Angiotensin II Type 1 receptor (AT1) signaling in astrocytes regulates synaptic degeneration-induced leukocyte entry to the central nervous system

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Füchtbauer, L; Groth-Rasmussen, Maria; Holm, Thomas Hellesøe

2011-01-01

Astrocytes are the major cellular component of the blood-brain barrier glia limitans and act as regulators of leukocyte infiltration via chemokine expression. We have studied angiotensin-II receptor Type 1 (AT1) and related NF-κB signaling in astrocytes. Angiotensin II derives from cleavage of an...

Expression and role of the angiotensin II AT2 receptor in human prostate tissue: in search of a new therapeutic option for prostate cancer.

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Guimond, Marie-Odile; Battista, Marie-Claude; Nikjouitavabi, Fatemeh; Carmel, Maude; Barres, Véronique; Doueik, Alexandre A; Fazli, Ladan; Gleave, Martin; Sabbagh, Robert; Gallo-Payet, Nicole

2013-07-01

Evidence shows that angiotensin II type 1 receptor (AT1R) blockers may be associated with improved outcome in prostate cancer patients. It has been proposed that part of this effect could be due to angiotensin II type 2 receptor (AT2R) activation, the only active angiotensin II receptor in this situation. This study aimed to characterize the localization and expression of AT2R in prostate tissues and to assess its role on cell morphology and number in prostatic epithelial cells in primary culture. AT2R and its AT2R-interacting protein (ATIP) expression were assessed on non-tumoral and tumoral human prostate using tissue microarray immunohistochemistry, binding assay, and Western blotting. AT2R effect on cell number was measured in primary cultures of epithelial cells from non-tumoral human prostate. AT2R was localized at the level of the acinar epithelial layer and its expression decreased in cancers with a Gleason score 6 or higher. In contrast, ATIP expression increased with cancer progression. Treatment of primary cell cultures from non-tumoral prostate tissues with C21/M024, a selective AT2R agonist, alone or in co-incubation with losartan, an AT1R antagonist, significantly decreased cell number compared to untreated cells. AT2R and ATIP are present in non-tumoral human prostate tissues and differentially regulated according to Gleason score. The decrease in non-tumoral prostate cell number upon selective AT2R stimulation suggests that AT2R may have a protective role against prostate cancer development. Treatment with a selective AT2R agonist could represent a new approach for prostate cancer prevention or for patients on active surveillance. Copyright © 2013 Wiley Periodicals, Inc.

The Angiotensin II Type 1 Receptor Antagonist Losartan Affects NHE1-Dependent Melanoma Cell Behavior

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Daniel Navin Olschewski

2018-03-01

Full Text Available Background/Aims: The peptide hormone angiotensin II (ATII plays a prominent role in regulating vasoconstriction and blood pressure. Its primary target is the angiotensin II receptor type 1 (AT1, the stimulation of which induces an increase in cytosolic [Ca2+] and calmodulin activation. Ca2+-bound (activated calmodulin stimulates the activity of the Na+/ H+ exchanger isoform 1 (NHE1; and increased NHE1 activity is known to promote melanoma cell motility. The competitive AT1 receptor inhibitor losartan is often used to lower blood pressure in hypertensive patients. Since AT1 mediates ATII-stimulated NHE1 activity, we set out to investigate whether ATII and losartan have an impact on NHE1-dependent behavior of human melanoma (MV3 cells. Methods: ATII receptor expression was verified by PCR, F-actin was visualized using fluorescently labeled phalloidin, and cytosolic [Ca2+] and pH were determined ratiometrically using Fura-2 and BCECF, respectively. MV3 cell behavior was analyzed using migration, adhesion, invasion and proliferation assays. Results: MV3 cells express both AT1 and the angiotensin II receptor type 2 (AT2. Stimulation of MV3 cells with ATII increased NHE1 activity which could be counteracted by both losartan and the Ca2+/ calmodulin inhibitor ophiobolin-A. ATII stimulation induced a decrease in MV3 cell migration and a more spherical cell morphology accompanied by an increase in the density of F-actin. Independently of the presence of ATII, both NHE1 and migratory activity were reduced when AT1 was blocked by losartan. On the other hand, losartan clearly increased cell adhesion to, and the invasion of, a collagen type I substrate. The AT2 inhibitor PD123319 did not affect NHE1 activity, proliferation and migration, but increased adhesion and invasion. Conclusion: Losartan inhibits NHE1 activity and the migration of human melanoma cells. At the same time, losartan promotes MV3 cell adhesion and invasion. The therapeutic use of AT1

Valsartan attenuates intimal hyperplasia in balloon-injured rat aortic arteries through modulating the angiotensin-converting enzyme 2-angiotensin-(1-7)-Mas receptor axis.

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Li, Yonghong; Cai, Shanglang; Wang, Qixin; Zhou, Jingwei; Hou, Bo; Yu, Haichu; Ge, Zhiming; Guan, Renyan; Liu, Xu

2016-05-15

The role of the Mas receptor in the activity of valsartan against intimal hyperplasia is unclear. Herein, we investigated the role of the angiotensin-converting enzyme 2 (ACE2)-angiotensin-(1-7)-Mas receptor axis on the activity of valsartan against intimal hyperplasiain balloon-injured rat aortic arteries. Wistar rats were randomized equally into the sham control group, injured group, and injured plus valsartan (20 mg/kg/d)-treated group. Valsartan significantly attenuated the vascular smooth muscle cell proliferation and intimal and medial thickening on days 14 and 28 after injury. The angiotensin-(1-7) levels as well as ACE2 and Mas receptor mRNA/protein expression were significantly decreased in the injured rats, compared to the uninjured rats; meanwhile, the angiotensin II level as well as the ACE and AT1 receptor mRNA/protein expression were increased (all P valsartan significantly increased the angiotensin-(1-7) levels as well as ACE2 and Mas receptor mRNA/protein expression but decreased the angiotensin II level, ACE and AT1 receptor mRNA/protein expression, as well as the p-ERK protein expression, compared to the injured group (all P valsartan attenuates neointimal hyperplasiain balloon-injured rat aortic arteries through activation of the ACE2-angiotensin-(1-7)-Mas axis as well as inhibition of the ACE-angiotensin II-AT1 and p-ERK pathways. Copyright © 2016 Elsevier Inc. All rights reserved.

