For this reason, our consideration of the effects of radiation on cardiovascular performance is limited to the circulatory derangements that occur in rat, dog, and monkey after supralethal doses and lead to radiation-induced cardiovascular dysfunction in these experimental models. The authors consider other recent data as they pertain to the etiology of cardiovascular dysfunction in irradiated animals

Multiple low-dose radiation prevents type 2 diabetes-induced renal damage through attenuation of dyslipidemia and insulin resistance and subsequent renal inflammation and oxidative stress.

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Minglong Shao

Full Text Available Dyslipidemia and lipotoxicity-induced insulin resistance, inflammation and oxidative stress are the key pathogeneses of renal damage in type 2 diabetes. Increasing evidence shows that whole-body low dose radiation (LDR plays a critical role in attenuating insulin resistance, inflammation and oxidative stress.The aims of the present study were to investigate whether LDR can prevent type 2 diabetes-induced renal damage and the underlying mechanisms.Mice were fed with a high-fat diet (HFD, 40% of calories from fat for 12 weeks to induce obesity followed by a single intraperitoneal injection of streptozotocin (STZ, 50 mg/kg to develop a type 2 diabetic mouse model. The mice were exposed to LDR at different doses (25, 50 and 75 mGy for 4 or 8 weeks along with HFD treatment. At each time-point, the kidney weight, renal function, blood glucose level and insulin resistance were examined. The pathological changes, renal lipid profiles, inflammation, oxidative stress and fibrosis were also measured.HFD/STZ-induced type 2 diabetic mice exhibited severe pathological changes in the kidney and renal dysfunction. Exposure of the mice to LDR for 4 weeks, especially at 50 and 75 mGy, significantly improved lipid profiles, insulin sensitivity and protein kinase B activation, meanwhile, attenuated inflammation and oxidative stress in the diabetic kidney. The LDR-induced anti-oxidative effect was associated with up-regulation of renal nuclear factor E2-related factor-2 (Nrf-2 expression and function. However, the above beneficial effects were weakened once LDR treatment was extended to 8 weeks.These results suggest that LDR exposure significantly prevented type 2 diabetes-induced kidney injury characterized by renal dysfunction and pathological changes. The protective mechanisms of LDR are complicated but may be mainly attributed to the attenuation of dyslipidemia and the subsequent lipotoxicity-induced insulin resistance, inflammation and oxidative stress.

Cardioprotective effects of gallic acid in diabetes-induced myocardial dysfunction in rats

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Patel, Snehal S.; Goyal, Ramesh K.

2011-01-01

Background: Normalization of hyperglycemia, hyperlipidemia, and oxidative stress is an important objective in preventing diabetes-induced cardiac dysfunction. Objective: This study was undertaken to examine the effects of gallic acid in myocardial dysfunctions associated with type-1 diabetes. Materials and Methods: Diabetes was induced by single intravenous injection of streptozotocin (STZ, 50 mg/kg i.v.). Gallic acid was administered daily at three different doses (100, 50, and 25 mg/kg p.o.) for 8 weeks at the end of which blood samples were collected and analyzed for various biochemical parameters. Results: Injection of STZ produced significant loss of body weight (BW), polyphagia, polydypsia, hyperglycemia, hypoinsulinemia, hyperlipidemia, hypertension, bradycardia, and myocardial functional alterations. Treatment with gallic acid significantly lowered fasting glucose, the AUCglucose level in a dose-dependent manner; however, the insulin level was not increased significantly at same the dose and prevented loss of BW, polyphagia, and polydypsia in diabetic rats. It also prevented STZ-induced hyperlipidemia, hypertension, bradycardia, structural alterations in cardiac tissue such as increase in force of contraction, left ventricular weight to body weight ratio, collagen content, protein content, serum lactate dehydrogenase, and creatinine kinase levels in a dose-dependent manner. Further, treatment also produced reduction in lipid peroxidation and increase in antioxidant parameters in heart of diabetic rats. Conclusion: The results of this study suggest that gallic acid to be beneficial for the treatment of myocardial damage associated with type-1 diabetes. PMID:22224046

Taurine decreased uric acid levels in hyperuricemic rats and alleviated kidney injury.

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Feng, Ying; Sun, Fang; Gao, Yongchao; Yang, Jiancheng; Wu, Gaofeng; Lin, Shumei; Hu, Jianmin

2017-07-29

Hyperuricemia can lead to direct kidney damage. Taurine participates in several renal physiological processes and has been shown as a renoprotective agent. It has been reported that taurine could reduce uric acid levels in diabetic rats, but to date there was no research on the effects of taurine on hyperuricemic rats with kidney injury. In present study, hyperuricemic rat models were induced by intragastric administration of adenine and ethambutol hydrochloride for 10 days, and taurine (1% or 2%) were added in the drinking water 7 days in advance for consecutively 17 days. The results showed that taurine alleviated renal morphological and pathological changes as well as kidney dysfunction in hyperuricemic rats. Taurine could efficiently decrease the elevated xanthine oxidase activities in hyperuricemic rats, indicating its effect on the regulation of uric acid formation. The reabsorption and secretion of uric acid are dependent on a number of urate transporters. Expressions of three urate transporters were significantly down-regulated in hyperuricemic rats, while taurine prevented the decrease of mRNA and protein expression levels of these urate transporters. The results indicate that taurine might play a role in the regulation of renal uric acid excretion. Therefore, taurine could be a promising agent for the treatment of hyperuricemia. Copyright © 2017 Elsevier Inc. All rights reserved.

High-dose benfotiamine rescues cardiomyocyte contractile dysfunction in streptozotocin-induced diabetes mellitus.

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Ceylan-Isik, Asli F; Wu, Shan; Li, Qun; Li, Shi-Yan; Ren, Jun

2006-01-01

Diabetic cardiomyopathy is characterized by cardiac dysfunction. This study was designed to examine the effect of benfotiamine, a lipophilic derivative of thiamine, on streptozotocin (STZ)-induced cardiac contractile dysfunction in mouse cardiomyocytes. Adult male FVB mice were made diabetic with a single injection of STZ (200 mg/kg ip). Fourteen days later, control and diabetic (fasting plasma glucose > 13.9 mM) mice were put on benfotiamine therapy (100 mg.kg(-1).day(-1) ip) for another 14 days. Mechanical and intracellular Ca2+ properties were evaluated in left ventricular myocytes using an IonOptix MyoCam system. The following indexes were evaluated: peak shortening (PS), time to PS (TPS), time to 90% relengthening (TR90), maximal velocity of shortening/relengthening, resting and rise of intracellular Ca2+ in response to electrical stimulus, sarcoplasmic reticulum (SR) Ca2+ load, and intracellular Ca2+ decay rate (tau). Two- or four-week STZ treatment led to hyperglycemia, prolonged TPS and TR90, reduced SR Ca2+ load, elevated resting intracellular Ca2+ level and prolonged tau associated with normal PS, maximal velocity of shortening/relengthening, and intracellular Ca2+ rise in response to electrical stimulus. Benfotiamine treatment abolished prolongation in TPS, TR90, and tau, as well as reduction in SR Ca2+ load without affecting hyperglycemia and elevated resting intracellular Ca2+. Diabetes triggered oxidative stress, measured by GSH-to-GSSG ratio and formation of advanced glycation end product (AGE) in the hearts. Benfotiamine treatment alleviated oxidative stress without affecting AGE or protein carbonyl formation. Collectively, our results indicated that benfotiamine may rescue STZ-induced cardiomyocyte dysfunction but not AGE formation in short-term diabetes.

Radiation-induced cognitive dysfunction: an experimental model in the old rat

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Lamproglou, Ioannis; Chen, QI Ming; Boisserie, Gilbert; Mazeron, Jean-Jacques; Poisson, Michel; Baillet, Francois; Le Poncin, Monique; Delattre, Jean-Yves

1995-01-01

Purpose: To develop a model of radiation-induced behavioral dysfunction. Methods and Materials: A course of whole brain radiation therapy (30 Gy/10 fractions/12 days) was administered to 26 Wistar rats ages 16-27 months, while 26 control rats received sham irradiation. Sequential behavioral studies including one-way avoidance, two-way avoidance, and a standard operant conditioning method (press-lever avoidance) were undertaken. In addition, rats were studied in a water maze 7 months postradiation therapy. Results: Prior to radiation therapy, both groups were similar. No difference was found 1 and 3 months postradiation therapy. At 6-7 months postradiation therapy, irradiated rats had a much lower percentage of avoidance than controls for one-way avoidance (23% vs. 55%, p {<=} 0.001) and two-way avoidance (18% vs. 40%, p {<=} 0.01). Seven months postradiation therapy the reaction time was increased (press-lever avoidance, 11.20 s vs. 8.43 s, p {<=} 0.05) and the percentage of correct response was lower (water maze, 53% vs. 82%) in irradiated rats compared with controls. Pathological examination did not demonstrate abnormalities of the irradiated brains at the light microscopic level. Conclusion: Behavioral dysfunction affecting mainly memory can be demonstrated following conventional radiation therapy in old rats. This model can be used to study the pathogenesis of radiation-induced cognitive changes.

Radiation-induced cognitive dysfunction: an experimental model in the old rat

International Nuclear Information System (INIS)

Lamproglou, Ioannis; Chen, QI Ming; Boisserie, Gilbert; Mazeron, Jean-Jacques; Poisson, Michel; Baillet, Francois; Le Poncin, Monique; Delattre, Jean-Yves

1995-01-01

Purpose: To develop a model of radiation-induced behavioral dysfunction. Methods and Materials: A course of whole brain radiation therapy (30 Gy/10 fractions/12 days) was administered to 26 Wistar rats ages 16-27 months, while 26 control rats received sham irradiation. Sequential behavioral studies including one-way avoidance, two-way avoidance, and a standard operant conditioning method (press-lever avoidance) were undertaken. In addition, rats were studied in a water maze 7 months postradiation therapy. Results: Prior to radiation therapy, both groups were similar. No difference was found 1 and 3 months postradiation therapy. At 6-7 months postradiation therapy, irradiated rats had a much lower percentage of avoidance than controls for one-way avoidance (23% vs. 55%, p ≤ 0.001) and two-way avoidance (18% vs. 40%, p ≤ 0.01). Seven months postradiation therapy the reaction time was increased (press-lever avoidance, 11.20 s vs. 8.43 s, p ≤ 0.05) and the percentage of correct response was lower (water maze, 53% vs. 82%) in irradiated rats compared with controls. Pathological examination did not demonstrate abnormalities of the irradiated brains at the light microscopic level. Conclusion: Behavioral dysfunction affecting mainly memory can be demonstrated following conventional radiation therapy in old rats. This model can be used to study the pathogenesis of radiation-induced cognitive changes

Radiation-induced cognitive dysfunction: An experimental model in the old rat

International Nuclear Information System (INIS)

Lamproglou, I.; Chen, Q.M.; Poisson, M.

1995-01-01

To develop a model of radiation-induced behavioral dysfunction. A course of whole brain radiation therapy (30 Gy/10 fractions/12 days) was administered to 26 Wistar rats ages 16-27 months, while 26 control rats received sham irradiation. Sequential behavioral studies including one-way avoidance, two-way avoidance, and a standard operant conditioning method (press-lever avoidance) were undertaken. In addition, rats were studied in a water maze 7 months postradiation therapy. Prior to radiation therapy, both groups were similar. No difference was found 1 and 3 months postradiation therapy. At 6-7 months postradiation therapy, irradiated rats had a much lower percentage of avoidance than controls for one-way avoidance (23% vs. 55%, p ≤ 0.001) and two-way avoidance (18% vs. 40%, p ≤ 0.01). Seven months postradiation therapy the reaction time was increased (press-lever avoidance, 11.20 s vs. 8.43 s, p ≤ 0.05) and the percentage of correct response was lower (water maze, 53% vs. 82%) in irradiated rats compared with controls. Pathological examination did not demonstrate abnormalities of the irradiated brains at the light microscopic level. Behavioral dysfunction affecting mainly memory can be demonstrated following conventional radiation therapy in old rats. This model can be used to study the pathogenesis of radiation-induced cognitive changes. 15 refs., 3 figs., 1 tab

Letter regarding the article “The impact of hypomagnesemia on erectile dysfunction in elderly, non-diabetic, stage 3 and 4 chronic kidney disease patients: a prospective cross-sectional study”

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Fatuzzo P

2017-04-01

Full Text Available Pasquale Fatuzzo,* Luca Zanoli,* Viviana Scollo Department of Clinical and Experimental Medicine, Section of Nephrology, University of Catania, Catania, Italy *These authors contributed equally to this work In an article published in a recent issue of Clinical Interventions in Aging, Toprak et al1 found that, among patients with stage 3–4 chronic kidney disease (CKD, the prevalence of erectile dysfunction was higher in patients with hypomagnesemia. This finding is clinically relevant because it supports the hypothesis that hypomagnesemia may lead to inflammation2 and endothelial dysfunction, two causes of erectile dysfunction. Toprak et al1 concluded that the detection of the serum magnesium level in non-diabetic elderly men with CKD could be useful to assess the risk of erectile dysfunction. Consequently, it is important to assess the causes of hypomagnesemia in patients with CKD, in particular the causes that are potentially reversible. With this in mind, hypomagnesemia could be caused by the long-term use of proton pump inhibitors,2,3 widely used in patients with CKD but not reported in the study of Toprak et al,1 alone or in combination with diuretics2 or cyclosporine.4 View the original paper by Toprak and colleagues 

NADPH oxidase 2-derived reactive oxygen species mediate FFAs-induced dysfunction and apoptosis of β-cells via JNK, p38 MAPK and p53 pathways.

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Huiping Yuan

2010-12-01

Full Text Available Dysfunction of β-cell is one of major characteristics in the pathogenesis of type 2 diabetes. The combination of obesity and type 2 diabetes, characterized as 'diabesity', is associated with elevated plasma free fatty acids (FFAs. Oxidative stress has been implicated in the pathogenesis of FFA-induced β-cell dysfunction. However, molecular mechanisms linking between reactive oxygen species (ROS and FFA-induced β-cell dysfunction and apoptosis are less clear. In the present study, we test the hypothesis that NOX2-derived ROS may play a critical role in dysfunction and apoptosis of β-cells induced by FFA. Our results show that palmitate and oleate (0.5 mmol/L, 48 h induced JNK activation and AKT inhibition which resulted in decreased phosphorylation of FOXO1 following nuclear localization and the nucleocytoplasmic translocation of PDX-1, leading to the reducing of insulin and ultimately dysfunction of pancreatic NIT-1 cells. We also found that palmitate and oleate stimulated apoptosis of NIT-1 cells through p38MAPK, p53 and NF-κB pathway. More interestingly, our data suggest that suppression of NOX2 may restore FFA-induced dysfunction and apoptosis of NIT-1 cells. Our findings provide a new insight of the NOX2 as a potential new therapeutic target for preservation of β-cell mass and function.

The beneficial effect of cynodon dactylon fractions on ethylene glycol-induced kidney calculi in rats.

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Khajavi Rad, Abolfazl; Hadjzadeh, Mousa-Al-Reza; Rajaei, Ziba; Mohammadian, Nema; Valiollahi, Saleh; Sonei, Mehdi

2011-01-01

To assess the beneficial effect of different fractions of Cynodon dactylon (C. dactylon) on ethylene glycol-induced kidney calculi in rats. Male Wistar rats were randomly divided into control, ethylene glycol, curative, and preventive groups. The control group received tap drinking water for 35 days. Ethylene glycol, curative, and preventive groups received 1% ethylene glycol for induction of calcium oxalate (CaOx) calculus formation. Preventive and curative subjects also received different fractions of C. dactylon extract in drinking water at 12.8 mg/kg, since day 0 and day 14, respectively. After 35 days, the kidneys were removed and examined for histopathological findings and counting the CaOx deposits in 50 microscopic fields. In curative protocol, treatment of rats with C. dactylon N-butanol fraction and N-butanol phase remnant significantly reduced the number of the kidney CaOx deposits compared to ethylene glycol group. In preventive protocol, treatment of rats with C. dactylon ethyl acetate fraction significantly decreased the number of CaOx deposits compared to ethylene glycol group. Fractions of C. dactylon showed a beneficial effect on preventing and eliminating CaOx deposition in the rat kidney. These results provide a scientific rational for preventive and treatment roles of C. dactylon in human kidney stone disease.

Vanillin mitigates potassium bromate-induced molecular, biochemical and histopathological changes in the kidney of adult mice.