Angiotensin II-AT1–receptor signaling is necessary for cyclooxygenase-2–dependent postnatal nephron generation

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Frölich, Stefanie; Slattery, Patrick; Thomas, Dominique

2017-01-01

was achievable. Plasma renin concentration in mouse pups showed a birth peak and a second peak around day P8 during the first 10 days post birth. Administration of the angiotensin II receptor AT1 antagonist telmisartan from day P1 to P3 did not result in cortical damage. However, telmisartan treatment from day P...... development. Inhibition of the renin angiotensin system by aliskiren and enalapril caused similar glomerular defects as telmisartan. Administration of the AT1 receptor agonist L162313 to COX-2-/- pups improved kidney growth, ameliorated renal defects, but had no beneficial effect on reduced cortical mass. L...

Stabilization of Angiotensin-(1-7) by key substitution with a cyclic non-natural amino acid.

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Wester, Anita; Devocelle, Marc; Tallant, E Ann; Chappell, Mark C; Gallagher, Patricia E; Paradisi, Francesca

2017-10-01

Angiotensin-(1-7) [Ang-(1-7)], a heptapeptide hormone of the renin-angiotensin-aldosterone system, is a promising candidate as a treatment for cancer that reflects its anti-proliferative and anti-angiogenic properties. However, the peptide's therapeutic potential is limited by the short half-life and low bioavailability resulting from rapid enzymatic metabolism by peptidases including angiotensin-converting enzyme (ACE) and dipeptidyl peptidase 3 (DPP 3). We report the facile assembly of three novel Ang-(1-7) analogues by solid-phase peptide synthesis which incorporates the cyclic non-natural δ-amino acid ACCA. The analogues containing the ACCA substitution at the site of ACE cleavage exhibit complete resistance to human ACE, while substitution at the DDP 3 cleavage site provided stability against DPP 3 hydrolysis. Furthermore, the analogues retain the anti-proliferative properties of Ang-(1-7) against the 4T1 and HT-1080 cancer cell lines. These results suggest that ACCA-substituted Ang-(1-7) analogues which show resistance against proteolytic degradation by peptidases known to hydrolyze the native heptapeptide may be novel therapeutics in the treatment of cancer.

Heterogeneous Downregulation of Angiotensin II AT1-A and AT1-B Receptors in Arterioles in STZ-Induced Diabetic Rat Kidneys

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Zsolt Razga

2014-01-01

Full Text Available Introduction. The renin granulation of kidney arterioles is enhanced in diabetes despite the fact that the level of angiotensin II in the diabetic kidney is elevated. Therefore, the number of angiotensin II AT1-A and AT1-B receptors in afferent and efferent arteriole’s renin-positive and renin-negative smooth muscle cells (SMC was estimated. Method. Immunohistochemistry at the electron microscopic level was combined with 3D stereological sampling techniques. Results. In diabetes the enhanced downregulation of AT1-B receptors in the renin-positive than in the renin-negative SMCs in both arterioles was resulted: the significant difference in the number of AT1 (AT1-A + AT1-B receptors between the two types of SMCs in the normal rats was further increased in diabetes and in contrast with the significant difference observed between the afferent and efferent arterioles in the normal animals, there was no such difference in diabetes. Conclusions. The enhanced downregulation of the AT1-B receptors in the renin-negative SMCs in the efferent arterioles demonstrates that the regulation of the glomerular filtration rate by the pre- and postglomerular arterioles is changed in diabetes. The enhanced downregulation of the AT1-B receptors in the renin-positive SMCs in the arterioles may result in an enhanced level of renin granulation in the arterioles.

Renin-angiotensin system at the crossroad of hypertension and hypercholesterolemia.

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Borghi, C; Urso, R; Cicero, A F

2017-02-01

The aim of this study is to discuss the reliable scientific evidence of an interactive link between hypertension and hypercholesterolemia considering the metabolic pathways and the pathogenetic mechanisms connecting the two risk factors. Hypertension and hypercholesterolemia are highly prevalent in the general population and their coexistence in the same subjects additively increases the risk of cardiovascular disease. Probably, hypercholesterolemia is also a risk factor for the development of hypertension. On the other side, it is also possible that lipid-lowering treatment could improve blood pressure control. Although the mechanisms of interaction between these two risk factors have not been completely elucidated thus far, there is rapidly growing evidence that the involvement of the renin-angiotensin system (RAS) can be considered as the common link between hypertension and hypercholesterolemia. In particular, hypercholesterolemia seems to promote the upregulation of type 1 angiotensin II (AT1) receptor genes because of an increase in the stability of mRNA followed by structural overexpression of vascular AT1 receptors for angiotensin II. The treatment of both risk factors greatly improves individual risk profile, especially when statins and RAS blockers are used together. Hypertension and hypercholesterolemia are highly coprevalent and strongly related from a pathophysiological point of view. The RAS could be the main mediator of this link. Copyright © 2016 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

The angiotensin-(1-7/Mas axis counteracts angiotensin II-dependent and –independent pro-inflammatory signaling in human vascular smooth muscle cells

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Laura A Villalobos

2016-12-01

Full Text Available Background and aims: Targeting inflammation is nowadays considered as a challenging pharmacological strategy to prevent or delay the development of vascular diseases. Angiotensin-(1-7 is a member of the renin-angiotensin system (RAS that binds Mas receptors and has gained growing attention in the last years as a regulator of vascular homeostasis. Here, we explored the capacity of Ang-(1-7 to counteract human aortic smooth muscle cell (HASMC inflammation triggered by RAS-dependent and –independent stimuli, such as Ang II or interleukin (IL-1.Methods and Results: In cultured HASMC, the expression of iNOS and the release of nitric oxide were stimulated by both Ang II and IL-1, as determined by Western blot and indirect immunofluorescence or the Griess method, respectively. iNOS induction was inhibited by Ang-(1-7 in a concentration-dependent manner. This effect was equally blocked by two different Mas receptor antagonists, A779 and D-Pro7-Ang-(1-7, suggesting the participation of a unique Mas receptor subtype. Using pharmacological inhibitors, the induction of iNOS was proven to rely on the consecutive upstream activation of NADPH oxidase and NF-B. Indeed, Ang-(1-7 markedly inhibited the activation of the NADPH oxidase and subsequently of NF-B, as determined by lucigenin-derived chemiluminiscence and electromobility shift assay, respectively.Conclusion: Ang-(1-7 can act as a counter-regulator of the inflammation of vascular smooth muscle cells triggered by Ang II, but also by other stimuli beyond the RAS. Activating or mimicking the Ang-(1-7/Mas axis may represent a pharmacological opportunity to attenuate the pro-inflammatory environment that promotes and sustains the development of vascular diseases.

Angiotensin II promotes development of the renal microcirculation through AT1 receptors

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Madsen, Kirsten; Marcussen, Niels; Pedersen, Michael

2010-01-01

Pharmacologic or genetic deletion of components of the renin-angiotensin system leads to postnatal kidney injury, but the roles of these components in kidney development are unknown. To test the hypothesis that angiotensin II supports angiogenesis during postnatal kidney development, we quantifie...

Immunohistochemical Localization of AT1a, AT1b, and AT2 Angiotensin II Receptor Subtypes in the Rat Adrenal, Pituitary, and Brain with a Perspective Commentary

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Courtney Premer

2013-01-01

Full Text Available Angiotensin II increases blood pressure and stimulates thirst and sodium appetite in the brain. It also stimulates secretion of aldosterone from the adrenal zona glomerulosa and epinephrine from the adrenal medulla. The rat has 3 subtypes of angiotensin II receptors: AT1a, AT1b, and AT2. mRNAs for all three subtypes occur in the adrenal and brain. To immunohistochemically differentiate these receptor subtypes, rabbits were immunized with C-terminal fragments of these subtypes to generate receptor subtype-specific antibodies. Immunofluorescence revealed AT1a and AT2 receptors in adrenal zona glomerulosa and medulla. AT1b immunofluorescence was present in the zona glomerulosa, but not the medulla. Ultrastructural immunogold labeling for the AT1a receptor in glomerulosa and medullary cells localized it to plasma membrane, endocytic vesicles, multivesicular bodies, and the nucleus. AT1b and AT2, but not AT1a, immunofluorescence was observed in the anterior pituitary. Stellate cells were AT1b positive while ovoid cells were AT2 positive. In the brain, neurons were AT1a, AT1b, and AT2 positive, but glia was only AT1b positive. Highest levels of AT1a, AT1b, and AT2 receptor immunofluorescence were in the subfornical organ, median eminence, area postrema, paraventricular nucleus, and solitary tract nucleus. These studies complement those employing different techniques to characterize Ang II receptors.

Estimation of the number of angiotensin II AT1 receptors in rat kidney afferent and efferent arterioles

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Razga, Zsolt; Nyengaard, Jens Randel

2007-01-01

of angiotensin II AT1 receptors along the length of the arterioles and per arteriole, we combined immunoelectron microscopy with stereology. RESULTS: The number of AT1 receptor molecules was significantly lower in the renin-positive smooth muscle cells (SMCs) than in the renin-negative SMCs of the afferent...

Angiotensin-Converting Enzymes Play a Dominant Role in Fertility

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Fan Jin

2013-10-01

Full Text Available According to the World Health Organization, infertility, associated with metabolic syndrome, has become a global issue with a 10%–20% incidence worldwide. An accumulating body of evidence has shown that the renin–angiotensin system is involved in the fertility problems observed in some populations. Moreover, alterations in the expression of angiotensin-converting enzyme-1, angiotensin-converting enzyme-2, and angiotensin-converting enzyme-3 might be one of the most important mechanisms underlying both female and male infertility. However, as a pseudogene in humans, further studies are needed to explore whether the abnormal angiotensin-converting enzyme-3 gene could result in the problems of human reproduction. In this review, the relationship between angiotensin-converting enzymes and fertile ability is summarized, and a new procedure for the treatment of infertility is discussed.

Characterization of Angiotensin II Molecular Determinants Involved in AT1 Receptor Functional Selectivity.

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Domazet, Ivana; Holleran, Brian J; Richard, Alexandra; Vandenberghe, Camille; Lavigne, Pierre; Escher, Emanuel; Leduc, Richard; Guillemette, Gaétan

2015-06-01

The octapeptide angiotensin II (AngII) exerts a variety of cardiovascular effects through the activation of the AngII type 1 receptor (AT1), a G protein-coupled receptor. The AT1 receptor engages and activates several signaling pathways, including heterotrimeric G proteins Gq and G12, as well as the extracellular signal-regulated kinases (ERK) 1/2 pathway. Additionally, following stimulation, βarrestin is recruited to the AT1 receptor, leading to receptor desensitization. It is increasingly recognized that specific ligands selectively bind and favor the activation of some signaling pathways over others, a concept termed ligand bias or functional selectivity. A better understanding of the molecular basis of functional selectivity may lead to the development of better therapeutics with fewer adverse effects. In the present study, we developed assays allowing the measurement of six different signaling modalities of the AT1 receptor. Using a series of AngII peptide analogs that were modified in positions 1, 4, and 8, we sought to better characterize the molecular determinants of AngII that underlie functional selectivity of the AT1 receptor in human embryonic kidney 293 cells. The results reveal that position 1 of AngII does not confer functional selectivity, whereas position 4 confers a bias toward ERK signaling over Gq signaling, and position 8 confers a bias toward βarrestin recruitment over ERK activation and Gq signaling. Interestingly, the analogs modified in position 8 were also partial agonists of the protein kinase C (PKC)-dependent ERK pathway via atypical PKC isoforms PKCζ and PKCι. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Live Cell Imaging and 3D Analysis of Angiotensin Receptor Type 1a Trafficking in Transfected Human Embryonic Kidney Cells Using Confocal Microscopy.