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Ben Saad, Hajer; Driss, Dorra; Ellouz Chaabouni, Samia; Boudawara, Tahia; Zeghal, Khaled Mounir; Hakim, Ahmed; Ben Amara, Ibtissem

2016-05-25

The present study aimed to explore the ability of vanillin to ameliorate the adverse effects induced by potassium bromate (KBrO3) in the renal tissue. Our results showed a significant increase in hydrogen peroxide, superoxide anion, malondialdehyde, advanced oxidation protein product and protein carbonyl levels in the kidney of KBrO3 treated mice, compared with the control group. Nephrotoxicity was evidenced by a decrease in plasma uric acid and kidney glutathione levels, Na(+)-K(+)-ATPase, lactate dehydrogenase and catalase activities. Additionally, creatinine and urea levels significantly increased in the plasma and declined in the urine. Also, Kidney glutathione peroxidase, superoxide dismutase, metallothionein (MT1 and MT2) mRNA expression remarkably increased. These modifications in biochemical and molecular values were substantiated by histopathological data. Co-treatment with vanillin restored these parameters to near control values. Interestingly, vanillin proved to possess, in vitro, a stronger scavenging radical activity than vitamin C and Trolox. Thus, vanillin inhibited KBrO3-induced damage via its antioxidant and antiradical activities as well as its capacity to protect genes expression and histopathological changes. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

C3 Glomerulopathy and Atypical Hemolytic Uremic Syndrome: Two Important Manifestations of Complement System Dysfunction

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Ravneet Bajwa

2018-02-01

Full Text Available The advances in our understanding of the alternative pathway have emphasized that uncontrolled hyperactivity of this pathway causes 2 distinct disorders that adversely impact the kidney. In the so-called atypical hemolytic uremic syndrome (aHUS, renal dysfunction occurs along with thrombocytopenia, anemia, and target organ injury to multiple organs, most commonly the kidney. On the other hand, in the so-termed C3 glomerulopathy, kidney involvement is not associated with thrombocytopenia, anemia, or other system involvement. In this report, we present 2 cases of alternative pathway dysfunction. The 60-year-old female patient had biopsy-proven C3 glomerulopathy, while the 32-year-old female patient was diagnosed with aHUS based on renal dysfunction, thrombocytopenia, anemia, and normal ADAMTS-13 level. The aHUS patient was successfully treated with the monoclonal antibody (eculizumab for complement blockade. The patient with C3 glomerulopathy did not receive the monoclonal antibody. In this patient, management focused on blood pressure and proteinuria control with an angiotensin-converting enzyme inhibitor. This article focuses on the clinical differences, pathophysiology, and treatment of aHUS and C3 glomerulopathy.

Role of humoral immune reactions as target for antirejection therapy in recipients of a spousal-donor kidney graft.

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Böhmig, G A; Regele, H; Säemann, M D; Exner, M; Druml, W; Kovarik, J; Hörl, W H; Zlabinger, G J; Watschinger, B

2000-04-01

Excellent graft outcome has been reported for spousal-donor kidney transplantation. In husband-to-wife transplantation, however, a tendency toward inferior graft survival has been described for recipients who were previously pregnant. In our series of spousal-kidney transplantations (nine transplantations; three female recipients), actual graft survival is 100% (median observation time, 339 days). Five patients experienced early allograft rejection. In four transplant recipients, rejection was easily reversible by conventional antirejection therapy. In a multiparous recipient, however, mild interstitial allograft rejection associated with early graft dysfunction was resistant to anticellular treatment (antilymphocyte antibody, tacrolimus rescue therapy). The particular finding of polymorphonuclear neutrophils in peritubular capillaries and the finding of diffuse capillary deposits of the complement split product, C4d, in a posttransplantation biopsy specimen suggested a role of antibody-mediated graft injury. Retrospective flow cytometry cross-matching showed the presence of preformed immunoglobulin G (IgG) antibodies to HLA class I antigens that were not detectable by pretransplantation lymphocytotoxic cross-match testing or screening for panel reactive antibodies. After transplantation, however, complement-fixing antibodies, also presumably triggered by reexposure to spousal-donor HLA antigens, could be detected in the patient's serum. These findings suggested antibody-mediated allograft rejection and led to the initiation of immunoadsorption therapy (14 sessions) with staphylococcal protein A. Selective removal of recipient IgG resulted in complete reversal of graft dysfunction. Our findings suggest that in husband-to-wife transplantation, donor-specific antibodies, presumably triggered by previous pregnancies, might occasionally induce sustained allograft dysfunction. Thus, in this particular setting, a detailed immunologic and histopathologic work-up regarding

Alcohol dehydrogenase accentuates ethanol-induced myocardial dysfunction and mitochondrial damage in mice: role of mitochondrial death pathway.

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Rui Guo

2010-01-01

Full Text Available Binge drinking and alcohol toxicity are often associated with myocardial dysfunction possibly due to accumulation of the ethanol metabolite acetaldehyde although the underlying mechanism is unknown. This study was designed to examine the impact of accelerated ethanol metabolism on myocardial contractility, mitochondrial function and apoptosis using a murine model of cardiac-specific overexpression of alcohol dehydrogenase (ADH.ADH and wild-type FVB mice were acutely challenged with ethanol (3 g/kg/d, i.p. for 3 days. Myocardial contractility, mitochondrial damage and apoptosis (death receptor and mitochondrial pathways were examined.Ethanol led to reduced cardiac contractility, enlarged cardiomyocyte, mitochondrial damage and apoptosis, the effects of which were exaggerated by ADH transgene. In particular, ADH exacerbated mitochondrial dysfunction manifested as decreased mitochondrial membrane potential and accumulation of mitochondrial O(2 (*-. Myocardium from ethanol-treated mice displayed enhanced Bax, Caspase-3 and decreased Bcl-2 expression, the effect of which with the exception of Caspase-3 was augmented by ADH. ADH accentuated ethanol-induced increase in the mitochondrial death domain components pro-caspase-9 and cytochrome C in the cytoplasm. Neither ethanol nor ADH affected the expression of ANP, total pro-caspase-9, cytosolic and total pro-caspase-8, TNF-alpha, Fas receptor, Fas L and cytosolic AIF.Taken together, these data suggest that enhanced acetaldehyde production through ADH overexpression following acute ethanol exposure exacerbated ethanol-induced myocardial contractile dysfunction, cardiomyocyte enlargement, mitochondrial damage and apoptosis, indicating a pivotal role of ADH in ethanol-induced cardiac dysfunction possibly through mitochondrial death pathway of apoptosis.

Alcohol dehydrogenase accentuates ethanol-induced myocardial dysfunction and mitochondrial damage in mice: role of mitochondrial death pathway.

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Guo, Rui; Ren, Jun

2010-01-18

Binge drinking and alcohol toxicity are often associated with myocardial dysfunction possibly due to accumulation of the ethanol metabolite acetaldehyde although the underlying mechanism is unknown. This study was designed to examine the impact of accelerated ethanol metabolism on myocardial contractility, mitochondrial function and apoptosis using a murine model of cardiac-specific overexpression of alcohol dehydrogenase (ADH). ADH and wild-type FVB mice were acutely challenged with ethanol (3 g/kg/d, i.p.) for 3 days. Myocardial contractility, mitochondrial damage and apoptosis (death receptor and mitochondrial pathways) were examined. Ethanol led to reduced cardiac contractility, enlarged cardiomyocyte, mitochondrial damage and apoptosis, the effects of which were exaggerated by ADH transgene. In particular, ADH exacerbated mitochondrial dysfunction manifested as decreased mitochondrial membrane potential and accumulation of mitochondrial O(2) (*-). Myocardium from ethanol-treated mice displayed enhanced Bax, Caspase-3 and decreased Bcl-2 expression, the effect of which with the exception of Caspase-3 was augmented by ADH. ADH accentuated ethanol-induced increase in the mitochondrial death domain components pro-caspase-9 and cytochrome C in the cytoplasm. Neither ethanol nor ADH affected the expression of ANP, total pro-caspase-9, cytosolic and total pro-caspase-8, TNF-alpha, Fas receptor, Fas L and cytosolic AIF. Taken together, these data suggest that enhanced acetaldehyde production through ADH overexpression following acute ethanol exposure exacerbated ethanol-induced myocardial contractile dysfunction, cardiomyocyte enlargement, mitochondrial damage and apoptosis, indicating a pivotal role of ADH in ethanol-induced cardiac dysfunction possibly through mitochondrial death pathway of apoptosis.

Optical monitoring of kidney oxygenation and hemodynamics using a miniaturized near-infrared sensor

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Shadgan, Babak; Macnab, Andrew; Nigro, Mark; Nguan, Christopher

2017-02-01

Background: Following human renal allograft transplant primary graft dysfunction can occur early in the postoperative period as a result of acute tubular necrosis, acute rejection, drug toxicity, and vascular complications. Successful treatment of graft dysfunction requires early detection and accurate diagnosis so that disease-specific medical and/or surgical intervention can be provided promptly. However, current diagnostic methods are not sensitive or specific enough, so that identifying the cause of graft dysfunction is problematic and often delayed. Near-infrared spectroscopy (NIRS) is an established optical method that monitors changes in tissue hemodynamics and oxygenation in real time. We report the feasibility of directly monitoring kidney the kidney in an animal model using NIRS to detect renal ischemia and hypoxia. Methods: In an anesthetized pig, a customized continuous wave spatially resolved (SR) NIRS sensor was fixed directly to the surface of the surgically exposed kidney. Changes in the concentration of oxygenated (O2Hb) deoxygenated (HHb) and total hemoglobin (THb) were monitored before, during and after renal artery clamping and reperfusion, and the resulting fluctuations in chromophore concentration from baseline used to measure variations in renal perfusion and oxygenation. Results: On clamping the renal artery THb and O2Hb concentrations declined progressively while HHb rose. With reperfusion after releasing the artery clamp O2Hb and THb rose while HHb fell with all parameters returning to its baseline. This pattern was similar in all three trials. Conclusion: This pilot study indicates that a miniaturized NIRS sensor applied directly to the surface of a kidney in an animal model can detect the onset of renal ischemia and tissue hypoxia. With modification, our NIRS-based method may contribute to early detection of renal vascular complications and graft dysfunction following renal transplant.

Neuroprotective efficacy of curcumin in arsenic induced cholinergic dysfunctions in rats.

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Yadav, Rajesh S; Chandravanshi, Lalit P; Shukla, Rajendra K; Sankhwar, Madhu L; Ansari, Reyaz W; Shukla, Pradeep K; Pant, Aditya B; Khanna, Vinay K

2011-12-01

Our recent studies have shown that curcumin protects arsenic induced neurotoxicity by modulating oxidative stress, neurotransmitter levels and dopaminergic system in rats. As chronic exposure to arsenic has been associated with cognitive deficits in humans, the present study has been carried out to implore the neuroprotective potential of curcumin in arsenic induced cholinergic dysfunctions in rats. Rats treated with arsenic (sodium arsenite, 20mg/kg body weight, p.o., 28 days) exhibited a significant decrease in the learning activity, assessed by passive avoidance response associated with decreased binding of (3)H-QNB, known to label muscarinic-cholinergic receptors in hippocampus (54%) and frontal cortex (27%) as compared to controls. Decrease in the activity of acetylcholinesterase in hippocampus (46%) and frontal cortex (33%), staining of Nissl body, immunoreactivity of choline acetyltransferase (ChAT) and expression of ChAT protein in hippocampal region was also observed in arsenic treated rats as compared to controls. Simultaneous treatment with arsenic and curcumin (100mg/kg body weight, p.o., 28 days) increased learning and memory performance associated with increased binding of (3)H-QNB in hippocampus (54%), frontal cortex (25%) and activity of acetylcholinesterase in hippocampus (41%) and frontal cortex (29%) as compared to arsenic treated rats. Increase in the expression of ChAT protein, immunoreactivity of ChAT and staining of Nissl body in hippocampal region was also observed in rats simultaneously treated with arsenic and curcumin as compared to those treated with arsenic alone. The results of the present study suggest that curcumin significantly modulates arsenic induced cholinergic dysfunctions in brain and also exhibits neuroprotective efficacy of curcumin. Copyright © 2011 Elsevier Inc. All rights reserved.

MLN64 induces mitochondrial dysfunction associated with increased mitochondrial cholesterol content

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Elisa Balboa

2017-08-01

Full Text Available MLN64 is a late endosomal cholesterol-binding membrane protein that has been implicated in cholesterol transport from endosomal membranes to the plasma membrane and/or mitochondria, in toxin-induced resistance, and in mitochondrial dysfunction. Down-regulation of MLN64 in Niemann-Pick C1 deficient cells decreased mitochondrial cholesterol content, suggesting that MLN64 functions independently of NPC1. However, the role of MLN64 in the maintenance of endosomal cholesterol flow and intracellular cholesterol homeostasis remains unclear. We have previously described that hepatic MLN64 overexpression increases liver cholesterol content and induces liver damage. Here, we studied the function of MLN64 in normal and NPC1-deficient cells and we evaluated whether MLN64 overexpressing cells exhibit alterations in mitochondrial function. We used recombinant-adenovirus-mediated MLN64 gene transfer to overexpress MLN64 in mouse liver and hepatic cells; and RNA interference to down-regulate MLN64 in NPC1-deficient cells. In MLN64-overexpressing cells, we found increased mitochondrial cholesterol content and decreased glutathione (GSH levels and ATPase activity. Furthermore, we found decreased mitochondrial membrane potential and mitochondrial fragmentation and increased mitochondrial superoxide levels in MLN64-overexpressing cells and in NPC1-deficient cells. Consequently, MLN64 expression was increased in NPC1-deficient cells and reduction of its expression restore mitochondrial membrane potential and mitochondrial superoxide levels. Our findings suggest that MLN64 overexpression induces an increase in mitochondrial cholesterol content and consequently a decrease in mitochondrial GSH content leading to mitochondrial dysfunction. In addition, we demonstrate that MLN64 expression is increased in NPC cells and plays a key role in cholesterol transport into the mitochondria.

Dual Kidney Transplantation Offers a Valuable Source for Kidneys With Good Functional Outcome.

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Khalid, U; Asderakis, A; Rana, T; Szabo, L; Chavez, R; Ilham, M A; Ablorsu, E

2016-01-01

Reasons for declining kidney donors are older age, with or without, hypertension, kidney dysfunction, and diabetes. Implantation of both kidneys into a single recipient from such donors may improve their acceptability and outcome. Patients who underwent dual kidney transplantation (DKT) between June 2010 and May 2014 were identified from a prospectively maintained database. Single kidney transplantations (SKT) with matching donor criteria were also identified. Donors considered for DKT were the following: DBDs >70 years of age with diabetes and/or hypertension; DCDs >65 years of age with diabetes and/or hypertension; and DCDs >70 years of age. Over a 4-year period, 34 patients underwent adult DKT, and 51, with matching donor criteria, underwent SKT. The median estimated glomerular filtration rate (eGFR) at 12 and 36 months of DKT was 49 (range, 5-79) and 42 (range, 15-85) mL/min compared with SKT of 35 (range, 10-65) and 32 (range, 6-65), respectively. The 1-year graft survival for DKT and SKT was 88% and 96% (P = .52), and patient survival was 94% and 98%, respectively (P = .12). Median hospital stay, intensive care unit admission, and wound complications were more frequent in the DKT group. Graft function following DKT is significantly better compared with matched criteria SKT; graft and patient survival are similar. There is an increased rate of complications following DKT, with longer hospital stay and ICU admission. Copyright © 2016 Elsevier Inc. All rights reserved.

Neural regulation of the kidney function in rats with cisplatin induced renal failure

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Goulding, Niamh E.; Johns, Edward J.