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Kadam, Parnika; McAllister, Ryan; Urbach, Jeffrey S; Sandberg, Kathryn; Mueller, Susette C

2017-03-27

Live-cell imaging is used to simultaneously capture time-lapse images of angiotensin type 1a receptors (AT1aR) and intracellular compartments in transfected human embryonic kidney-293 (HEK) cells following stimulation with angiotensin II (Ang II). HEK cells are transiently transfected with plasmid DNA containing AT1aR tagged with enhanced green fluorescent protein (EGFP). Lysosomes are identified with a red fluorescent dye. Live-cell images are captured on a laser scanning confocal microscope after Ang II stimulation and analyzed by software in three dimensions (3D, voxels) over time. Live-cell imaging enables investigations into receptor trafficking and avoids confounds associated with fixation, and in particular, the loss or artefactual displacement of EGFP-tagged membrane receptors. Thus, as individual cells are tracked through time, the subcellular localization of receptors can be imaged and measured. Images must be acquired sufficiently rapidly to capture rapid vesicle movement. Yet, at faster imaging speeds, the number of photons collected is reduced. Compromises must also be made in the selection of imaging parameters like voxel size in order to gain imaging speed. Significant applications of live-cell imaging are to study protein trafficking, migration, proliferation, cell cycle, apoptosis, autophagy and protein-protein interaction and dynamics, to name but a few.

No effect of angiotensin II AT(2)-receptor antagonist PD 123319 on cerebral blood flow autoregulation

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Estrup, T M; Paulson, O B; Strandgaard, S

2001-01-01

Blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin AT1-receptor antagonists shift the limits of autoregulation of cerebral blood flow (CBF) towards lower blood pressure (BP). The role of AT2-receptors in the regulation of the cerebral cir...

Angiotensin-II type 1 receptor gene polymorphism and diabetic microangiopathy

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Tarnow, L; Cambien, Francois; Rossing, P

1996-01-01

with proliferative retinopathy and without diabetic retinopathy was found either: 77 (50%) / 66 (42%) / 13 (8%) vs. 42 (63%) / 22 (33%) / 3 (4%) had AA/AC/CC genotypes, respectively. CONCLUSIONS: The A1166-->C polymorphism in the angiotensin-II type 1 receptor gene does not contribute to the genetic susceptibility...... is present particularly in vascular smooth muscle cells, myocardium and the kidney. A transversion of adenine to cytosine at nucleotide position 1166 in the gene coding for the angiotensin-II type 1 receptor has been associated with hypertension in the non-diabetic population. METHODS: We studied...... the relationship between the A1166-->C polymorphism in the angiotensin-II type 1 receptor gene in patients with insulin dependent diabetes mellitus (IDDM) and diabetic nephropathy (121 men, 77 women, age 41 +/- 10 years, diabetes duration 27 +/- 8 years) and in IDDM patients with normoalbuminuria (116 men, 74...

Angiotensin II inhibits cortical cholinergic function: Implications for cognition

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Barnes, J.M.; Barnes, N.M.; Costall, B.; Horovitz, Z.P.; Ironside, J.W.; Naylor, R.J.; Williams, T.J.

1990-01-01

In the present studies we have shown that angiotensin II (AT II), in a concentration-dependent manner in rat tissue (10(-9)-10(-5) M) or at a single concentration in human tissue (10(-6) M), can inhibit potassium-stimulated release of [3H]acetylcholine ( [3H]Ach) from slices of rat entorhinal cortex and human temporal cortex preloaded with [3H]choline for the biochemical analyses. The inhibitory effects of AT II (10(-6) M) were antagonised by the specific AT II receptor antagonist [1-sarcosine, 8-threonine]AT II in a concentration-dependent manner in rat tissue (10(-11)-10(-8) M) and at the single concentration employed in the human studies (10(-7) M). Also demonstrated were other components of the angiotensin system in the human temporal cortex; ACE activity was present (1.03 nmol min-1 mg-1 protein), as were AT II recognition sites (Bmax = 8.6 fmol mg-1 protein). It is hypothesised that the potential cognitive enhancing properties of ACE inhibitors may reflect their action to prevent the formation of AT II and so remove an inhibitory modulator of cholinergic function

Genetic variation and activity of the renin-angiotensin system and severe hypoglycemia in type 1 diabetes

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Pedersen-Bjergaard, U.; Dhamrait, S.S.; Sethi, A.A.

2008-01-01

BACKGROUND: The deletion-allele of the angiotensin-converting enzyme (ACE) gene and elevated ACE activity are associated with increased risk of severe hypoglycemia in type 1 diabetes. We explored whether genetic and phenotypic variations in other components of the renin-angiotensin system...... are similarly associated. METHODS: Episodes of severe hypoglycemia were recorded in 171 consecutive type 1 diabetic outpatients during a 1-year follow-up. Participants were characterized at baseline by gene polymorphisms in angiotensinogen, ACE, angiotensin-II receptor types 1 (AT1R) and 2 (AT2R), and by plasma...... associate with high risk of severe hypoglycemia in type 1 diabetes. A potential preventive effect of renin-angiotensin system blocking drugs in patients with recurrent severe hypoglycemia merits further investigation Udgivelsesdato: 2008/3...

"Assessment of human AT1 Binding Affinity of Some Novel 2-alkylthio-1-[4-(N-α-ethoxycarbonyl-nzylaminobenzyl-5-hydroxymethylimidazoles "

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Setareh Badakhshannoory

2004-06-01

Full Text Available Antagonists of various components of the renin-angiotensin system have been the subject of many studies for the control of blood pressure. Compounds with a phenoxyphenylacetic acid moiety that mimic the structure of losartan which is a powerful competitive antagonist of angiotensin receptor, have shown to be effective. In this study, the affinity of some 2-alkylthio-1-[4-(N-α-ethoxycarbonylbenzylaminobenzyl]-5-hydroxymethyl imidazoles for the human AT1 receptor was assessed in a radioligand binding assay. It was found that an alkyl chain of appropriate length would be most suitable if situated on the imidazole ring. Furthermore, variations of the lower phenyl rings demonstrated that introduction of a methyl group in this position will account for the most desired effect.

Angiotensin-(1-7): A Novel Peptide to Treat Hypertension and Nephropathy in Diabetes?

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Padda, Ranjit Singh; Shi, Yixuan; Lo, Chao-Sheng; Zhang, Shao-Ling; Chan, John S D

2015-10-14

The renin-angiotensin system (RAS) plays a pivotal role in mammalian homeostasis physiology. The RAS can be delineated into a classical RAS (the pressor arm) including angiotensinogen (Agt), renin, angiotensin-converting enzyme (ACE), angiotensin II (Ang II) and angiotensin type 1 receptor (AT1R), and a counterbalancing novel RAS (the depressor arm) including Agt, renin, angiotensin-converting enzyme-2 (ACE-2), angiotensin-(1-7) (Ang 1-7) and Ang 1-7 receptor (or Mas receptor (MasR)). Hyperglycemia (diabetes) induces severe tissue oxidative stress, which stimulates the pressor arm of the renal RAS axis and leads to an increase in ACE/ACE-2 ratio, with excessive formation of Ang II. There is a growing body of evidence for beneficial effects of the depressor arm of RAS (ACE-2/Ang 1-7/MasR) axis in diabetes, hypertension and several other diseased conditions. Evidence from in vitro, in vivo and clinical studies reflects anti-oxidant, anti-fibrotic, and anti-inflammatory properties of Ang 1-7. Most of the currently available therapies only target suppression of the pressor arm of RAS with angiotensin receptor blockers (ARBs) and ACE inhibitors (ACEi). However, it is time to consider simultaneous activation of the depressor arm for more effective outcomes. This review summarizes the recent updates on the protective role of Ang 1-7 in hypertension and kidney injury in diabetes, as well as the possible underlying mechanism(s) of Ang 1-7 action, suggesting that the ACE-2/Ang 1-7/MasR axis can be developed as a therapeutic target for the treatment of diabetes-induced hypertension and renal damage.

Angiotensin IV and the human esophageal mucosa: An exploratory study in healthy subjects and gastroesophageal reflux disease patients.

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Björkman, Eleonora; Edebo, Anders; Fändriks, Lars; Casselbrant, Anna

2015-09-01

The human esophageal mucosa expresses various components of the renin-angiotensin system (RAS), e.g. the main effector peptide angiotensin II (AngII). The aim of this study was to investigate the esophageal presence of angiotensin III (AngIII) and angiotensin IV (AngIV) forming enzymes and the AngIV receptor (AT4R). The aim was also to study the actions of AngIV and to look for aberrations in patients with gastroesophageal reflux disease (GERD). Esophageal biopsies were collected from healthy volunteers (n: 19) and individuals with erosive reflux disease (n: 14). Gene transcripts and protein expression of aminopeptidase A, -B and -M, and the AT4R were investigated by reverse transcriptase polymerase chain reaction (rt-PCR), western blot (WB) and immunohistochemistry (IHC). The functional impact of AngIV was examined in an Ussing chamber. Aminopeptidase A, -B and -M and the AT4R were expressed in the esophageal epithelium. The AT4R was less prominent in certain areas in the mucosa of reflux patients. AngIV influenced the esophageal epithelial ion transport. The impact was lower in patients with GERD. The AT4R and formation enzymes of AngIII and AngIV are present in the human esophageal epithelium. Moreover, the present results suggest that AngIV exert regulatory impact on the epithelium and that RAS is involved in mucosal aberrations associated with GERD. © The Author(s) 2014.

Renin-Angiotensin System in Diabetes.

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Rein, Johannes; Bader, Michael

2017-11-17

The renin-angiotensin system (RAS) has two different axes, the classical one with the effector peptide angiotensin II and the new one with the effector peptide angiotensin (1-7). Both peptides have been shown to be involved in the pathogenesis of diabetes mellitus and its consequences, nephropathy, retinopathy and cardiomyopathy in animal models and patients. In diabetes, angiotensin II acts mostly deleterious and angiotensin (1-7) protective. In this review we summarize the knowledge about the role of the different RAS axes in diabetes mellitus and the use of drugs interfering with the RAS in the therapy of the disease. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Design of a MCoTI-Based Cyclotide with Angiotensin (1-7-Like Activity

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Teshome Aboye

2016-01-01

Full Text Available We report for the first time the design and synthesis of a novel cyclotide able to activate the unique receptor of angiotensin (1-7 (AT1-7, the MAS1 receptor. This was accomplished by grafting an AT1-7 peptide analog onto loop 6 of cyclotide MCoTI-I using isopeptide bonds to preserve the α-amino and C-terminal carboxylate groups of AT1-7, which are required for activity. The resulting cyclotide construct was able to adopt a cyclotide-like conformation and showed similar activity to that of AT1-7. This cyclotide also showed high stability in human serum thereby providing a promising lead compound for the design of a novel type of peptide-based in the treatment of cancer and myocardial infarction.

Predominance of AT1 Blockade Over Mas–Mediated Angiotensin-(1–7) Mechanisms in the Regulation of Blood Pressure and Renin–Angiotensin System in mRen2.Lewis Rats

Science.gov (United States)

2013-01-01

BACKGROUND We investigated whether the antihypertensive actions of the angiotensin II (Ang II) receptor (AT1-R) blocker, olmesartan medoxomil, may in part be mediated by increased Ang-(1–7) in the absence of significant changes in plasma Ang II. METHODS mRen2.Lewis congenic hypertensive rats were administered either a vehicle (n = 14) or olmesartan (0.5mg/kg/day; n = 14) by osmotic minipumps. Two weeks later, rats from both groups were further randomized to receive either the mas receptor antagonist A-779 (0.5mg/kg/day; n = 7 per group) or its vehicle (n = 7 per group) for the next 4 weeks. Blood pressure was monitored by telemetry, and circulating and tissue components of the renin–angiotensin system (RAS) were measured at the completion of the experiments. RESULTS Antihypertensive effects of olmesartan were associated with an increase in plasma renin concentration, plasma Ang I, Ang II, and Ang-(1–7), whereas serum aldosterone levels and kidney Ang II content were reduced. Preserved Ang-(1–7) content in kidneys was associated with increases of ACE2 protein but not activity and no changes on serum and kidney ACE activity. There was no change in cardiac peptide levels after olmesartan treatment. The antihypertensive effects of olmesartan were not altered by concomitant administration of the Ang-(1–7) receptor antagonist except for a mild further increase in plasma renin concentration. CONCLUSIONS Our study highlights the independent regulation of RAS among plasma, heart, and kidney tissue in response to AT1-R blockade. Ang-(1–7) through the mas receptor does not mediate long-term effects of olmesartan besides counterbalancing renin release in response to AT1-R blockade. PMID:23459599