2015-01-01

Aim: Chronic kidney disease (CKD) is often associated with a disturbed cardiovascular homeostasis. This investigation explored the role of the renal innervation in mediating deranged baroreflex control of renal sympathetic nerve activity (RSNA) and renal excretory function in cisplatin-induced renal failure. Methods: Rats were either intact or bilaterally renally denervated 4 days prior to receiving cisplatin (5 mg/kg i.p.) and entered a chronic metabolic study for 8 days. At day 8, other groups of rats were prepared for acute measurement of RSNA or renal function with either intact or denervated kidneys. Results: Following the cisplatin challenge, creatinine clearance was 50% lower while fractional sodium excretion and renal cortical and medullary TGF-β1 concentrations were 3–4 fold higher in both intact and renally denervated rats compared to control rats. In cisplatin-treated rats, the maximal gain of the high-pressure baroreflex curve was only 20% that of control rats, but following renal denervation not different from that of renally denervated control rats. Volume expansion reduced RSNA by 50% in control and in cisplatin-treated rats but only following bilateral renal denervation. The volume expansion mediated natriuresis/diuresis was absent in the cisplatin-treated rats but was normalized following renal denervation. Conclusions: Cisplatin-induced renal injury impaired renal function and caused a sympatho-excitation with blunting of high and low pressure baroreflex regulation of RSNA, which was dependent on the renal innervation. It is suggested that in man with CKD there is a dysregulation of the neural control of the kidney mediated by its sensory innervation. PMID:26175693

Humanin rescues cultured rat cortical neurons from NMDA-induced toxicity through the alleviation of mitochondrial dysfunction

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Cui A

2017-04-01

Full Text Available Ai-Ling Cui,1 Ying-Hua Zhang,2 Jian-Zhong Li,3 Tianbin Song,4 Xue-Min Liu,1 Hui Wang,2 Ce Zhang,5 Guo-Lin Ma,6 Hui Zhang,7 Kefeng Li8 1Anatomy Department, Changzhi Medical College, Changzhi, Shanxi, 2Key Laboratory of Tissue Regeneration of Henan Province, Xinxiang Medical University, Xinxiang, Henan, 3Clinical Laboratory of Heji Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, 4Department of Nuclear Medicine, Xuanwu Hospital, Capital Medical University, Beijing, 5Department of Physiology, Shanxi Medical University, Taiyuan, Shanxi, 6Department of Radiology, China-Japan Friendship Hospital, Beijing, 7Department of Radiology, First Clinical Medical College, Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China; 8School of Medicine, University of California – San Diego, San Diego, CA, USA Abstract: N-methyl-D-aspartate (NDMA receptor-mediated excitotoxicity has been implicated in a variety of pathological situations such as Alzheimer’s disease (AD and Parkinson’s disease. However, no effective treatments for the same have been developed so far. Humanin (HN is a 24-amino acid peptide originally cloned from the brain of patients with AD and it prevents stress-induced cell death in many cells/tissues. In our previous study, HN was found to effectively rescue rat cortical neurons. It is still not clear whether HN protects the neurons through the attenuation of mitochondrial dysfunction. In this study, excitatory toxicity was induced by NMDA, which binds the NMDA receptor in primarily cultured rat cortical neurons. We found that NMDA (100 µmol/L dramatically induced the decrease of cell viability and caused mitochondrial dysfunction. Pretreatment of the neurons with HN (1 µmol/L led to significant increases of mitochondrial succinate dehydrogenase (SDH activity and membrane potential. In addition, HN pretreatment significantly reduced the excessive production of both reactive oxygen species (ROS and nitric

Contrast-induced acute kidney injury in children with cardiovascular defects – results of a pilot study

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Daria Tomczyk

2016-12-01

Full Text Available Introduction: Contrast-induced nephropathy – acute kidney injury is an acquired kidney injury that is an important factor in short- and long-term cardiovascular complications. Contrast-induced nephropathy – acute kidney injury continues to be diagnosed based on serum creatinine level. Serum creatinine, however, is a delayed indicator of contrast-induced nephropathy, as its levels typically peak between 1 and 3 days following contrast exposure. Currently, more sensitive biomarkers of kidney injury are sought, with human neutrophil lipocalin (also known as neutrophil gelatinase-associated lipocalin highlighted in literature as a troponin-like biomarker of early nephropathy. Aim of the study: Changes in serum and urine neutrophil gelatinase-associated lipocalin levels were assessed in children with congenital heart diseases, following a scheduled cardiac catheterization procedure. Material and methods: The group studied comprised 16 patients. The neutrophil gelatinaseassociated lipocalin and creatinine levels, along with urine and serum neutrophil gelatinase-associated lipocalin/creatinine ratio were evaluated five times at different time intervals from the procedure. The group did not vary in respect of kidney function, preprocedure management, and volume expansion (hydration therapy prior to the procedure. Results: In the assessed material, median neutrophil gelatinase-associated lipocalin rose as early as 2 hours after exposure to contrast as compared with baseline [median = 28.2 ng/mL (Quartile 1 = 22.8 – Quartile 3 = 33.77 vs. median = 25.87 ng/mL (Quartile 1 = 19.4 – Quartile 3 = 29.6]. Serum neutrophil gelatinase-associated lipocalin level peaked in hour 6 of our study: median – 30.6 ng/mL (Quartile 1 = 22.32 – Quartile 3 = 42.17, then reverting to normal. Urine neutrophil gelatinaseassociated lipocalin peaked in hour 24 of the study, subsequently dropping below baseline in hour 48

Impact of chronic kidney disease on the natural history of alkaptonuria

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Faria, Bernardo; Vidinha, Joana; Pêgo, Cátia; Correia, Hugo; Sousa, Tânia

2012-01-01

In alkaptonuria, deficiency of homogentisate 1,2-dioxygenase leads to the accumulation of homogentisic acid (HGA) and its metabolites in the body, resulting in ochronosis. Reports of patients with alkaptonuria who have decreased kidney function are rare, but this seems to play an important role in the natural history of the disease. We describe a 68-year-old female with chronic kidney disease (CKD) of unknown etiology who started peritoneal dialysis (PD) after 5 years of follow-up and who was diagnosed with alkaptonuria at this time. Progressive exacerbation of ochronotic manifestations had been noted during these last few years, as kidney function worsened. After PD initiation, the disease continued to progress, and death occurred after one year and a half, due to severe aortic stenosis-related complications. Her 70-year-old sister was evaluated and also diagnosed with alkaptonuria. She had no renal dysfunction. Higher HGA excretion and significantly milder ochronosis than that of her sister were found. We present two alkaptonuric sisters with similar comorbidities except for the presence of CKD, who turned out to have totally different evolutions of their disease. This report confirms that kidney dysfunction may be an important factor in determining the natural history of alkaptonuria. PMID:25874097

Atorvastatin restores arsenic-induced vascular dysfunction in rats: Modulation of nitric oxide signaling and inflammatory mediators

International Nuclear Information System (INIS)

Kesavan, Manickam; Sarath, Thengumpallil Sasindran; Kannan, Kandasamy; Suresh, Subramaniyam; Gupta, Priyanka; Vijayakaran, Karunakaran; Sankar, Palanisamy; Kurade, Nitin Pandurang; Mishra, Santosh Kumar; Sarkar, Souvendra Nath

2014-01-01

We evaluated whether atorvastatin, an extensively prescribed statin for reducing the risks of cardiovascular diseases, can reduce the risk of arsenic-induced vascular dysfunction and inflammation in rats and whether the modulation could be linked to improvement in vascular NO signaling. Rats were exposed to sodium arsenite (100 ppm) through drinking water for 90 consecutive days. Atorvastatin (10 mg/kg bw, orally) was administered once daily during the last 30 days of arsenic exposure. On the 91 st day, blood was collected for measuring serum C-reactive protein. Thoracic aorta was isolated for assessing reactivity to phenylephrine, sodium nitroprusside and acetylcholine; evaluating eNOS and iNOS mRNA expression and measuring NO production, while abdominal aorta was used for ELISA of cytokines, chemokine and vascular cell adhesion molecules. Histopathology was done in aortic arches. Arsenic did not alter phenylephrine-elicited contraction. Atorvastatin inhibited E max of phenylephrine, but it augmented the contractile response in aortic rings from arsenic-exposed animals. Sodium nitroprusside-induced relaxation was not altered with any treatment. However, arsenic reduced acetylcholine-induced relaxation and affected aortic eNOS at the levels of mRNA expression, protein concentration, phosphorylation and NO production. Further, it increased aortic iNOS mRNA expression, iNOS-derived NO synthesis, production of pro-inflammatory mediators (IL-1β, IL-6, MCP-1, VCAM, sICAM) and serum C-reactive protein and aortic vasculopathic lesions. Atorvastatin attenuated these arsenic-mediated functional, biochemical and structural alterations. Results show that atorvastatin has the potential to ameliorate arsenic-induced vascular dysfunction and inflammation by restoring endothelial function with improvement in NO signaling and attenuating production of pro-inflammatory mediators and cell adhesion molecules. - Highlights: • We evaluated if atorvastatin reduce arsenic-induced

Atorvastatin restores arsenic-induced vascular dysfunction in rats: Modulation of nitric oxide signaling and inflammatory mediators

Energy Technology Data Exchange (ETDEWEB)

Kesavan, Manickam; Sarath, Thengumpallil Sasindran; Kannan, Kandasamy; Suresh, Subramaniyam; Gupta, Priyanka; Vijayakaran, Karunakaran; Sankar, Palanisamy; Kurade, Nitin Pandurang; Mishra, Santosh Kumar; Sarkar, Souvendra Nath, E-mail: snsarkar1911@rediffmail.com

2014-10-01

We evaluated whether atorvastatin, an extensively prescribed statin for reducing the risks of cardiovascular diseases, can reduce the risk of arsenic-induced vascular dysfunction and inflammation in rats and whether the modulation could be linked to improvement in vascular NO signaling. Rats were exposed to sodium arsenite (100 ppm) through drinking water for 90 consecutive days. Atorvastatin (10 mg/kg bw, orally) was administered once daily during the last 30 days of arsenic exposure. On the 91{sup st} day, blood was collected for measuring serum C-reactive protein. Thoracic aorta was isolated for assessing reactivity to phenylephrine, sodium nitroprusside and acetylcholine; evaluating eNOS and iNOS mRNA expression and measuring NO production, while abdominal aorta was used for ELISA of cytokines, chemokine and vascular cell adhesion molecules. Histopathology was done in aortic arches. Arsenic did not alter phenylephrine-elicited contraction. Atorvastatin inhibited E{sub max} of phenylephrine, but it augmented the contractile response in aortic rings from arsenic-exposed animals. Sodium nitroprusside-induced relaxation was not altered with any treatment. However, arsenic reduced acetylcholine-induced relaxation and affected aortic eNOS at the levels of mRNA expression, protein concentration, phosphorylation and NO production. Further, it increased aortic iNOS mRNA expression, iNOS-derived NO synthesis, production of pro-inflammatory mediators (IL-1β, IL-6, MCP-1, VCAM, sICAM) and serum C-reactive protein and aortic vasculopathic lesions. Atorvastatin attenuated these arsenic-mediated functional, biochemical and structural alterations. Results show that atorvastatin has the potential to ameliorate arsenic-induced vascular dysfunction and inflammation by restoring endothelial function with improvement in NO signaling and attenuating production of pro-inflammatory mediators and cell adhesion molecules. - Highlights: • We evaluated if atorvastatin reduce arsenic-induced

Acute restraint stress induces endothelial dysfunction: role of vasoconstrictor prostanoids and oxidative stress.

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Carda, Ana P P; Marchi, Katia C; Rizzi, Elen; Mecawi, André S; Antunes-Rodrigues, José; Padovan, Claudia M; Tirapelli, Carlos R

2015-01-01

We hypothesized that acute stress would induce endothelial dysfunction. Male Wistar rats were restrained for 2 h within wire mesh. Functional and biochemical analyses were conducted 24 h after the 2-h period of restraint. Stressed rats showed decreased exploration on the open arms of an elevated-plus maze (EPM) and increased plasma corticosterone concentration. Acute restraint stress did not alter systolic blood pressure, whereas it increased the in vitro contractile response to phenylephrine and serotonin in endothelium-intact rat aortas. NG-nitro-l-arginine methyl ester (l-NAME; nitric oxide synthase, NOS, inhibitor) did not alter the contraction induced by phenylephrine in aortic rings from stressed rats. Tiron, indomethacin and SQ29548 reversed the increase in the contractile response to phenylephrine induced by restraint stress. Increased systemic and vascular oxidative stress was evident in stressed rats. Restraint stress decreased plasma and vascular nitrate/nitrite (NOx) concentration and increased aortic expression of inducible (i) NOS, but not endothelial (e) NOS. Reduced expression of cyclooxygenase (COX)-1, but not COX-2, was observed in aortas from stressed rats. Restraint stress increased thromboxane (TX)B(2) (stable TXA(2) metabolite) concentration but did not affect prostaglandin (PG)F2α concentration in the aorta. Restraint reduced superoxide dismutase (SOD) activity, whereas concentrations of hydrogen peroxide (H(2)O(2)) and reduced glutathione (GSH) were not affected. The major new finding of our study is that restraint stress increases vascular contraction by an endothelium-dependent mechanism that involves increased oxidative stress and the generation of COX-derived vasoconstrictor prostanoids. Such stress-induced endothelial dysfunction could predispose to the development of cardiovascular diseases.

Thyroid Disorders and Chronic Kidney Disease

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Mohamed Mohamedali

2014-01-01

Full Text Available Thyroid hormones play a very important role regulating metabolism, development, protein synthesis, and influencing other hormone functions. The two main hormones produced by the thyroid are triiodothyronine (T3 and thyroxine (T4. These hormones can also have significant impact on kidney disease so it is important to consider the physiological association of thyroid dysfunction in relation to chronic kidney disease (CKD. CKD has been known to affect the pituitary-thyroid axis and the peripheral metabolism of thyroid hormones. Low T3 levels are the most common laboratory finding followed by subclinical hypothyroidism in CKD patients. Hyperthyroidism is usually not associated with CKD but has been known to accelerate it. One of the most important links between thyroid disorders and CKD is uremia. Patients who are appropriately treated for thyroid disease have a less chance of developing renal dysfunction. Clinicians need to be very careful in treating patients with low T3 levels who also have an elevation in TSH, as this can lead to a negative nitrogen balance. Thus, clinicians should be well educated on the role of thyroid hormones in relation to CKD so that proper treatment can be delivered to the patient.

Trichodermin induces cell apoptosis through mitochondrial dysfunction and endoplasmic reticulum stress in human chondrosarcoma cells

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Su, Chen-Ming; Wang, Shih-Wei; Lee, Tzong-Huei; Tzeng, Wen-Pei; Hsiao, Che-Jen; Liu, Shih-Chia; Tang, Chih-Hsin

2013-01-01

Chondrosarcoma is the second most common primary bone tumor, and it responds poorly to both chemotherapy and radiation treatment. Nalanthamala psidii was described originally as Myxosporium in 1926. This is the first study to investigate the anti-tumor activity of trichodermin (trichothec-9-en-4-ol, 12,13-epoxy-, acetate), an endophytic fungal metabolite from N. psidii against human chondrosarcoma cells. We demonstrated that trichodermin induced cell apoptosis in human chondrosarcoma cell lines (JJ012 and SW1353 cells) instead of primary chondrocytes. In addition, trichodermin triggered endoplasmic reticulum (ER) stress protein levels of IRE1, p-PERK, GRP78, and GRP94, which were characterized by changes in cytosolic calcium levels. Furthermore, trichodermin induced the upregulation of Bax and Bid, the downregulation of Bcl-2, and the dysfunction of mitochondria, which released cytochrome c and activated caspase-3 in human chondrosarcoma. In addition, animal experiments illustrated reduced tumor volume, which led to an increased number of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive cells and an increased level of cleaved PARP protein following trichodermin treatment. Together, this study demonstrates that trichodermin is a novel anti-tumor agent against human chondrosarcoma cells both in vitro and in vivo via mitochondrial dysfunction and ER stress. - Highlights: • Trichodermin induces chondrosarcoma apoptosis. • ER stress is involved in trichodermin-induced cell death. • Trichodermin induces chondrosarcoma death in vivo.

Trichodermin induces cell apoptosis through mitochondrial dysfunction and endoplasmic reticulum stress in human chondrosarcoma cells

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Su, Chen-Ming [Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan (China); Wang, Shih-Wei [Department of Medicine, Mackay Medical College, New Taipei City, Taiwan (China); Lee, Tzong-Huei [Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei, Taiwan (China); Tzeng, Wen-Pei [Graduate Institute of Sports and Health, National Changhua University of Education, Changhua, Taiwan (China); Hsiao, Che-Jen [School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan (China); Liu, Shih-Chia [Department of Orthopaedics, Mackay Memorial Hospital, Taipei, Taiwan (China); Tang, Chih-Hsin, E-mail: chtang@mail.cmu.edu.tw [Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan (China); Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan (China); Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan (China)

2013-10-15

Chondrosarcoma is the second most common primary bone tumor, and it responds poorly to both chemotherapy and radiation treatment. Nalanthamala psidii was described originally as Myxosporium in 1926. This is the first study to investigate the anti-tumor activity of trichodermin (trichothec-9-en-4-ol, 12,13-epoxy-, acetate), an endophytic fungal metabolite from N. psidii against human chondrosarcoma cells. We demonstrated that trichodermin induced cell apoptosis in human chondrosarcoma cell lines (JJ012 and SW1353 cells) instead of primary chondrocytes. In addition, trichodermin triggered endoplasmic reticulum (ER) stress protein levels of IRE1, p-PERK, GRP78, and GRP94, which were characterized by changes in cytosolic calcium levels. Furthermore, trichodermin induced the upregulation of Bax and Bid, the downregulation of Bcl-2, and the dysfunction of mitochondria, which released cytochrome c and activated caspase-3 in human chondrosarcoma. In addition, animal experiments illustrated reduced tumor volume, which led to an increased number of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive cells and an increased level of cleaved PARP protein following trichodermin treatment. Together, this study demonstrates that trichodermin is a novel anti-tumor agent against human chondrosarcoma cells both in vitro and in vivo via mitochondrial dysfunction and ER stress. - Highlights: • Trichodermin induces chondrosarcoma apoptosis. • ER stress is involved in trichodermin-induced cell death. • Trichodermin induces chondrosarcoma death in vivo.

Multi-color autofluorescence and scattering spectroscopy provides rapid assessment of kidney function following ischemic injury

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Raman, Rajesh N.; Pivetti, Chris D.; Ramsamooj, Rajendra; Troppmann, Christoph; Demos, Stavros G.

2018-02-01

A major source of kidneys for transplant comes from deceased donors whose tissues have suffered an unknown amount of warm ischemia prior to retrieval, with no quantitative means to assess function before transplant. Toward addressing this need, non-contact monitoring of optical signatures in rat kidneys was performed in vivo during ischemia and reperfusion. Kidney autofluorescence images were captured under ultraviolet illumination (355 nm, 325 nm, and 266 nm) in order to provide information on related metabolic and non-metabolic response. In addition, light scattering images under 355 nm, 325 nm, and 266 nm, 500 nm illumination were monitored to report on changes in kidney optical properties giving rise to the observed autofluorescence signals during these processes. During reperfusion, various signal ratios were generated from the recorded signals and then parametrized. Time-dependent parameters derived from the ratio of autofluorescence under 355 nm excitation to that under 266 nm excitation, as well as from 500 nm scattered signal, were found capable of discriminating dysfunctional kidneys from those that were functional (p Kidney dysfunction was confirmed by subsequent survival study and histology following autopsy up to a week later. Physiologic changes potentially giving rise to the observed signals, including those in cellular metabolism, vascular response, tissue microstructure, and microenvironment chemistry, are discussed.