Discovery of a Series of Imidazo[4,5-b]pyridines with Dual Activity at Angiotensin II Type 1 Receptor and Peroxisome Proliferator-Activated Receptor-[gamma

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Casimiro-Garcia, Agustin; Filzen, Gary F.; Flynn, Declan; Bigge, Christopher F.; Chen, Jing; Davis, Jo Ann; Dudley, Danette A.; Edmunds, Jeremy J.; Esmaeil, Nadia; Geyer, Andrew; Heemstra, Ronald J.; Jalaie, Mehran; Ohren, Jeffrey F.; Ostroski, Robert; Ellis, Teresa; Schaum, Robert P.; Stoner, Chad (Pfizer)

2013-03-07

Mining of an in-house collection of angiotensin II type 1 receptor antagonists to identify compounds with activity at the peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}) revealed a new series of imidazo[4,5-b]pyridines 2 possessing activity at these two receptors. Early availability of the crystal structure of the lead compound 2a bound to the ligand binding domain of human PPAR{gamma} confirmed the mode of interaction of this scaffold to the nuclear receptor and assisted in the optimization of PPAR{gamma} activity. Among the new compounds, (S)-3-(5-(2-(1H-tetrazol-5-yl)phenyl)-2,3-dihydro-1H-inden-1-yl)-2-ethyl-5-isobutyl-7-methyl-3H-imidazo[4,5-b]pyridine (2l) was identified as a potent angiotensin II type I receptor blocker (IC{sub 50} = 1.6 nM) with partial PPAR{gamma} agonism (EC{sub 50} = 212 nM, 31% max) and oral bioavailability in rat. The dual pharmacology of 2l was demonstrated in animal models of hypertension (SHR) and insulin resistance (ZDF rat). In the SHR, 2l was highly efficacious in lowering blood pressure, while robust lowering of glucose and triglycerides was observed in the male ZDF rat.

The angiotensin II type 1 receptor antagonist Losartan binds and activates bradykinin B2 receptor signaling

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Bonde, Marie Mi; Olsen, Kristine Boisen; Erikstrup, Niels

2011-01-01

The angiotensin II type 1 receptor (AT1R) blocker (ARB) Losartan has cardioprotective effects during ischemia-reperfusion injury and inhibits reperfusion arrhythmias -effects that go beyond the benefits of lowering blood pressure. The renin-angiotensin and kallikrein-kinin systems are intricately...

Can intradermal administration of angiotensin II influence human heat loss responses during whole body heat stress?

Science.gov (United States)

Fujii, Naoto; Meade, Robert D; Paull, Gabrielle; McGinn, Ryan; Foudil-bey, Imane; Akbari, Pegah; Kenny, Glen P

2015-05-01

It is unclear if angiotensin II, which can increase the production of reactive oxygen species (oxidative stress), modulates heat loss responses of cutaneous blood flow and sweating. We tested the hypothesis that angiotensin II-induced increases in oxidative stress impair cutaneous perfusion and sweating during rest and exercise in the heat. Eleven young (24 ± 4 yr) healthy adults performed two 30-min cycling bouts at a fixed rate of metabolic heat production (400 W) in the heat (35°C). The first and second exercises were followed by a 20- and 40-min recovery. Four microdialysis fibers were placed in the forearm skin for continuous administration of either: 1) lactated Ringer (control), 2) 10 μM angiotensin II, 3) 10 mM ascorbate (an antioxidant), or 4) a combination of 10 μM angiotensin II + 10 mM ascorbate. Cutaneous vascular conductance (CVC; laser-Doppler perfusion units/mean arterial pressure) and sweating (ventilated capsule) were evaluated at each skin site. Compared with control, angiotensin II reduced both CVC and sweating at baseline resting and during each recovery in the heat (all P 0.05). When ascorbate was coinfused with angiotensin II, the effect of angiotensin II on sweating was abolished (all P > 0.05); however, its effect on CVC at baseline resting and during each recovery remained intact (all P stress, while it impairs sweating through increasing oxidative stress during exposure to an ambient heat stress before and following exercise. Copyright © 2015 the American Physiological Society.

Angiotensin type 2 receptor (AT2R) and receptor Mas

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Villela, Daniel; Leonhardt, Julia; Patel, Neal

2015-01-01

The angiotensin type 2 receptor (AT2R) and the receptor Mas are components of the protective arms of the renin-angiotensin system (RAS), i.e. they both mediate tissue protective and regenerative actions. The spectrum of actions of these two receptors and their signalling mechanisms display striki...

Attenuation of myocardial fibrosis with curcumin is mediated by modulating expression of angiotensin II AT1/AT2 receptors and ACE2 in rats