Melatonin limits paclitaxel‐induced mitochondrial dysfunction in vitro and protects against paclitaxel‐induced neuropathic pain in the rat

OpenAIRE

Galley, Helen F.; McCormick, Barry; Wilson, Kirsten L.; Lowes, Damon A.; Colvin, Lesley; Torsney, Carole

2017-01-01

Chemotherapy-induced neuropathic pain is a debilitating and common side effect of cancer treatment. Mitochondrial dysfunction associated with oxidative stress in peripheral nerves has been implicated in the underlying mechanism. We investigated the potential of melatonin, a potent antioxidant that preferentially acts within mitochondria, to reduce mitochondrial damage and neuropathic pain resulting from the chemotherapeutic drug paclitaxel. In vitro, paclitaxel caused a 50% reduction of mitoc...

Direct and Indirect Effects of Cytomegalovirus-induced gamma-delta T Cells after Kidney Transplantation

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Lionel eCouzi

2015-01-01

Full Text Available Despite effective anti-viral therapies, cytomegalovirus (CMV is still associated with direct (CMV disease and indirect effects (rejection and poor graft survival in kidney transplant recipients. Recently, an unconventional T cell population (collectively designated as Vδ2neg γδ T cells has been characterized during the anti-CMV immune response in all solid-organ and bone-marrow transplant recipients, neonates, and healthy people. These CMV-induced γδ T cells undergo a dramatic and stable expansion after CMV infection, in a conventional ‘adaptive’ manner. Similarly as CMV-specific CD8+ αβ T cells, they exhibit an effector/memory TEMRA phenotype and cytotoxic effector functions. Activation of Vd2neg gd T cells by CMV-infected cells involves the TCR and still ill-defined co-stimulatory molecules such LFA-1. A multiple of Vd2neg gd TCR ligands are apparently recognized on CMV-infected cells, the first one identified being the MHC-related molecule endothelial protein C receptor (EPCR. A singularity of CMV-induced Vd2neg gd T cells is to acquire CD16 expression and to exert an antibody-dependent cell-mediated inhibition on CMV replication, which is controlled by a specific cytokine microenvironment. Beyond the well-demonstrated direct anti-CMV effect of Vδ2neg γδ T cells, unexpected indirect effects of these cells have been also observed in the context of kidney transplantation. CMV-induced Vδ2neg γδ T cells have been involved in surveillance of malignancy subsequent to long term immunosuppression. Moreover, CMV-induced CD16+ γδ T cells are cell effectors of antibody-mediated rejection of kidney transplants, and represent a new physiopathological contribution to the well-known association between CMV infection and poor graft survival. All these basic and clinical studies paved the road to the development of a future γδ T cell-based immunotherapy. In the meantime, γδ T cell monitoring should prove a valuable immunological

Respiration-induced motion of the kidneys in whole abdominal radiotherapy: implications for treatment planning and late toxicity

International Nuclear Information System (INIS)

Ahmad, N.R.; Huq, M.S.; Corn, B.W.

1997-01-01

Purpose: Whole abdominal radiotherapy (WAR) has potential utility in the management of several malignancies. The limited radiation tolerance of the kidneys is an important consideration in the design of WAR fields. Although renal blocking is standard for WAR, few guidelines exist in the literature to factor respiration-induced kidney motion into the design of these blocks. Methods: Radiographs were obtained to measure kidney excursion under forced respiratory conditions in eight patients (14 visualized kidneys). Intravenous contrast was administered and AP films were obtained at maximum inspiration and expiration. Renal excursion was measured relative to a horizontal reference line at the bottom of the L3 vertebral body. The kidney position on the actual treatment simulation film was also determined using this technique. Treatment isodose distributions through the kidneys were obtained for a sample patient using phantom measurements and two blocking schemes: AP/PA and PA only. These provided quantification of the actual dose received by the kidney in a typical WAR treatment. Results: In the worst case scenario, the left kidney block required an additional 10 mm above and 15 mm below the renal silhouette on the simulation film in order to account for all phases of respiration. The corresponding values for the right kidney were 2 mm and 19 mm, respectively. The dose received by the kidney under the center of the block was 20% of prescribed using AP/PA blocks and 50% of prescribed using PA blocks only. However, portions of 'blocked' kidney received up to 90% of the prescribed dose with either technique. Conclusions: Although kidney motion under forced respiratory conditions is not representative of typical treatment conditions, the data highlight the possibility of renal movement during treatment. This is particularly important in light of the significant dose (20 to 50%) delivered to the kidney under the center of the kidney block in typical treatments. Given the

Restoration of dietary-fat induced blood–brain barrier dysfunction by anti-inflammatory lipid-modulating agents

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Pallebage-Gamarallage Menuka

2012-09-01

Full Text Available Abstract Background Several studies have identified use of non-steroidal-anti-inflammatory drugs and statins for prevention of dementia, but their efficacy in slowing progression is not well understood. Cerebrovascular disturbances are common pathological feature of Alzheimer’s disease. We previously reported chronic ingestion of saturated fatty acids (SFA compromises blood–brain barrier (BBB integrity resulting in cerebral extravasation of plasma proteins and inflammation. However, the SFA-induced parenchymal accumulation of plasma proteins could be prevented by co-administration of some cholesterol lowering agents. Restoration of BBB dysfunction is clinically relevant, so the purpose of this study was to explore lipid-lowering agents could reverse BBB disturbances induced by chronic ingestion of SFA’s. Methods Wild-type mice were fed an SFA diet for 12 weeks to induce BBB dysfunction, and then randomised to receive atorvastatin, pravastatin or ibuprofen in combination with the SFA-rich diet for 2 or 8 weeks. Abundance of plasma-derived immunoglobulin-G (IgG and amyloid-β enriched apolipoprotein (apo-B lipoproteins within brain parenchyme were quantified utilising immunofluorescence microscopy. Results Atorvastatin treatment for 2 and 8 weeks restored BBB integrity, indicated by a substantial reduction of IgG and apo B, particularly within the hippocampus. Pravastatin, a water-soluble statin was less effective than atorvastatin (lipid-soluble. Statin effects were independent of changes in plasma lipid homeostasis. Ibuprofen, a lipid-soluble cyclooxygenase inhibitor attenuated cerebral accumulation of IgG and apo B as effectively as atorvastatin. Our findings are consistent with the drug effects being independent of plasma lipid homeostasis. Conclusion Our findings suggest that BBB dysfunction induced by chronic ingestion of SFA is reversible with timely introduction and sustained treatment with agents that suppress inflammation.

High-fat-diet-induced obesity causes an inflammatory and tumor-promoting microenvironment in the rat kidney

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Kerstin Stemmer

2012-09-01

Obesity and concomitant comorbidities have emerged as public health problems of the first order. For instance, obese individuals have an increased risk for kidney cancer. However, direct mechanisms linking obesity with kidney cancer remain elusive. We hypothesized that diet-induced obesity (DIO promotes renal carcinogenesis by inducing an inflammatory and tumor-promoting microenvironment. We compared chow-fed lean Wistar rats with those that were sensitive (DIOsens or partially resistant (DIOres to DIO to investigate the impact of body adiposity versus dietary nutrient overload in the development of renal preneoplasia and activation of tumor-promoting signaling pathways. Our data clearly show a correlation between body adiposity, the severity of nephropathy, and the total number and incidence of preneoplastic renal lesions. However, similar plasma triglyceride, plasma free fatty acid and renal triglyceride levels were found in chow-fed, DIOres and DIOsens rats, suggesting that lipotoxicity is not a critical contributor to the renal pathology. Obesity-related nephropathy was further associated with regenerative cell proliferation, monocyte infiltration and higher renal expression of monocyte chemotactic protein-1 (MCP-1, interleukin (IL-6, IL-6 receptor and leptin receptor. Accordingly, we observed increased signal transducer and activator of transcription 3 (STAT3 and mammalian target of rapamycin (mTOR phosphorylation in tubules with preneoplastic phenotypes. In summary, our results demonstrate that high body adiposity induces an inflammatory and proliferative microenvironment in rat kidneys that promotes the development of preneoplastic lesions, potentially via activation of the STAT3 and mTOR signaling pathways.

Vinpocetine reduces diclofenac-induced acute kidney injury through inhibition of oxidative stress, apoptosis, cytokine production, and NF-κB activation in mice.

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Fattori, Victor; Borghi, Sergio M; Guazelli, Carla F S; Giroldo, Andressa C; Crespigio, Jefferson; Bussmann, Allan J C; Coelho-Silva, Letícia; Ludwig, Natasha G; Mazzuco, Tânia L; Casagrande, Rubia; Verri, Waldiceu A

2017-06-01

Acute kidney injury (AKI) represents a complex clinical condition associated with significant morbidity and mortality. Approximately, 19-33% AKI episodes in hospitalized patients are related to drug-induced nephrotoxicity. Although, considered safe, non-steroidal anti-inflammatory drugs such as diclofenac have received special attention in the past years due to the potential risk of renal damage. Vinpocetine is a nootropic drug known to have anti-inflammatory properties. In this study, we investigated the effect and mechanisms of vinpocetine in a model of diclofenac-induced AKI. We observed that diclofenac increased proteinuria and blood urea, creatinine, and oxidative stress levels 24h after its administration. In renal tissue, diclofenac also increased oxidative stress and induced morphological changes consistent with renal damage. Moreover, diclofenac induced kidney cells apoptosis, up-regulated proinflammatory cytokines, and induced the activation of NF-κB in renal tissue. On the other hand, vinpocetine reduced diclofenac-induced blood urea and creatinine. In the kidneys, vinpocetine inhibited diclofenac-induced oxidative stress, morphological changes, apoptosis, cytokine production, and NF-κB activation. To our knowledge, this is the first study demonstrating that diclofenac-induced AKI increases NF-κB activation, and that vinpocetine reduces the nephrotoxic effects of diclofenac. Therefore, vinpocetine is a promising molecule for the treatment of diclofenac-induced AKI. Copyright © 2017 Elsevier Ltd. All rights reserved.

Peroxiredoxin 5 Protects TGF-β Induced Fibrosis by Inhibiting Stat3 Activation in Rat Kidney Interstitial Fibroblast Cells.

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Hoon-In Choi

Full Text Available Renal fibrosis is a common final pathway of end-stage kidney disease which is induced by aberrant accumulation of myofibroblasts. This process is triggered by reactive oxygen species (ROS and proinflammatory cytokines generated by various source of injured kidney cells. Peroxiredoxin 5 (Prdx5 is a thiol-dependent peroxidase that reduces oxidative stress by catalyzing intramolecular disulfide bonds. Along with its antioxidant effects, expression level of Prdx5 also was involved in inflammatory regulation by immune stimuli. However, the physiological effects and the underlying mechanisms of Prdx5 in renal fibrosis have not been fully characterized. Sprague-Dawley rats were subjected to unilateral ureteral obstruction (UUO for 1 or 7 days. For the in vitro model, NRK49F cells, a rat kidney interstitial fibroblast cell lines, were treated with transforming growth factor β (TGF-β for 0, 1, 3, or 5 days. To access the involvement of its peroxidase activity in TGF-β induced renal fibrosis, wild type Prdx5 (WT and double mutant Prdx5 (DM, converted two active site cysteines at Cys 48 and Cys 152 residue to serine, were transiently expressed in NRK49F cells. The protein expression of Prdx5 was reduced in UUO kidneys. Upregulation of fibrotic markers, such as fibronectin and alpha-smooth muscle actin (α-SMA, declined at 5 days in time point of higher Prdx5 expression in TGF-β treated NRK49F cells. The overexpression of wild type Prdx5 by transient transfection in NRK49F cells attenuated the TGF-β induced upregulation of fibronectin and α-SMA. On the other hand, the transient transfection of double mutant Prdx5 did not prevent the activation of fibrotic markers. Overexpression of Prdx5 also suppressed the TGF-β induced upregulation of Stat3 phosphorylation, while phosphorylation of Smad 2/3 was unchanged. In conclusion, Prdx5 protects TGF-β induced fibrosis in NRK49F cells by modulating Stat3 activation in a peroxidase activity dependent manner.

Increasing extracellular matrix collagen level and MMP activity induces cyst development in polycystic kidney disease.

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Liu, Bin; Li, Chenghai; Liu, Zijuan; Dai, Zonghan; Tao, Yunxia

2012-09-11

Polycystic Kidney Disease (PKD) kidneys exhibit increased extracellular matrix (ECM) collagen expression and metalloproteinases (MMPs) activity. We investigated the role of these increases on cystic disease progression in PKD kidneys. We examined the role of type I collagen (collagen I) and membrane bound type 1 MMP (MT1-MMP) on cyst development using both in vitro 3 dimensional (3D) collagen gel culture and in vivo PCK rat model of PKD. We found that collagen concentration is critical in controlling the morphogenesis of MDCK cells cultured in 3D gels. MDCK cells did not form 3D structures at collagen I concentrations lower than 1 mg/ml but began forming tubules when the concentration reaches 1 mg/ml. Significantly, these cells began to form cyst when collagen I concentration reached to 1.2 mg/ml, and the ratios of cyst to tubule structures increased as the collagen I concentration increased. These cells exclusively formed cyst structures at a collagen I concentration of 1.8 mg/ml or higher. Overexpression of MT1-MMP in MDCK cells significantly induced cyst growth in 3D collagen gel culture. Conversely, inhibition of MMPs activity with doxycycline, a FDA approved pan-MMPs inhibitor, dramatically slowed cyst growth. More importantly, the treatment of PCK rats with doxycycline significantly decreased renal tubule cell proliferation and markedly inhibited the cystic disease progression. Our data suggest that increased collagen expression and MMP activity in PKD kidneys may induce cyst formation and expansion. Our findings also suggest that MMPs may serve as a therapeutic target for the treatment of human PKD.

Increasing extracellular matrix collagen level and MMP activity induces cyst development in polycystic kidney disease

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Liu Bin

2012-09-01

Full Text Available Abstract Background Polycystic Kidney Disease (PKD kidneys exhibit increased extracellular matrix (ECM collagen expression and metalloproteinases (MMPs activity. We investigated the role of these increases on cystic disease progression in PKD kidneys. Methods We examined the role of type I collagen (collagen I and membrane bound type 1 MMP (MT1-MMP on cyst development using both in vitro 3 dimensional (3D collagen gel culture and in vivo PCK rat model of PKD. Results We found that collagen concentration is critical in controlling the morphogenesis of MDCK cells cultured in 3D gels. MDCK cells did not form 3D structures at collagen I concentrations lower than 1 mg/ml but began forming tubules when the concentration reaches 1 mg/ml. Significantly, these cells began to form cyst when collagen I concentration reached to 1.2 mg/ml, and the ratios of cyst to tubule structures increased as the collagen I concentration increased. These cells exclusively formed cyst structures at a collagen I concentration of 1.8 mg/ml or higher. Overexpression of MT1-MMP in MDCK cells significantly induced cyst growth in 3D collagen gel culture. Conversely, inhibition of MMPs activity with doxycycline, a FDA approved pan-MMPs inhibitor, dramatically slowed cyst growth. More importantly, the treatment of PCK rats with doxycycline significantly decreased renal tubule cell proliferation and markedly inhibited the cystic disease progression. Conclusions Our data suggest that increased collagen expression and MMP activity in PKD kidneys may induce cyst formation and expansion. Our findings also suggest that MMPs may serve as a therapeutic target for the treatment of human PKD.

An in vivo photodynamic therapy with diode laser to cell activation of kidney dysfunction

International Nuclear Information System (INIS)

Astuti, Suryani Dyah; Prasaja, Brahma Indra; Prijo, Tri Anggono

2017-01-01

This study aims to analyze the effect of photodynamic therapy (PDT) low level laser therapy (LLLT) 650 nm in the experimental animals mice ( Musmuculus ) suffering from kidney organ damage in mice ( Musmuculus ) in vivo. Exposure laser acupuncture was performed on the kidney BL-23. The conditioning of kidney damage in mice used carbofuraan 35 at a dose of 0.041697 mg/mice. LLLT 650 nm exposure was done on a wide variety of energy (0.5; 1.0; 1.5; 2.0; 4.0; 5.0; 6.0; 7.0) J. The histopathological kidney cells in mice renal impairment showed that exposure to 650 nm laser energy 1 Joule resulted in the reduction of damaged cells (necrosis) and normal cells were increased with the improvement of renal tubular cells (64.14 ± 8:02)%. Therefore, exposure to 650 nm LLLT on acupuncture points Shenshu (BL-23) has the ability to proliferation of renal tubular cells of mice. (paper)

An in vivo photodynamic therapy with diode laser to cell activation of kidney dysfunction

Science.gov (United States)

Dyah Astuti, Suryani; Indra Prasaja, Brahma; Anggono Prijo, Tri

2017-05-01

This study aims to analyze the effect of photodynamic therapy (PDT) low level laser therapy (LLLT) 650 nm in the experimental animals mice (Musmuculus) suffering from kidney organ damage in mice (Musmuculus) in vivo. Exposure laser acupuncture was performed on the kidney BL-23. The conditioning of kidney damage in mice used carbofuraan 35 at a dose of 0.041697 mg/mice. LLLT 650 nm exposure was done on a wide variety of energy (0.5; 1.0; 1.5; 2.0; 4.0; 5.0; 6.0; 7.0) J. The histopathological kidney cells in mice renal impairment showed that exposure to 650 nm laser energy 1 Joule resulted in the reduction of damaged cells (necrosis) and normal cells were increased with the improvement of renal tubular cells (64.14 ± 8:02)%. Therefore, exposure to 650 nm LLLT on acupuncture points Shenshu (BL-23) has the ability to proliferation of renal tubular cells of mice.

Blood transfusion improves renal oxygenation and renal function in sepsis-induced acute kidney injury in rats

NARCIS (Netherlands)

L. Zafrani (Lara); B. Ergin (Bulent); Kapucu, A. (Aysegul); C. Ince (Can)

2016-01-01

textabstractBackground: The effects of blood transfusion on renal microcirculation during sepsis are unknown. This study aimed to investigate the effect of blood transfusion on renal microvascular oxygenation and renal function during sepsis-induced acute kidney injury. Methods: Twenty-seven Wistar

Quercetin prevents chronic unpredictable stress induced behavioral dysfunction in mice by alleviating hippocampal oxidative and inflammatory stress.

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Mehta, Vineet; Parashar, Arun; Udayabanu, Malairaman

2017-03-15

It is now evident that chronic stress is associated with anxiety, depression and cognitive dysfunction and very few studies have focused on identifying possible methods to prevent these stress-induced disorders. Previously, we identified abundance of quercetin in Urtica dioica extract, which efficiently attenuated stress related complications. Therefore, current study was designed to investigate the effect of quercetin on chronic unpredicted stress (CUS) induced behavioral dysfunction, oxidative stress and neuroinflammation in the mouse hippocampus. Animals were subjected to unpredicted stress for 21days, during which 30mg/kg quercetin was orally administered to them. Effect of CUS and quercetin treatment on animal behavior was assessed between day 22-26. Afterward, the hippocampus was processed to evaluate neuronal damage, oxidative and inflammatory stress. Results revealed that stressed animals were highly anxious (Elevated Plus Maze and Open Field), showed depressive-like behavior (sucrose preference task), performed poorly in short-term and long-term associative memory task (passive avoidance step-through task) and displayed reduced locomotion (open field). Quercetin alleviated behavioral dysfunction in chronically stressed animals. Compared to CUS, quercetin treatment significantly reduced anxiety, attenuated depression, improved cognitive dysfunction and normalized locomotor activity. Further, CUS elevated the levels of oxidative stress markers (TBARS, nitric oxide), lowered antioxidants (total thiol, catalase), enhanced expression of pro-inflammatory cytokines (IL-6, TNF-α, IL-1β and COX-2) in the hippocampus and damaged hippocampal neurons. Quercetin treatment significantly lowered oxidative and inflammatory stress and prevented neural damage. In conclusion, quercetin can efficiently prevent stress induced neurological complications by rescuing brain from oxidative and inflammatory stress. Copyright © 2017 Elsevier Inc. All rights reserved.

Acute kidney injury in pediatric patients: diagnosis and management in the emergency department [digest].

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Mohrer, Daniel; Langhan, Melissa; Chaudhari, Pradip

2017-05-22

Pediatric acute kidney injury is a condition that is underdiagnosed among children seen in the emergency department, and it has been associated with significant morbidity and mortality, including increased risk for chronic kidney disease. The most common etiologies in pediatric patients are now known to be due to hypovolemia, sepsis, shock, and cardiac dysfunction. This issue compares 3 classification systems for the diagnosis and staging of acute kidney injury and reviews the etiologies that lead to kidney injury in children. The management of pediatric acute kidney injury focuses on identifying patients at high risk, monitoring intravascular volume status, avoiding nephrotoxic medication exposure, and involving a pediatric nephrologist once acute kidney injury is diagnosed. [Points & Pearls is a digest of Pediatric Emergency Medicine Practice].

Microglia PACAP and glutamate: Friends or foes in seizure-induced autonomic dysfunction and SUDEP?

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Bhandare, Amol M; Kapoor, Komal; Farnham, Melissa M J; Pilowsky, Paul M

2016-06-01

Seizure-induced cardiorespiratory autonomic dysfunction is a major cause of sudden unexpected death in epilepsy (SUDEP), and the underlying mechanism is unclear. Seizures lead to increased synthesis, and release of glutamate, pituitary adenylate cyclase activating polypeptide (PACAP), and other neurotransmitters, and cause extensive activation of microglia at multiple regions in the brain including central autonomic cardiorespiratory brainstem nuclei. Glutamate contributes to neurodegeneration, and inflammation in epilepsy. PACAP has neuroprotective, and anti-inflammatory properties, whereas microglia are key players in inflammatory responses in CNS. Seizure-induced increase in PACAP is neuroprotective. PACAP produces neuroprotective effects acting on microglial PAC1 and VPAC1 receptors. Microglia also express glutamate transporters, and their expression can be increased by PACAP in response to harmful or stressful situations such as seizures. Here we discuss the mechanism of autonomic cardiorespiratory dysfunction in seizure, and the role of PACAP, glutamate and microglia in regulating cardiorespiratory brainstem neurons in their physiological state that could provide future therapeutic options for SUDEP. Copyright © 2016 Elsevier B.V. All rights reserved.

Protective Effects of Hydrogen Sulfide in the Ageing Kidney.

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Hou, Cui-Lan; Wang, Ming-Jie; Sun, Chen; Huang, Yong; Jin, Sheng; Mu, Xue-Pan; Chen, Ying; Zhu, Yi-Chun

2016-01-01

Aims . The study aimed to examine whether hydrogen sulfide (H 2 S) generation changed in the kidney of the ageing mouse and its relationship with impaired kidney function. Results . H 2 S levels in the plasma, urine, and kidney decreased significantly in ageing mice. The expression of two known H 2 S-producing enzymes in kidney, cystathionine γ -lyase (CSE) and cystathionine- β -synthase (CBS), decreased significantly during ageing. Chronic H 2 S donor (NaHS, 50  μ mol/kg/day, 10 weeks) treatment could alleviate oxidative stress levels and renal tubular interstitial collagen deposition. These protective effects may relate to transcription factor Nrf2 activation and antioxidant proteins such as HO-1, SIRT1, SOD1, and SOD2 expression upregulation in the ageing kidney after NaHS treatment. Furthermore, the expression of H 2 S-producing enzymes changed with exogenous H 2 S administration and contributed to elevated H 2 S levels in the ageing kidney. Conclusions . Endogenous hydrogen sulfide production in the ageing kidney is insufficient. Exogenous H 2 S can partially rescue ageing-related kidney dysfunction by reducing oxidative stress, decreasing collagen deposition, and enhancing Nrf2 nuclear translocation. Recovery of endogenous hydrogen sulfide production may also contribute to the beneficial effects of NaHS treatment.

A developmentally plastic adult mouse kidney cell line spontaneously generates multiple adult kidney structures

Energy Technology Data Exchange (ETDEWEB)

Webb, Carol F., E-mail: carol-webb@omrf.org [Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK (United States); Immunobiology and Cancer Research, Oklahoma Medical Research Foundation, Oklahoma City, OK (United States); Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK (United States); Ratliff, Michelle L., E-mail: michelle-ratliff@omrf.org [Immunobiology and Cancer Research, Oklahoma Medical Research Foundation, Oklahoma City, OK (United States); Powell, Rebecca, E-mail: rebeccapowell@gmail.com [Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK (United States); Wirsig-Wiechmann, Celeste R., E-mail: celeste-wirsig@ouhsc.edu [Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK (United States); Lakiza, Olga, E-mail: olga-lakiza@ouhsc.edu [Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK (United States); Obara, Tomoko, E-mail: tomoko-obara@ouhsc.edu [Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK (United States)

2015-08-07

Despite exciting new possibilities for regenerative therapy posed by the ability to induce pluripotent stem cells, recapitulation of three-dimensional kidneys for repair or replacement has not been possible. ARID3a-deficient mouse tissues generated multipotent, developmentally plastic cells. Therefore, we assessed the adult mouse ARID3a−/− kidney cell line, KKPS5, which expresses renal progenitor surface markers as an alternative cell source for modeling kidney development. Remarkably, these cells spontaneously developed into multicellular nephron-like structures in vitro, and engrafted into immunocompromised medaka mesonephros, where they formed mouse nephron structures. These data implicate KKPS5 cells as a new model system for studying kidney development. - Highlights: • An ARID3a-deficient mouse kidney cell line expresses multiple progenitor markers. • This cell line spontaneously forms multiple nephron-like structures in vitro. • This cell line formed mouse kidney structures in immunocompromised medaka fish kidneys. • Our data identify a novel model system for studying kidney development.

A developmentally plastic adult mouse kidney cell line spontaneously generates multiple adult kidney structures

International Nuclear Information System (INIS)

Webb, Carol F.; Ratliff, Michelle L.; Powell, Rebecca; Wirsig-Wiechmann, Celeste R.; Lakiza, Olga; Obara, Tomoko

2015-01-01

Despite exciting new possibilities for regenerative therapy posed by the ability to induce pluripotent stem cells, recapitulation of three-dimensional kidneys for repair or replacement has not been possible. ARID3a-deficient mouse tissues generated multipotent, developmentally plastic cells. Therefore, we assessed the adult mouse ARID3a−/− kidney cell line, KKPS5, which expresses renal progenitor surface markers as an alternative cell source for modeling kidney development. Remarkably, these cells spontaneously developed into multicellular nephron-like structures in vitro, and engrafted into immunocompromised medaka mesonephros, where they formed mouse nephron structures. These data implicate KKPS5 cells as a new model system for studying kidney development. - Highlights: • An ARID3a-deficient mouse kidney cell line expresses multiple progenitor markers. • This cell line spontaneously forms multiple nephron-like structures in vitro. • This cell line formed mouse kidney structures in immunocompromised medaka fish kidneys. • Our data identify a novel model system for studying kidney development

The Protective Role of Zinc Sulphate on Ethanol -Induced Liver and Kidney Damages in Rats

International Nuclear Information System (INIS)

Al-Damegh, Mona Abdalla

2007-01-01

Around the world more and more people suffer from alcoholism. Addiction problems, alcoholism and excessive use of drugs both medical and nonmedical, are major causes of liver and kidney damage in adults. The purpose of this study was to investigate on the protective role of zinc sulphate on liver and kidney in rats with acute alcoholism. Wistar albino rats were divided into four groups. Group I; control group, group 2; given only Zinc Sulphate (100 mg/kg/day for 3days), group 3; rats given absolute ethanol (1 ml of absolute ethanol administrated by gavage technique to each rat), group 4 given Zinc sulphate prior to the administration of absolute ethanol. The results of this study revealed that acute ethanol exposure caused degenerative morphological changes in the liver and kidney. Significant difference were found in the levels of serum, liver, kidney super oxide dismutase(SOD), catalase (CAT), nitric oxide(NO), and malondialdehyde (MDA) in the ethanol group compared to the control group. Moreover ,serum urea, creatnine, uric acid, alkaline phoshpatase and transaminases activities (GOTand GPT) were increased in the ethanol group compared to the control group. On the other hand,administration of zinc sulphate in the ethanol group caused a significant decrease in the degenerative changes, lipid peroxidation, antioxidant enzymes, and nitric oxide in serum, liver, and kidney. It can be concluded that zinc Sulphate has a protective role on the ethanol induced liver and kidney injury. In addition ,nitric oxide is involved in the mechanism of acute alcohol intoxication. (author)

Pharmacological Inhibition of Macrophage Toll-like Receptor 4/Nuclear Factor-kappa B Alleviates Rhabdomyolysis-induced Acute Kidney Injury.

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Huang, Rong-Shuang; Zhou, Jiao-Jiao; Feng, Yu-Ying; Shi, Min; Guo, Fan; Gou, Shen-Ju; Salerno, Stephen; Ma, Liang; Fu, Ping

2017-09-20

Acute kidney injury (AKI) is the most common and life-threatening systemic complication of rhabdomyolysis. Inflammation plays an important role in the development of rhabdomyolysis-induced AKI. This study aimed to investigate the kidney model of AKI caused by rhabdomyolysis to verify the role of macrophage Toll-like receptor 4/nuclear factor-kappa B (TLR4/NF-κB) signaling pathway. C57BL/6 mice were injected with a 50% glycerin solution at bilateral back limbs to induce rhabdomyolysis, and CLI-095 or pyrrolidine dithiocarbamate (PDTC) was intraperitoneally injected at 0.5 h before molding. Serum creatinine levels, creatine kinase, the expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6, and hematoxylin and eosin stainings of kidney tissues were tested. The infiltration of macrophage, mRNA levels, and protein expression of TLR4 and NF-κB were investigated by immunofluorescence double-staining techniques, reverse transcriptase-quantitative polymerase chain reaction, and Western blotting, respectively. In vitro, macrophage RAW264.7 was stimulated by ferrous myoglobin; the cytokines, TLR4 and NF-κB expressions were also detected. In an in vivo study, using CLI-095 or PDTC to block TLR4/NF-κB, functional and histologic results showed that the inhibition of TLR4 or NF-κB alleviated glycerol-induced renal damages (P rhabdomyolysis-induced AKI by the regulation of proinflammatory cytokine production and macrophage infiltration.

Mesenchymal stem cells ameliorate rhabdomyolysis-induced acute kidney injury via the activation of M2 macrophages

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2014-01-01

Introduction The mortality of rhabdomyolysis-induced acute kidney injury (AKI) is still high, as there is no effective therapy. It has been shown that bone marrow-derived mesenchymal stem cells (MSCs) can induce M2 macrophages, which mediate MSC protection in other experimental inflammation-related organ injury. This study was designed to investigate the protective effects of macrophage activation in MSC therapy of rhabdomyolysis-induced AKI. Methods MSCs were injected into glycerol-induced rhabdomyolysis mice. Renal injury was evaluated using the serum creatinine, urea nitrogen, renal pathology and acute tubular necrosis score. The distribution of MSCs was detected using two-photon fluorescence confocal imaging. Immunofluorescence of anti-F4/80 and anti-CD206 was performed to determine macrophages and M2 macrophages in the tissues of the kidney, and M2 macrophage infiltration was also evaluated using western blotting analyses. After depletion of macrophages using clodronate liposomes at the phase of kidney repair, renal injury was re-evaluated. RAW 264.7 macrophages were incubated with lipopolysaccharide and co-cultured with MSCs and subsequently visualised using immunofluorescence staining and flow cytometry analysis. Finally, disparate phenotype macrophages, including normal macrophages (M0), lipopolysaccharide-stimulated macrophages (M1), and MSC-co-cultured macrophages (M2), were infused into mice with AKI, which were pre-treated with liposomal clodronate. Results In vivo infusion of MSCs protected AKI mice from renal function impairment and severe tubular injury, which was accompanied by a time-dependent increase in CD206-positive M2 macrophage infiltration. In addition, depleting macrophages with clodronate delayed restoration of AKI. In vitro, macrophages co-cultured with MSCs acquired an anti-inflammatory M2 phenotype, which was characterised by an increased expression of CD206 and the secretory cytokine interleukin (IL)-10. The concentrations of IL-10, IL

Rare acute kidney injury secondary to hypothyroidism-induced rhabdomyolysis.

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Cai, Ying; Tang, Lin

2013-01-01

Acute kidney injury (AKI) caused by hypothyroidism-induced rhabdomyolysis is a rare and potentially life-threatening syndrome. The aim of this study was to investigate the clinical characteristics of such patients. We retrospectively analyzed five patients treated at the Second Affiliated Hospital of Chongqing Medical University with AKI secondary to hypothyroidism- induced rhabdomyolysis from January 2006 to December 2010. Of the five cases reviewed (4 males, age range of 37 to 62 years), adult primary hypothyroidism was caused by amiodarone (1 case), chronic autoimmune thyroiditis (1 case), and by uncertain etiologies (3 cases). All patients presented with facial and lower extremity edema. Three patients presented with weakness, while two presented with blunted facies and oliguria. Only one patient reported experiencing myalgia and proximal muscle weakness, in addition to fatigue and chills. Creatine kinase, lactate dehydrogenase, and renal function normalized after thyroid hormone replacement, except in two patients who improved through blood purification. Hypothyroidism should be considered in patients presenting with renal impairment associated with rhabdomyolysis. Moreover, further investigation into the etiology of the hypothyroidism is warranted.

Markers of bone metabolism are affected by renal function and growth hormone therapy in children with chronic kidney disease

DEFF Research Database (Denmark)

Doyon, Anke; Fischer, Dagmar Christiane; Bayazit, Aysun Karabay

2015-01-01

Objectives: The extent and relevance of altered bone metabolism for statural growth in children with chronic kidney disease is controversial. We analyzed the impact of renal dysfunction and recombinant growth hormone therapy on a panel of serum markers of bone metabolism in a large pediatric...... turnover state in children with chronic kidney disease. Growth hormone induces an osteoanabolic pattern and normalizes osteocyte activity. The osteocyte markers cFGF23 and sclerostin are associated with standardized height, and the markers of bone turnover predict height velocity......./min/ 1.73m2. 41 children receiving recombinant growth hormone therapy were compared to an untreated matched control group. Results: Standardized levels of BAP, TRAP5b and cFGF-23 were increased whereas sclerostin was reduced. BAP was correlated positively and cFGF-23 inversely with eGFR. Intact serum...