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Pang XF

2015-11-01

Full Text Available Xue-Fen Pang,1 Li-Hui Zhang,2 Feng Bai,1 Ning-Ping Wang,3 Ron E Garner,3 Robert J McKallip,4 Zhi-Qing Zhao1,3 1Department of Physiology, Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China; 2Department of Cardiology, Shanxi Academy of Medical Sciences and Shanxi Dayi Hospital, Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China; 3Department of Basic Biomedical Sciences, Mercer University School of Medicine, Savannah, GA, USA; 4Division of Basic Biomedical Sciences, Mercer University School of Medicine, Macon, GA, USA Abstract: Curcumin is known to improve cardiac function by balancing degradation and synthesis of collagens after myocardial infarction. This study tested the hypothesis that inhibition of myocardial fibrosis by curcumin is associated with modulating expression of angiotensin II (Ang II receptors and angiotensin-converting enzyme 2 (ACE2. Male Sprague Dawley rats were subjected to Ang II infusion (500 ng/kg/min using osmotic minipumps for 2 and 4 weeks, respectively, and curcumin (150 mg/kg/day was fed by gastric gavage during Ang II infusion. Compared to the animals with Ang II infusion, curcumin significantly decreased the mean arterial blood pressure during the course of the observation. The protein level of the Ang II type 1 (AT1 receptor was reduced, and the Ang II type 2 (AT2 receptor was up-regulated, evidenced by an increased ratio of the AT2 receptor over the AT1 receptor in the curcumin group (1.2±0.02% vs in the Ang II group (0.7±0.03%, P<0.05. These changes were coincident with less locally expressed AT1 receptor and enhanced AT2 receptor in the intracardiac vessels and intermyocardium. Along with these modulations, curcumin significantly decreased the populations of macrophages and alpha smooth muscle actin-expressing myofibroblasts, which were accompanied by reduced expression of transforming growth factor beta 1 and phosphorylated-Smad2/3. Collagen I synthesis was

The Protective Arm of the Renin Angiotensin System (RAS)

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understanding of the protective side of the Renin Angiotensin System (RAS) involving angiotensin AT2 receptor, ACE2, and Ang(1-7)/Mas receptor Combines the knowledge of editors who pioneered research on the protective renin angiotensin system including; Dr. Thomas Unger, one of the founders of AT2 receptor......The Protective Arm of the Renin Angiotensin System: Functional Aspects and Therapeutic Implications is the first comprehensive publication to signal the protective role of a distinct part of the renin-angiotensin system (RAS), providing readers with early insight into a complex system which...... will become of major medical importance in the near future. Focusing on recent research, The Protective Arm of the Renin Angiotensin System presents a host of new experimental studies on specific components of the RAS, namely angiotensin AT2 receptors (AT2R), the angiotensin (1-7) peptide with its receptor...

Neuroprotective Mechanisms of the ACE2-Angiotensin-(1-7)-Mas Axis in Stroke

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Bennion, Douglas M; Haltigan, Emily; Regenhardt, Robert W

2015-01-01

The discovery of beneficial neuroprotective effects of the angiotensin converting enzyme 2-angiotensin-(1-7)-Mas axis [ACE2-Ang-(1-7)-Mas] in ischemic and hemorrhagic stroke has spurred interest in a more complete characterization of its mechanisms of action. Here, we summarize findings that desc......The discovery of beneficial neuroprotective effects of the angiotensin converting enzyme 2-angiotensin-(1-7)-Mas axis [ACE2-Ang-(1-7)-Mas] in ischemic and hemorrhagic stroke has spurred interest in a more complete characterization of its mechanisms of action. Here, we summarize findings...... that describe the protective role of the ACE2-Ang-(1-7)-Mas axis in stroke, along with a focused discussion on the potential mechanisms of neuroprotective effects of Ang-(1-7) in stroke. The latter incorporates evidence describing the actions of Ang-(1-7) to counter the deleterious effects of angiotensin II...... complete understanding of the mechanisms of action of Ang-(1-7) to elicit neuroprotection will serve as an essential step toward research into potential targeted therapeutics in the clinical setting....

Angiotensin II Regulates Th1 T Cell Differentiation Through Angiotensin II Type 1 Receptor-PKA-Mediated Activation of Proteasome.

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Qin, Xian-Yun; Zhang, Yun-Long; Chi, Ya-Fei; Yan, Bo; Zeng, Xiang-Jun; Li, Hui-Hua; Liu, Ying

2018-01-01

Naive CD4+ T cells differentiate into T helper cells (Th1 and Th2) that play an essential role in the cardiovascular diseases. However, the molecular mechanism by which angiotensin II (Ang II) promotes Th1 differentiation remains unclear. The aim of this study was to determine whether the Ang II-induced Th1 differentiation regulated by ubiquitin-proteasome system (UPS). Jurkat cells were treated with Ang II (100 nM) in the presence or absence of different inhibitors. The gene mRNA levels were detected by real-time quantitative PCR analysis. The protein levels were measured by ELISA assay or Western blot analysis, respectively. Ang II treatment significantly induced a shift from Th0 to Th1 cell differentiation, which was markedly blocked by angiotensin II type 1 receptor (AT1R) inhibitor Losartan (LST). Moreover, Ang II significantly increased the activities and the expression of proteasome catalytic subunits (β1, β1i, β2i and β5i) in a dose- and time-dependent manner. However, Ang II-induced proteasome activities were remarkably abrogated by LST and PKA inhibitor H-89. Mechanistically, Ang II-induced Th1 differentiation was at least in part through proteasome-mediated degradation of IκBα and MKP-1 and activation of STAT1 and NF-κB. This study for the first time demonstrates that Ang II activates AT1R-PKA-proteasome pathway, which promotes degradation of IκBα and MKP-1 and activation of STAT1 and NF-κB thereby leading to Th1 differentiation. Thus, inhibition of proteasome activation might be a potential therapeutic target for Th1-mediated diseases. © 2018 The Author(s). Published by S. Karger AG, Basel.

No effect of angiotensin II AT(2)-receptor antagonist PD 123319 on cerebral blood flow autoregulation

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Estrup, T M; Paulson, O B; Strandgaard, S

2001-01-01

Blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin AT1-receptor antagonists shift the limits of autoregulation of cerebral blood flow (CBF) towards lower blood pressure (BP). The role of AT2-receptors in the regulation of the cerebral...... group. CBF was measured by the intracarotid 133xenon injection method and BP was raised by noradrenaline infusion and lowered by controlled haemorrhage in separate groups of rats. The limits of autoregulation were determined by computed least-sum-of-squares analysis. PD 123319 did not influence baseline...

Gene expression profiling associated with angiotensin II type 2 receptor-induced apoptosis in human prostate cancer cells.