Serial Manifestation of Acute Kidney Injury and Nephrotic Syndrome in a Patient with TAFRO syndrome.

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Ito, Seigo; Uchida, Takahiro; Itai, Hiroki; Yamashiro, Aoi; Yamagata, Akira; Matsubara, Hidehito; Imakiire, Toshihiko; Shimazaki, Hideyuki; Kumagai, Hiroo; Oshima, Naoki

2018-06-06

A 76-year-old woman suddenly developed anasarca and a fever, and an examination revealed thrombocytopenia, reticulin fibrosis, and acute kidney injury, yielding the diagnosis of TAFRO syndrome. Renal replacement therapy and steroid treatment were soon started. Her proteinuria was minor at first; however, once the kidney function improved, nephrotic syndrome occurred. A kidney biopsy showed membranoproliferative glomerulonephritis-like glomerulopathy with massive macrophage infiltration. Although kidney dysfunction is often observed in TAFRO syndrome patients, its detailed mechanism is unclear. This case suggests that TAFRO syndrome involves both acute kidney injury with minor proteinuria and nephrotic syndrome, and these disorders can develop serially in the same patient.

Chronic kidney disease and subclinical lacunar infarction are independently associated with frontal lobe dysfunction in community-dwelling elderly subjects. The sefuri brain MRI study

International Nuclear Information System (INIS)

Yao, Hiroshi; Takashima, Yuki; Hashimoto, Manabu; Yuzuriha, Takefumi; Miwa, Yoshikazu; Sasaguri, Toshiyuki; Yahara, Koji; Uchino, Akira

2011-01-01

Although recent studies have found that chronic kidney disease (CKD) is an independent risk factor for cognitive impairment in population-based cohorts, the mechanisms of cognitive impairment in subjects with CKD are unclear. We examined 503 elderly subjects (mean age: 72.4 years), who were living independently at home without apparent dementia, using MRI. The subject was judged as having frontal lobe dysfunction if the scores on the modified Stroop test were higher than the fifth quintile for each given decade. Serum creatinine values, measured by the enzymatic method, were used for the Japanese equation of estimated glomerular filtration rate (eGFR). Subjects in the frontal lobe dysfunction group tended to have higher blood pressure, lower eGFR and more lacunar infarcts, and were less educated. When possible confounders were entered into the multivariate logistic regression model, the independent predictors of frontal lobe dysfunction were eGFR (odds ratio 0.854; 95% confidence interval (CI) 0.743-0.983 per 10 ml min -1 per 1.73 m 2 ) and the number of lacunar infarction (odds ratio 1.460; 95% CI 1.127-1.892). The mean of the logarithmically transformed Stroop test scores in the eGFR -1 per 1.73 m 2 group was 1.376 (95% CI 1.301-1.451), which was significantly higher than that (1.250) for the eGFR 60-89 ml min -1 per 1.73 m 2 group (95% CI 1.215-1.285) (P=0.009) and tended to be higher than that (1.264) for the eGFR ≥90 ml min -1 per 1.73 m 2 group (95% CI 1.188-1.340) (analysis of covariance, adjusted for age). The present study showed that CKD and subclinical lacunar infarction independently contributed to frontal lobe dysfunction in healthy elderly subjects. (author)

The mitochondria-targeted antioxidants and remote kidney preconditioning ameliorate brain damage through kidney-to-brain cross-talk.

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Denis N Silachev

Full Text Available BACKGROUND: Many ischemia-induced neurological pathologies including stroke are associated with high oxidative stress. Mitochondria-targeted antioxidants could rescue the ischemic organ by providing specific delivery of antioxidant molecules to the mitochondrion, which potentially suffers from oxidative stress more than non-mitochondrial cellular compartments. Besides direct antioxidative activity, these compounds are believed to activate numerous protective pathways. Endogenous anti-ischemic defense may involve the very powerful neuroprotective agent erythropoietin, which is mainly produced by the kidney in a redox-dependent manner, indicating an important role of the kidney in regulation of brain ischemic damage. The goal of this study is to track the relations between the kidney and the brain in terms of the amplification of defense mechanisms during SkQR1 treatment and remote renal preconditioning and provide evidence that the kidney can generate signals inducing a tolerance to oxidative stress-associated brain pathologies. METHODOLOGY/PRINCIPAL FINDINGS: We used the cationic plastoquinone derivative, SkQR1, as a mitochondria-targeted antioxidant to alleviate the deleterious consequences of stroke. A single injection of SkQR1 before cerebral ischemia in a dose-dependent manner reduces infarction and improves functional recovery. Concomitantly, an increase in the levels of erythropoietin in urine and phosphorylated glycogen synthase kinase-3β (GSK-3β in the brain was detected 24 h after SkQR1 injection. However, protective effects of SkQR1 were not observed in rats with bilateral nephrectomy and in those treated with the nephrotoxic antibiotic gentamicin, indicating the protective role of humoral factor(s which are released from functional kidneys. Renal preconditioning also induced brain protection in rats accompanied by an increased erythropoietin level in urine and kidney tissue and P-GSK-3β in brain. Co-cultivation of SkQR1-treated

The mitochondria-targeted antioxidants and remote kidney preconditioning ameliorate brain damage through kidney-to-brain cross-talk.

Science.gov (United States)

Silachev, Denis N; Isaev, Nikolay K; Pevzner, Irina B; Zorova, Ljubava D; Stelmashook, Elena V; Novikova, Svetlana V; Plotnikov, Egor Y; Skulachev, Vladimir P; Zorov, Dmitry B

2012-01-01

Many ischemia-induced neurological pathologies including stroke are associated with high oxidative stress. Mitochondria-targeted antioxidants could rescue the ischemic organ by providing specific delivery of antioxidant molecules to the mitochondrion, which potentially suffers from oxidative stress more than non-mitochondrial cellular compartments. Besides direct antioxidative activity, these compounds are believed to activate numerous protective pathways. Endogenous anti-ischemic defense may involve the very powerful neuroprotective agent erythropoietin, which is mainly produced by the kidney in a redox-dependent manner, indicating an important role of the kidney in regulation of brain ischemic damage. The goal of this study is to track the relations between the kidney and the brain in terms of the amplification of defense mechanisms during SkQR1 treatment and remote renal preconditioning and provide evidence that the kidney can generate signals inducing a tolerance to oxidative stress-associated brain pathologies. We used the cationic plastoquinone derivative, SkQR1, as a mitochondria-targeted antioxidant to alleviate the deleterious consequences of stroke. A single injection of SkQR1 before cerebral ischemia in a dose-dependent manner reduces infarction and improves functional recovery. Concomitantly, an increase in the levels of erythropoietin in urine and phosphorylated glycogen synthase kinase-3β (GSK-3β) in the brain was detected 24 h after SkQR1 injection. However, protective effects of SkQR1 were not observed in rats with bilateral nephrectomy and in those treated with the nephrotoxic antibiotic gentamicin, indicating the protective role of humoral factor(s) which are released from functional kidneys. Renal preconditioning also induced brain protection in rats accompanied by an increased erythropoietin level in urine and kidney tissue and P-GSK-3β in brain. Co-cultivation of SkQR1-treated kidney cells with cortical neurons resulted in enchanced

Blood transfusion improves renal oxygenation and renal function in sepsis-induced acute kidney injury in rats

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Zafrani, Lara; Ergin, Bulent; Kapucu, Aysegul; Ince, Can

2016-01-01

The effects of blood transfusion on renal microcirculation during sepsis are unknown. This study aimed to investigate the effect of blood transfusion on renal microvascular oxygenation and renal function during sepsis-induced acute kidney injury. Twenty-seven Wistar albino rats were randomized into

AS101 prevents diabetic nephropathy progression and mesangial cell dysfunction: regulation of the AKT downstream pathway.

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Itay Israel Shemesh

Full Text Available Diabetic nephropathy (DN is characterized by proliferation of mesangial cells, mesangial expansion, hypertrophy and extracellular matrix accumulation. Previous data have cross-linked PKB (AKT to TGFβ induced matrix modulation. The non-toxic compound AS101 has been previously shown to favorably affect renal pathology in various animal models and inhibits AKT activity in leukemic cells. Here, we studied the pharmacological properties of AS101 against the progression of rat DN and high glucose-induced mesangial dysfunction. In-vivo administration of AS101 to Streptozotocin injected rats didn't decreased blood glucose levels but ameliorated kidney hypotrophy, proteinuria and albuminuria and downregulated cortical kidney phosphorylation of AKT, GSK3β and SMAD3. AS101 treatment of primary rat glomerular mesangial cells treated with high glucose significantly reduced their elevated proliferative ability, as assessed by XTT assay and cell cycle analysis. This reduction was associated with decreased levels of p-AKT, increased levels of PTEN and decreased p-GSK3β and p-FoxO3a expression. Pharmacological inhibition of PI3K, mTORC1 and SMAD3 decreased HG-induced collagen accumulation, while inhibition of GSK3β did not affect its elevated levels. AS101 also prevented HG-induced cell growth correlated to mTOR and (rpS6 de-phosphorylation. Thus, pharmacological inhibition of the AKT downstream pathway by AS101 has clinical potential in alleviating the progression of diabetic nephropathy.

Down-regulation of vascular PPAR-γ contributes to endothelial dysfunction in high-fat diet-induced obese mice exposed to chronic intermittent hypoxia.

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Zhang, Yanan; Zhang, Chunlian; Li, Haiou; Hou, Jingdong

2017-10-14

Obstructive sleep apnea (OSA), characterized by chronic intermittent hypoxia (CIH), is associated with endothelial dysfunction. The prevalence of OSA is linked to an epidemic of obesity. CIH has recently been reported to cause endothelial dysfunction in diet-induced obese animals by exaggerating oxidative stress and inflammation, but the underlying mechanism remains unclear. PPAR-γ, a ligand-inducible transcription factor that exerts anti-oxidant and anti-inflammatory effects, is down-regulated in the peripheral tissues in diet-induce obesity. We tested the hypothesis that down-regulation of vascular PPAR-γ in diet-induced obesity enhances inflammation and oxidative stress in response to CIH, resulting in endothelial dysfunction. Male C57BL/6 mice were fed either a high-fat diet (HFD) or a low-fat diet (LFD) and simultaneously exposed to CIH or intermittent air for 6 weeks. An additional HFD group received a combination of CIH and PPAR-γ agonist pioglitazone for 6 weeks. Endothelial-dependent vasodilation was impaired only in HFD group exposed to CIH, compared with other groups, but was restored by concomitant pioglitazone treatment. Molecular studies revealed that vascular PPAR-γ expression and activity were reduced in HFD groups, compared with LFD groups, but were reversed by pioglitazone treatment. In addition, CIH elevated vascular expression of NADPH oxidase 4 and dihydroethidium fluorescence, and increased expression of proinflammatory cytokines TNF-α and IL-1β in both LFD and HFD groups, but these increases was significantly greater in HFD group, along with decreased vascular eNOS activity. Pioglitazone treatment of HFD group prevented CIH-induced changes in above molecular markers. The results suggest that HFD-induced obesity down-regulates vascular PPAR-γ, which results in exaggerated oxidative stress and inflammation in response to CIH, contributing to endothelial dysfunction. This finding may provide new insights into the mechanisms by which OSA

Sulfated lentinan induced mitochondrial dysfunction leads to programmed cell death of tobacco BY-2 cells.

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Wang, Jie; Wang, Yaofeng; Shen, Lili; Qian, Yumei; Yang, Jinguang; Wang, Fenglong

2017-04-01

Sulphated lentinan (sLTN) is known to act as a resistance inducer by causing programmed cell death (PCD) in tobacco suspension cells. However, the underlying mechanism of this effect is largely unknown. Using tobacco BY-2 cell model, morphological and biochemical studies revealed that mitochondrial reactive oxygen species (ROS) production and mitochondrial dysfunction contribute to sLNT induced PCD. Cell viability, and HO/PI fluorescence imaging and TUNEL assays confirmed a typical cell death process caused by sLNT. Acetylsalicylic acid (an ROS scavenger), diphenylene iodonium (an inhibitor of NADPH oxidases) and protonophore carbonyl cyanide p-trifluoromethoxyphenyl hydrazone (a protonophore and an uncoupler of mitochondrial oxidative phosphorylation) inhibited sLNT-induced H 2 O 2 generation and cell death, suggesting that ROS generation linked, at least partly, to a mitochondrial dysfunction and caspase-like activation. This conclusion was further confirmed by double-stained cells with the mitochondria-specific marker MitoTracker RedCMXRos and the ROS probe H 2 DCFDA. Moreover, the sLNT-induced PCD of BY-2 cells required cellular metabolism as up-regulation of the AOX family gene transcripts and induction of the SA biosynthesis, the TCA cycle, and miETC related genes were observed. It is concluded that mitochondria play an essential role in the signaling pathway of sLNT-induced ROS generation, which possibly provided new insight into the sLNT-mediated antiviral response, including PCD. Copyright © 2016. Published by Elsevier Inc.

Tongxinluo Prevents Endothelial Dysfunction Induced by Homocysteine Thiolactone In Vivo via Suppression of Oxidative Stress

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Yi Zhang

2015-01-01

Full Text Available Aim. To explore whether Chinese traditional medicine, tongxinluo (TXL, exerts beneficial effects on endothelial dysfunction induced by homocysteine thiolactone (HTL and to investigate the potential mechanisms. Methods and Results. Incubation of cultured human umbilical vein endothelial cells with HTL (1 mM for 24 hours significantly reduced cell viabilities assayed by MTT, and enhanced productions of reactive oxygen species. Pretreatment of cells with TXL (100, 200, and 400 μg/mL for 1 hour reversed these effects induced by HTL. Further, coincubation with GW9662 (0.01, 0.1 mM abolished the protective effects of TXL on HTL-treated cells. In ex vivo experiments, exposure of isolated aortic rings from rats to HTL (1 mM for 1 hour dramatically impaired acetylcholine-induced endothelium-dependent relaxation, reduced SOD activity, and increased malondialdehyde content in aortic tissues. Preincubation of aortic rings with TXL (100, 200, and 400 μg/mL normalized the disorders induced by HTL. Importantly, all effects induced by TXL were reversed by GW9662. In vivo analysis indicated that the administration of TXL (1.0 g/kg/d remarkably suppressed oxidative stress and prevented endothelial dysfunction in rats fed with HTL (50 mg/kg/d for 8 weeks. Conclusions. TXL improves endothelial functions in rats fed with HTL, which is related to PPARγ-dependent suppression of oxidative stress.

The Plant Decapeptide OSIP108 Can Alleviate Mitochondrial Dysfunction Induced by Cisplatin in Human Cells

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Pieter Spincemaille

2014-09-01

Full Text Available We investigated the effect of the Arabidopsis thaliana-derived decapeptide OSIP108 on human cell tolerance to the chemotherapeutic agent cisplatin (Cp, which induces apoptosis and mitochondrial dysfunction. We found that OSIP108 increases the tolerance of HepG2 cells to Cp and prevents Cp-induced changes in basic cellular metabolism. More specifically, we demonstrate that OSIP108 reduces Cp-induced inhibition of respiration, decreases glycolysis and prevents Cp-uptake in HepG2 cells. Apart from its protective action against Cp in human cells, OSIP108 also increases the yeast Saccharomyces cerevisiae tolerance to Cp. A limited yeast-based study of OSIP108 analogs showed that cyclization does not severely affect its activity, which was further confirmed in HepG2 cells. Furthermore, the similarity in the activity of the D-stereoisomer (mirror image form of OSIP108 with the L-stereoisomer suggests that its mode of action does not involve binding to a stereospecific receptor. In addition, as OSIP108 decreases Cp uptake in HepG2 cells and the anti-Cp activity of OSIP108 analogs without free cysteine is reduced, OSIP108 seems to protect against Cp-induced toxicity only partly via complexation. Taken together, our data indicate that OSIP108 and its cyclic derivatives can protect against Cp-induced toxicity and, thus, show potential as treatment options for mitochondrial dysfunction- and apoptosis-related conditions.

Effect of adipose-derived mesenchymal stem cell transplantation on vascular calcification in rats with adenine-induced kidney disease

OpenAIRE

Yokote, Shinya; Katsuoka, Yuichi; Yamada, Akifumi; Ohkido, Ichiro; Yokoo, Takashi

2017-01-01

Previous studies have investigated the use of mesenchymal stem cells (MSCs) to treat damaged kidneys. However, the effect of adipose-derived MSCs (ASCs) on vascular calcification in chronic kidney disease (CKD) is still poorly understood. In the present study, we explored the potential of ASCs for the treatment of CKD and vascular calcification. CKD was induced in male Sprague-Dawley rats by feeding them a diet containing 0.75% adenine for 4 weeks. ASCs transplantation significantly reduced s...

Nonpharmacological Strategies to Prevent Contrast-Induced Acute Kidney Injury

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Paweena Susantitaphong

2014-01-01

Full Text Available Contrast-induced AKI (CI-AKI has been one of the leading causes for hospital-acquired AKI and is associated with independent risk for adverse clinical outcomes including morbidity and mortality. The aim of this review is to provide a brief summary of the studies that focus on nonpharmacological strategies to prevent CI-AKI, including routine identification of at-risk patients, use of appropriate hydration regimens, withdrawal of nephrotoxic drugs, selection of low-osmolar contrast media or isoosmolar contrast media, and using the minimum volume of contrast media as possible. There is no need to schedule dialysis in relation to injection of contrast media or injection of contrast agent in relation to dialysis program. Hemodialysis cannot protect the poorly functioning kidney against CI-AKI.

World Workshop on Oral Medicine VI : a systematic review of medication-induced salivary gland dysfunction

NARCIS (Netherlands)

Villa, Alessandro; Wolff, A.; Narayana, N.; Dawes, C.; Aframian, D. J.; Pedersen, A. M. Lynge; Vissink, A.; Aliko, A.; Sia, Y. W.; Joshi, R. K.; McGowan, R.; Jensen, S. B.; Kerr, A. R.; Ekstrom, J.; Proctor, G.

The aim of this paper was to perform a systematic review of the pathogenesis of medication-induced salivary gland dysfunction (MISGD). Review of the identified papers was based on the standards regarding the methodology for systematic reviews set forth by the World Workshop on Oral Medicine IV and

Antidepressant-Induced Female Sexual Dysfunction.

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Lorenz, Tierney; Rullo, Jordan; Faubion, Stephanie

2016-09-01

Because 1 in 6 women in the United States takes antidepressants and a substantial proportion of patients report some disturbance of sexual function while taking these medications, it is a near certainty that the practicing clinician will need to know how to assess and manage antidepressant-related female sexual dysfunction. Adverse sexual effects can be complex because there are several potentially overlapping etiologies, including sexual dysfunction associated with the underlying mood disorder. As such, careful assessment of sexual function at the premedication visit followed by monitoring at subsequent visits is critical. Treatment of adverse sexual effects can be pharmacological (dose reduction, drug discontinuation or switching, augmentation, or using medications with lower adverse effect profiles), behavioral (exercising before sexual activity, scheduling sexual activity, vibratory stimulation, psychotherapy), complementary and integrative (acupuncture, nutraceuticals), or some combination of these modalities. Copyright © 2016 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

CKD in diabetes: diabetic kidney disease versus nondiabetic kidney disease.

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Anders, Hans-Joachim; Huber, Tobias B; Isermann, Berend; Schiffer, Mario

2018-06-01

The increasing global prevalence of type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) has prompted research efforts to tackle the growing epidemic of diabetic kidney disease (DKD; also known as diabetic nephropathy). The limited success of much of this research might in part be due to the fact that not all patients diagnosed with DKD have renal dysfunction as a consequence of their diabetes mellitus. Patients who present with CKD and diabetes mellitus (type 1 or type 2) can have true DKD (wherein CKD is a direct consequence of their diabetes status), nondiabetic kidney disease (NDKD) coincident with diabetes mellitus, or a combination of both DKD and NDKD. Preclinical studies using models that more accurately mimic these three entities might improve the ability of animal models to predict clinical trial outcomes. Moreover, improved insights into the pathomechanisms that are shared by these entities - including sodium-glucose cotransporter 2 (SGLT2) and renin-angiotensin system-driven glomerular hyperfiltration and tubular hyper-reabsorption - as well as those that are unique to individual entities might lead to the identification of new treatment targets. Acknowledging that the clinical entity of CKD plus diabetes mellitus encompasses NDKD as well as DKD could help solve some of the urgent unmet medical needs of patients affected by these conditions.

Ursolic acid protects monocytes against metabolic stress-induced priming and dysfunction by preventing the induction of Nox4

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Sarah L. Ullevig

2014-01-01

Conclusion: UA protects THP-1 monocytes against dysfunction by suppressing metabolic stress-induced Nox4 expression, thereby preventing the Nox4-dependent dysregulation of redox-sensitive processes, including actin turnover and MAPK-signaling, two key processes that control monocyte migration and adhesion. This study provides a novel mechanism for the anti-inflammatory and athero- and renoprotective properties of UA and suggests that dysfunctional blood monocytes may be primary targets of UA and related compounds.

Multiple organ dysfunction syndrome associated with Mycoplasma pneumoniae infection

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Shu-Bo Zhai

2012-03-01

Full Text Available In this study, we report one case of a three-year-old boy infected with Mycoplasma pneumonia (MP and presenting concomitant multiple organ damage of the heart, kidney, lung and liver, among others, together with a brief review for the diagnosis and treatment of MP infection with multiple organ dysfunction syndrome (MODS.

A review of dietary supplement-induced renal dysfunction.

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Gabardi, Steven; Munz, Kristin; Ulbricht, Catherine

2007-07-01

Complementary and alternative medicine (CAM) is a multibillion-dollar industry. Almost half of the American population uses some form of CAM, with many using them in addition to prescription medications. Most patients fail to inform their health care providers of their CAM use, and physicians rarely inquire. Annually, thousands of dietary supplement-induced adverse events are reported to Poison Control Centers nationwide. CAM manufacturers are not responsible for proving safety and efficacy, because the Food and Drug Administration does not regulate them. However, concern exists surrounding the safety of CAM. A literature search using MEDLINE and EMBASE was undertaken to explore the impact of CAM on renal function. English-language studies and case reports were selected for inclusion but were limited to those that consisted of human subjects, both adult and pediatric. This review provides details on dietary supplements that have been associated with renal dysfunction and focuses on 17 dietary supplements that have been associated with direct renal injury, CAM-induced immune-mediated nephrotoxicity, nephrolithiasis, rhabdomyolysis with acute renal injury, and hepatorenal syndrome. It is concluded that it is imperative that use of dietary supplements be monitored closely in all patients. Health care practitioners must take an active role in identifying patients who are using CAM and provide appropriate patient education.

Urinary granzyme A mRNA is a biomarker to diagnose subclinical and acute cellular rejection in kidney transplant recipients

NARCIS (Netherlands)

van Ham, S. Marieke; Heutinck, Kirstin M.; Jorritsma, Tineke; Bemelman, Fréderike J.; Strik, Merel C. M.; Vos, Wim; Muris, Jettie J. F.; Florquin, Sandrine; ten Berge, Ineke J. M.; Rowshani, Ajda T.

2010-01-01

The distinction between T-cell-mediated rejection (TCMR) and other causes of kidney transplant dysfunction such as tubular necrosis requires biopsy. Subclinical rejection (SCR), an established risk factor for chronic allograft dysfunction, can only be diagnosed by protocol biopsy. A specific

Fluctuations of Estimated Glomerular Filtration Rate Outside Kidney Disease Improving Global Outcomes Diagnostic Criteria for Acute Kidney Injury in End-Stage Liver Disease Outpatients and Outcome Postliver Transplantation

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Federica Fiacco, MD

2018-01-01

Full Text Available Background. Renal dysfunction in end-stage liver disease (ESLD results from systemic conditions that affect both liver and kidney with activation of vasoconstrictor systems. In this setting, estimated glomerular filtration rate (eGFR may undergo variations often outside Kidney Disease Improving Global Outcomes criteria for acute kidney injury (AKI diagnosis, whose meaning is not clear. The aim of this study was to evaluate eGFR variations in ESLD outpatients listed for liver transplant (liver Tx and the association with post-Tx outcome. Methods. Fifty-one patients with ESLD were retrospectively evaluated from listing to transplant (L-Tx time, intraoperatively (Tx time, and up to 5 years post-Tx time. Variations between the highest and the lowest eGFR occurring in more than 48 hours, not satisfying Kidney Disease Improving Global Outcomes guideline, were considered as fluctuations (eGFR-F. Fluctuations of eGFR greater than 50% were defined as eGFR drops (DeGFR. Early graft dysfunction, AKI within 7 days, chronic kidney disease, and short- and long-term patient survivals were considered as outcomes. Results. All patients presented eGFR-F, whereas DeGFR were observed in 18 (35.3% of 51 (DeGFR+ group. These patients presented higher levels of Model for End-stage Liver Disease score, pre-Tx bilirubin and significantly greater incidence of post-Tx AKI stages 2 to 3 compared with patients without drops (DeGFR−. DeGFR was the only independent predictive factor of the occurrence of post-Tx AKI. The occurrence of AKI post-Tx was associated with the development of chronic kidney disease at 3 months and 5 years post-Tx. Conclusions. Drops of eGFR are more frequently observed in patients with a worse degree of ESLD and are associated with a worse post-Tx kidney outcome.

The protective effect of hydroalcoholic extract of Ginger (Zingiber officinale Rosc. against iron-induced functional and histological damages in rat liver and kidney

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Firouzeh Gholampour

2017-10-01

Full Text Available Objective: Iron overload in the body is related with toxic effects and threatens the health. The aim of this study was to evaluate the protective role of hydroalcoholic extract of ginger (Zingiber officinale against ferrous sulfate-induced hepatic and renal functional disorders and histological damages in rats. Materials and Methods: The rats were divided into four groups (n=7: Sham, Sham + G.E (ginger extract, 400 mg/kg/day for 14 days, FS (ferrous sulfate, 30 mg/kg/day for 14 days, FS+G.E (ferrous sulfate, 30 mg/kg/day for 14 days; ginger extract, 400 mg/kg/day for 11 days from the fourth day of ferrous sulfate injection. After 24 hr, blood, urine and tissue samples were collected. Results: Compared with Sham and Sham + G.E groups, administration of ferrous sulfate resulted in liver and kidney dysfunction as evidenced by significantly higher levels of serum hepatic markers and bilirubin, and lower levels of serum albumin, total protein, triglyceride, cholesterol and glucose, as well as lower creatinine clearance and higher fractional excretion of sodium (p

Molecular fingerprint of high fat diet induced urinary bladder metabolic dysfunction in a rat model.

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Andreas Oberbach

Full Text Available AIMS/HYPOTHESIS: Diabetic voiding dysfunction has been reported in epidemiological dimension of individuals with diabetes mellitus. Animal models might provide new insights into the molecular mechanisms of this dysfunction to facilitate early diagnosis and to identify new drug targets for therapeutic interventions. METHODS: Thirty male Sprague-Dawley rats received either chow or high-fat diet for eleven weeks. Proteomic alterations were comparatively monitored in both groups to discover a molecular fingerprinting of the urinary bladder remodelling/dysfunction. Results were validated by ELISA, Western blotting and immunohistology. RESULTS: In the proteome analysis 383 proteins were identified and canonical pathway analysis revealed a significant up-regulation of acute phase reaction, hypoxia, glycolysis, β-oxidation, and proteins related to mitochondrial dysfunction in high-fat diet rats. In contrast, calcium signalling, cytoskeletal proteins, calpain, 14-3-3η and eNOS signalling were down-regulated in this group. Interestingly, we found increased ubiquitin proteasome activity in the high-fat diet group that might explain the significant down-regulation of eNOS, 14-3-3η and calpain. CONCLUSIONS/INTERPRETATION: Thus, high-fat diet is sufficient to induce significant remodelling of the urinary bladder and alterations of the molecular fingerprint. Our findings give new insights into obesity related bladder dysfunction and identified proteins that may indicate novel pathophysiological mechanisms and therefore constitute new drug targets.

Subclinical chronic kidney disease modifies the diagnosis of experimental acute kidney injury.

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Succar, Lena; Pianta, Timothy J; Davidson, Trent; Pickering, John W; Endre, Zoltán H

2017-09-01

Extensive structural damage within the kidney must be present before serum creatinine increases. However, a subclinical phase of chronic kidney disease (CKD) usually goes undetected. Here we tested whether experimental subclinical CKD would modify functional and damage biomarker profiles of acute kidney injury (AKI). Subclinical CKD was induced in rats by adenine or aristolochic acid models but without increasing serum creatinine. After prolonged recovery (three to six weeks), AKI was induced with a subnephrotoxic dose of cisplatin. Urinary levels of kidney injury molecule-1 (KIM-1), cytochrome C, monocyte chemotactic protein-1 (MCP-1), clusterin, and interleukin-18 increased during CKD induction, without an increase in serum creatinine. After AKI in adenine-induced CKD, serum creatinine increased more rapidly, while increased urinary KIM-1, clusterin, and MCP-1 were delayed and reduced. Increased serum creatinine and biomarker excretion were associated with diffuse tubulointerstitial injury in the outer stripe of outer medulla coupled with over 50% cortical damage. Following AKI in aristolochic acid-induced CKD, increased serum creatinine, urinary KIM-1, clusterin, MCP-1, cytochrome C, and interleukin-18 concentrations and excretion were greater at day 21 than day 42 and inversely correlated with cortical injury. Subclinical CKD modified functional and damage biomarker profiles in diametrically opposite ways. Functional biomarker profiles were more sensitive, while damage biomarker diagnostic thresholds and increases were diminished and delayed. Damage biomarker concentrations and excretion were inversely linked to the extent of prior cortical damage. Thus, thresholds for AKI biomarkers may need to be lower or sampling delayed in the known presence of CKD. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

Mechanisms by Which Dehydration May Lead to Chronic Kidney Disease.

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Roncal-Jimenez, C; Lanaspa, M A; Jensen, T; Sanchez-Lozada, L G; Johnson, R J

2015-01-01

Dehydration, a condition that characterizes excessive loss of body water, is well known to be associated with acute renal dysfunction; however, it has largely been considered reversible and to be associated with no long-term effects on the kidney. Recently, an epidemic of chronic kidney disease has emerged in Central America in which the major risk factor seems to be recurrent heat-associated dehydration. This has led to studies investigating whether recurrent dehydration may lead to permanent kidney damage. Three major potential mechanisms have been identified, including the effects of vasopressin on the kidney, the activation of the aldose reductase-fructokinase pathway, and the effects of chronic hyperuricemia. The discovery of these pathways has also led to the recognition that mild dehydration may be a risk factor in progression of all types of chronic kidney diseases. Furthermore, there is some evidence that increasing hydration, particularly with water, may actually prevent CKD. Thus, a whole new area of investigation is developing that focuses on the role of water and osmolarity and their influence on kidney function and health. © 2015 S. Karger AG, Basel.

Functional evaluation of the kidney by diffusion-weighted MR imaging

International Nuclear Information System (INIS)

Hasegawa, Taro; Hasegawa, Norio; Irie, Takeo; Fukuda, Kunihiko

2003-01-01

The purpose of this study was to determine the relationship between the apparent diffusion coefficient (ADC) and diffuse renal disease by diffusion-weighted echo planar magnetic resonance (MR) imaging (EPI). Ten volunteers, seven patients with chronic renal failure and eighteen recipients of renal transplants were examined with diffusion-weighted EPI. We compared renal function (serum creatinine level) with provided ADC value. The average ADC values were 2.63 x 10 -3 mm 2 /sec for the whole kidney, 2.67 x 10 -3 mm 2 /sec for the cortex and 2.61 x 10 -3 mm 2 /sec for the medulla in normal kidneys. ADC values in the whole kidney, the cortex and the medulla in chronic renal failure were significantly lower than those for normal kidneys. In renal transplantation kidneys, the ADC values in the cortex were significantly lower than those for normal kidney. There was a linear correlation between ADC value and serum creatinine level. Our results show that diffusion-weighted MR imaging may be useful to identify renal dysfunction. (author)

Endoglin haploinsufficiency attenuates radiation-induced deterioration of kidney function in mice

International Nuclear Information System (INIS)

Scharpfenecker, Marion; Floot, Ben; Russell, Nicola S.; Coppes, Rob P.; Stewart, Fiona A.

2013-01-01

Background and Purpose: Endoglin is a transforming growth receptor beta (TGF-β) co-receptor, which plays a crucial role in the development of late normal tissue damage. Mice with halved endoglin levels (Eng +/- mice) develop less inflammation, vascular damage and fibrosis after kidney irradiation compared to their wild type littermates (Eng +/+ mice). This study was aimed at investigating whether reduced tissue damage in Eng +/- mice also results in superior kidney function. Material and Methods: Kidneys of Eng +/+ and Eng +/- mice were irradiated with a single dose of 14 Gy. Functional kidney parameters and kidney histology were analysed at 20, 30 and 40 weeks after irradiation. Results: Eng +/- mice displayed improved kidney parameters (haematocrit, BUN) compared to Eng +/+ mice at 40 weeks after irradiation. Irradiation of Eng +/+ kidneys damaged the vascular network and led to an increase in PDGFR-β positive cells, indicative of fibrosis-promoting myofibroblasts. Compared to Eng +/+ kidneys, vascular perfusion and number of PDGFR-β positive cells were reduced in Eng +/- control mice; however, this did not further deteriorate after irradiation. Conclusions: Taken together, we show that not only kidney morphology, but also kidney function is improved after irradiation in Eng +/- compared to Eng +/+ mice

Selective Killing Effects of Cold Atmospheric Pressure Plasma with NO Induced Dysfunction of Epidermal Growth Factor Receptor in Oral Squamous Cell Carcinoma.

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Jung-Hwan Lee

Full Text Available The aim of this study is to investigate the effects of cold atmospheric pressure plasma (CAP-induced radicals on the epidermal growth factor receptor (EGFR, which is overexpressed by oral squamous cell carcinoma, to determine the underlying mechanism of selective killing. CAP-induced highly reactive radicals were observed in both plasma plume and cell culture media. The selective killing effect was observed in oral squamous cell carcinoma compared with normal human gingival fibroblast. Degradation and dysfunction of EGFRs were observed only in the EGFR-overexpressing oral squamous cell carcinoma and not in the normal cell. Nitric oxide scavenger pretreatment in cell culture media before CAP treatment rescued above degradation and dysfunction of the EGFR as well as the killing effect in oral squamous cell carcinoma. CAP may be a promising cancer treatment method by inducing EGFR dysfunction in EGFR-overexpressing oral squamous cell carcinoma via nitric oxide radicals.

Selective Killing Effects of Cold Atmospheric Pressure Plasma with NO Induced Dysfunction of Epidermal Growth Factor Receptor in Oral Squamous Cell Carcinoma.

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Lee, Jung-Hwan; Om, Ji-Yeon; Kim, Yong-Hee; Kim, Kwang-Mahn; Choi, Eun-Ha; Kim, Kyoung-Nam

2016-01-01

The aim of this study is to investigate the effects of cold atmospheric pressure plasma (CAP)-induced radicals on the epidermal growth factor receptor (EGFR), which is overexpressed by oral squamous cell carcinoma, to determine the underlying mechanism of selective killing. CAP-induced highly reactive radicals were observed in both plasma plume and cell culture media. The selective killing effect was observed in oral squamous cell carcinoma compared with normal human gingival fibroblast. Degradation and dysfunction of EGFRs were observed only in the EGFR-overexpressing oral squamous cell carcinoma and not in the normal cell. Nitric oxide scavenger pretreatment in cell culture media before CAP treatment rescued above degradation and dysfunction of the EGFR as well as the killing effect in oral squamous cell carcinoma. CAP may be a promising cancer treatment method by inducing EGFR dysfunction in EGFR-overexpressing oral squamous cell carcinoma via nitric oxide radicals.

IGF-1 Alleviates High Fat Diet-Induced Myocardial Contractile Dysfunction: Role of Insulin Signaling and Mitochondrial Function

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Zhang, Yingmei; Yuan, Ming; Bradley, Katherine M.; Dong, Feng; Anversa, Piero; Ren, Jun

2012-01-01

Obesity is often associated with reduced plasma IGF-1 levels, oxidative stress, mitochondrial damage and cardiac dysfunction. This study was designed to evaluate the impact of IGF-1 on high fat diet-induced oxidative, myocardial, geometric and mitochondrial responses. FVB and cardiomyocyte-specific IGF-1 overexpression transgenic mice were fed a low (10%) or high fat (45%) diet to induce obesity. High fat diet feeding led to glucose intolerance, elevated plasma levels of leptin, interleukin-6, insulin and triglyceride as well as reduced circulating IGF-1 levels. Echocardiography revealed reduced fractional shortening, increased end systolic and diastolic diameter, increased wall thickness, and cardiac hypertrophy in high fat-fed FVB mice. High fat diet promoted ROS generation, apoptosis, protein and mitochondrial damage, reduced ATP content, cardiomyocyte cross-sectional area, contractile and intracellular Ca2+ dysregulation, including depressed peak shortening and maximal velocity of shortening/relengthening, prolonged duration of relengthening, and dampened intracellular Ca2+ rise and clearance. Western blot analysis revealed disrupted phosphorylation of insulin receptor, post-receptor signaling molecules IRS-1 (tyrosine/serine phosphorylation), Akt, GSK3β, Foxo3a, mTOR, as well as downregulated expression of mitochondrial proteins PPARγ coactivator 1α (PGC1α) and UCP-2. Intriguingly, IGF-1 mitigated high fat diet feeding-induced alterations in ROS, protein and mitochondrial damage, ATP content, apoptosis, myocardial contraction, intracellular Ca2+ handling and insulin signaling, but not whole body glucose intolerance and cardiac hypertrophy. Exogenous IGF-1 treatment also alleviated high fat diet-induced cardiac dysfunction. Our data revealed that IGF-1 alleviates high fat diet-induced cardiac dysfunction despite persistent cardiac remodeling, possibly due to preserved cell survival, mitochondrial function and insulin signaling. PMID:22275536

Skeletal Muscle and Lymphocyte Mitochondrial Dysfunctions in Septic Shock Trigger ICU-Acquired Weakness and Sepsis-Induced Immunoparalysis

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Quentin Maestraggi

2017-01-01

Full Text Available Fundamental events driving the pathological processes of septic shock-induced multiorgan failure (MOF at the cellular and subcellular levels remain debated. Emerging data implicate mitochondrial dysfunction as a critical factor in the pathogenesis of sepsis-associated MOF. If macrocirculatory and microcirculatory dysfunctions undoubtedly participate in organ dysfunction at the early stage of septic shock, an intrinsic bioenergetic failure, sometimes called “cytopathic hypoxia,” perpetuates cellular dysfunction. Short-term failure of vital organs immediately threatens patient survival but long-term recovery is also severely hindered by persistent dysfunction of organs traditionally described as nonvital, such as skeletal muscle and peripheral blood mononuclear cells (PBMCs. In this review, we will stress how and why a persistent mitochondrial dysfunction in skeletal muscles and PBMC could impair survival in patients who overcome the first acute phase of their septic episode. First, muscle wasting protracts weaning from mechanical ventilation, increases the risk of mechanical ventilator-associated pneumonia, and creates a state of ICU-acquired muscle weakness, compelling the patient to bed. Second, failure of the immune system (“immunoparalysis” translates into its inability to clear infectious foci and predisposes the patient to recurrent nosocomial infections. We will finally emphasize how mitochondrial-targeted therapies could represent a realistic strategy to promote long-term recovery after sepsis.

Variation in Cancer Incidence among Patients with ESRD during Kidney Function and Nonfunction Intervals.

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Yanik, Elizabeth L; Clarke, Christina A; Snyder, Jon J; Pfeiffer, Ruth M; Engels, Eric A

2016-05-01

Among patients with ESRD, cancer risk is affected by kidney dysfunction and by immunosuppression after transplant. Assessing patterns across periods of dialysis and kidney transplantation may inform cancer etiology. We evaluated 202,195 kidney transplant candidates and recipients from a linkage between the Scientific Registry of Transplant Recipients and cancer registries, and compared incidence in kidney function intervals (time with a transplant) with incidence in nonfunction intervals (waitlist or time after transplant failure), adjusting for demographic factors. Incidence of infection-related and immune-related cancer was higher during kidney function intervals than during nonfunction intervals. Incidence was most elevated for Kaposi sarcoma (hazard ratio [HR], 9.1; 95% confidence interval (95% CI), 4.7 to 18), non-Hodgkin's lymphoma (HR, 3.2; 95% CI, 2.8 to 3.7), Hodgkin's lymphoma (HR, 3.0; 95% CI, 1.7 to 5.3), lip cancer (HR, 3.4; 95% CI, 2.0 to 6.0), and nonepithelial skin cancers (HR, 3.8; 95% CI, 2.5 to 5.8). Conversely, ESRD-related cancer incidence was lower during kidney function intervals (kidney cancer: HR, 0.8; 95% CI, 0.7 to 0.8 and thyroid cancer: HR, 0.7; 95% CI, 0.6 to 0.8). With each successive interval, incidence changed in alternating directions for non-Hodgkin's lymphoma, melanoma, and lung, pancreatic, and nonepithelial skin cancers (higher during function intervals), and kidney and thyroid cancers (higher during nonfunction intervals). For many cancers, incidence remained higher than in the general population across all intervals. These data indicate strong short-term effects of kidney dysfunction and immunosuppression on cancer incidence in patients with ESRD, suggesting a need for persistent cancer screening and prevention. Copyright © 2016 by the American Society of Nephrology.

Atorvastatin attenuates experimental contrast-induced acute kidney injury: a role for TLR4/MyD88 signaling pathway.

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Yue, Rongzheng; Zuo, Chuan; Zeng, Jing; Su, Baihai; Tao, Ye; Huang, Songmin; Zeng, Rui

2017-11-01

To investigate the protective effect of different atorvastatin doses on contrast-induced acute kidney injury and the related mechanism. Healthy male Sprague-Dawley (SD) rats were randomly divided into the blank control group, experimental control group and different-dose atorvastatin groups. A rat model of contrast-induced acute kidney injury was established. We detected changes in serum creatinine (Scr) and blood urea nitrogen (BUN) before and after model establishment, observed and scored renal tubular injury, analyzed rat renal cell apoptosis, and measure the expression of signal pathway proteins and downstream inflammatory factors. After contrast agent injection, the Scr and BUN levels of the experimental control group were significantly increased, the different doses applied in the atorvastatin group significantly reduced the Scr and BUN levels (p atorvastatin doses have protective effects on contrast-induced acute renal tubular injury in rats, possibly by targeting TLR4, suppressing TLR4 expression, regulating the TLR4/Myd88 signaling pathway, and inhibiting the expression of downstream inflammatory factors.

Medial septal dysfunction by Aβ-induced KCNQ channel-block in glutamatergic neurons

DEFF Research Database (Denmark)

Leão, Richardson N.; Colom, Luis V.; Borgius, Lotta

2012-01-01

(MS) neurons in mice. In glutamatergic neurons Aβ increases firing frequency and blocks the A- and the M-current (IA and IM, respectively). While the IA block is similar in other MS neuron classes, the block of IM is specific to glutamatergic neurons. IM block and a simulated Aβ block mimic the Aβ......-induced increase in spontaneous firing in glutamatergic neurons. Calcium imaging shows that under control conditions glutamatergic neurons rarely fire while nonglutamatergic neurons fire coherently at theta frequencies. Aβ increases the firing rate of glutamatergic neurons while nonglutamatergic neurons lose theta...... firing coherence. Our results demonstrate that Aβ-induced dysfunction of glutamatergic neurons via IM decrease diminishes MS rhythmicity, which may negatively affect hippocampal rhythmogenesis and underlie the memory loss observed in Alzheimer's disease....

Calcineurin Dysregulation Underlies Spinal Cord Injury-Induced K+ Channel Dysfunction in DRG Neurons.

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Zemel, Benjamin M; Muqeem, Tanziyah; Brown, Eric V; Goulão, Miguel; Urban, Mark W; Tymanskyj, Stephen R; Lepore, Angelo C; Covarrubias, Manuel

2017-08-23

Dysfunction of the fast-inactivating Kv3.4 potassium current in dorsal root ganglion (DRG) neurons contributes to the hyperexcitability associated with persistent pain induced by spinal cord injury (SCI). However, the underlying mechanism is not known. In light of our previous work demonstrating modulation of the Kv3.4 channel by phosphorylation, we investigated the role of the phosphatase calcineurin (CaN) using electrophysiological, molecular, and imaging approaches in adult female Sprague Dawley rats. Pharmacological inhibition of CaN in small-diameter DRG neurons slowed repolarization of the somatic action potential (AP) and attenuated the Kv3.4 current. Attenuated Kv3.4 currents also exhibited slowed inactivation. We observed similar effects on the recombinant Kv3.4 channel heterologously expressed in Chinese hamster ovary cells, supporting our findings in DRG neurons. Elucidating the molecular basis of these effects, mutation of four previously characterized serines within the Kv3.4 N-terminal inactivation domain eliminated the effects of CaN inhibition on the Kv3.4 current. SCI similarly induced concurrent Kv3.4 current attenuation and slowing of inactivation. Although there was little change in CaN expression and localization after injury, SCI induced upregulation of the native regulator of CaN 1 (RCAN1) in the DRG at the transcript and protein levels. Consistent with CaN inhibition resulting from RCAN1 upregulation, overexpression of RCAN1 in naive DRG neurons recapitulated the effects of pharmacological CaN inhibition on the Kv3.4 current and the AP. Overall, these results demonstrate a novel regulatory pathway that links CaN, RCAN1, and Kv3.4 in DRG neurons. Dysregulation of this pathway might underlie a peripheral mechanism of pain sensitization induced by SCI. SIGNIFICANCE STATEMENT Pain sensitization associated with spinal cord injury (SCI) involves poorly understood maladaptive modulation of neuronal excitability. Although central mechanisms have

Erectile Dysfunction in Males on Hemodialysis

International Nuclear Information System (INIS)

Haider, E.; Iftikhar, R.; Ghazanfar, A.; Afzal, M.; Mir, A. W.; Mansoor, K.; Taj, R.; Samiullah, R.

2013-01-01

Objective: The determine the frequency of erectile dysfunction in males on hemodialysis. Study Design: Descriptive study. Place and duration: Hemodialysis unit, Combined Military Hospital Kharian from October 2011 to April 2012. Patients and Methods: A total of 150 married male patients of end stage renal disease (ESRD) on hemodialysis were included in the study. Patients with cognitive and/or communication deficits and on hemodialysis for less than 06 months were excluded from the study. Erectile dysfunction (ED) was assessed using International Index of Erectile Function-5 (IIEF-5). Frequency of erectile dysfunction (ED) was analyzed using Statistical Package for Social Sciences (SPSS) version 17. Results: Mean age of the patients were 52.89 = 8.25 years. Mean duration of hemodialysis was 34 +- 9.62 months. The underlying etiology of end stage renal disease were diabetic nephropathy 69(46%), hypertensive nephropathy 51(34%), obstructive nephropathy 18(12%), glomerulonephritis 9(6%), autosomal polycystic kidney disease 3(2%). Mean IIEF-5 score was 13.29 +- 6.38. The frequency of erectile dysfunction was 74%. The majority of the patients, 73(48.7%) had moderate erectile dysfunction, while 24 (16%) had severe and 14 (9.3%) had mild erectile dysfunction. Out of total 150 patients enrolled, 39 (26%) patients had no erectile dysfunction. Conclusion: ED is a highly prevalent problem in men with ESRD. Physicians are urged to recognize the high prevalence of erection problems in men with ESRD and proactively question all patients regarding their sexual function. This will not only improve the recognition of this condition among these patients but also improve the quality of life after adequate treatment. (author)

Vasopressin-related copeptin is a novel predictor of early endothelial dysfunction in patients with adult polycystic kidney disease.

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Kocyigit, Ismail; Yilmaz, Mahmut Ilker; Gungor, Ozkan; Eroglu, Eray; Unal, Aydin; Orscelik, Ozcan; Tokgoz, Bulent; Sipahioglu, Murat; Sen, Ahmet; Carrero, Juan Jesús; Oymak, Oktay; Axelsson, Jonas

2016-11-30

In this study, we examined the relative usefulness of serum copeptin levels as a surrogate marker of vasopressin (AVP) in adult polycystic kidney disease (ADPKD) by correlating it with baseline and longitudinal changes in markers of both renal function and common CVD manifestations (hypertensive vascular disease, atherosclerosis and endothelial dysfunction) that accompany the progression of this disease. We studied a cohort of young and otherwise healthy ADPKD patients (n = 235) and measured cardiovascular function using flow-mediation dilatation (FMD), carotid intima media thickness (cIMT) and pulse wave velocity (PWV), as well as serum copeptin (commercial ELISA, a stable marker of AVP activity). The same analyses were carried out at baseline and after 3 years of follow-up. At baseline, median eGFR was 69 mL/min./1.73 m 2 , mean FMD 6.9 ± 0.9%, cIMT 0.7 ± 0.1 mm, and PWV 8.1 ± 1.2 m/s. At follow-up, equivalent values were 65 (44-75) mL/min./1.73 m 2 , 5.8 ± 0.9%, 0.8 ± 0.1 mm. and 8.2 ± 1.3 m/s. with all changes statistically significant. Plasma copeptin also rose from 0.62 ± 0.12 to 0.94 ± 0.19 ng/mL and this change correlated with ΔeGFR (-0.33, p 0.76], and ΔPWV [cut-off:≤7.80]. Vascular dysfunction as reflected by FMD and cIMT, but not PWV or an altered cardiac geometry, precede most other signs of disease in ADPKD but is predicted by elevated levels of the circulating AVP-marker copeptin.

Exercise and reproductive dysfunction.

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Chen, E C; Brzyski, R G

1999-01-01

To provide an overview of our current understanding of exercise-induced reproductive dysfunction and an approach to its evaluation and management. A MEDLINE search was performed to review all articles with title words related to menstrual dysfunction, amenorrhea, oligomenorrhea, exercise, and athletic activities from 1966 to 1998. The pathophysiology, proposed mechanisms, clinical manifestations, evaluation, and management of exercise-associated reproductive dysfunction were compiled. Exercise-induced menstrual irregularity appears to be multifactorial in origin and remains a diagnosis of exclusion. The underlying mechanisms are mainly speculative. Clinical manifestations range from luteal phase deficiency to anovulation, amenorrhea, and even delayed menarche. Evaluation should include a thorough history and a complete physical plus pelvic examination. Most cases are reversible with dietary and exercise modifications. Hormonal replacement in cases of a prolonged hypoestrogenic state with evidence of increased bone loss is recommended, although the long-term consequences of prolonged hormonal deficiency are ill-defined.