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Nana Pei

Full Text Available Increased expression of angiotensin II type 2 receptor (AT2R induces apoptosis in numerous tumor cell lines, with either Angiotensin II-dependent or Angiotensin II-independent regulation, but its molecular mechanism remains poorly understood. Here, we used PCR Array analysis to determine the gene and microRNA expression profiles in human prostate cancer cell lines transduced with AT2R recombinant adenovirus. Our results demonstrated that AT2R over expression leads to up-regulation of 6 apoptosis-related genes (TRAIL-R2, BAG3, BNIPI, HRK, Gadd45a, TP53BP2, 2 cytokine genes (IL6 and IL8 and 1 microRNA, and down-regulation of 1 apoptosis-related gene TNFSF10 and 2 cytokine genes (BMP6, BMP7 in transduced DU145 cells. HRK was identified as an up-regulated gene in AT2R-transduced PC-3 cells by real-time RT-PCR. Next, we utilized siRNAs to silence the up-regulated genes to further determine their roles on AT2R overexpression mediated apoptosis. The results showed downregulation of Gadd45a reduced the apoptotic effect by ∼30% in DU145 cells, downregulation of HRK reduced AT2R-mediated apoptosis by more than 50% in PC-3 cells, while downregulation of TRAIL-R2 enhanced AT2R-mediated apoptosis more than 4 times in DU145 cells. We also found that the effects on AT2R-mediated apoptosis caused by downregulation of Gadd45a, TRAIL-R2 and HRK were independent in activation of p38 MAPK, p44/42 MAPK and p53. Taken together, our results demonstrated that TRAIL-R2, Gadd45a and HRK may be novel target genes for further study of the mechanism of AT2R-mediated apoptosis in prostate cancer cells.

Brain angiotensin-(1-7)/Mas axis: A new target to reduce the cardiovascular risk to emotional stress.

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Fontes, Marco Antônio Peliky; Martins Lima, Augusto; Santos, Robson Augusto Souza dos

2016-04-01

Emotional stress is now considered a risk factor for several diseases including cardiac arrhythmias and hypertension. It is well known that the activation of neuroendocrine and autonomic mechanisms features the response to emotional stress. However, its link to cardiovascular diseases and the regulatory mechanisms involved remain to be further comprehended. The renin-angiotensin system (RAS) plays an important role in homeostasis on all body systems. Specifically in the brain, the RAS regulates a number of physiological aspects. Recent data indicate that the activation of angiotensin-converting enzyme/angiotensin II/AT1 receptor axis facilitates the emotional stress responses. On the other hand, growing evidence indicates that its counterregulatory axis, the angiotensin-converting enzyme 2 (ACE2)/(Ang)iotensin-(1-7)/Mas axis, reduces anxiety and attenuates the physiological responses to emotional stress. The present review focuses on angiotensin-(1-7)/Mas axis as a promising target to attenuate the physiological response to emotional stress reducing the risk of cardiovascular diseases. Copyright © 2015 Elsevier Ltd. All rights reserved.

Distortion of maternal-fetal angiotensin II type 1 receptor allele transmission in pre-eclampsia.

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Morgan, L; Crawshaw, S; Baker, P N; Brookfield, J F; Broughton Pipkin, F; Kalsheker, N

1998-01-01

OBJECTIVE: To investigate the fetal angiotensin II type 1 receptor genotype in pre-eclampsia. DESIGN: Case-control study. POPULATION: Forty-one maternal-fetal pairs from pre-eclamptic pregnancies and 80 maternal-fetal pairs from normotensive pregnancies. METHODS: Maternal and fetal DNA was genotyped at three diallelic polymorphisms, at nucleotides 573, 1062, and 1166, in the coding exon of the angiotensin II type 1 receptor gene, and at a dinucleotide repeat polymorphism in its 3' flanking region. RESULTS: Allele and genotype frequencies at the four polymorphic regions investigated did not differ between pre-eclamptic and normotensive groups, in either fetal or maternal samples. Mothers heterozygous for the dinucleotide repeat allele designated A4 transmitted this allele to the fetus in 15 of 18 informative pre-eclamptic pregnancies and in eight of 26 normotensive pregnancies. This was greater than the expected probability in pre-eclamptic pregnancies (p=0.04) and less than expected in normotensive pregnancies (p<0.005). The 573T variant, which is in partial linkage disequilibrium with the A4 allele, showed a similar distortion of maternal-fetal transmission. CONCLUSION: Angiotensin II type 1 receptor gene expression in the fetus may contribute to the aetiology of pre-eclampsia. It is unclear whether susceptibility is conferred by the fetal genotype acting alone, or by allele sharing by mother and fetus. Possible mechanisms for the effect of the angiotensin II type 1 receptor gene are suggested by the association of the 573T variant with low levels of surface receptor expression on platelets. If receptor expression is similarly genetically determined in the placenta, responsiveness to angiotensin II may be affected, with the potential to influence placentation or placental prostaglandin secretion. PMID:9719367

Edaravone inhibits pressure overload-induced cardiac fibrosis and dysfunction by reducing expression of angiotensin II AT1 receptor

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Zhang WW

2017-10-01

Full Text Available Wei-Wei Zhang,1,2 Feng Bai,1 Jin Wang,1 Rong-Hua Zheng,1 Li-Wang Yang,1 Erskine A James,3 Zhi-Qing Zhao1,4 1Department of Physiology, Shanxi Medical University, 2Department of Anesthesiology, Shanxi Provincial People’s Hospital, Taiyuan, Shanxi, China; 3Department of Internal Medicine, Navicent Health, Macon, 4Department of Basic Biomedical Sciences, Mercer University School of Medicine, Savannah, GA, USA Abstract: Angiotensin II (Ang II is known to be involved in the progression of ventricular dysfunction and heart failure by eliciting cardiac fibrosis. The purpose of this study was to demonstrate whether treatment with an antioxidant compound, edaravone, reduces cardiac fibrosis and improves ventricular function by inhibiting Ang II AT1 receptor. The study was conducted in a rat model of transverse aortic constriction (TAC. In control, rats were subjected to 8 weeks of TAC. In treated rats, edaravone (10 mg/kg/day or Ang II AT1 receptor blocker, telmisartan (10 mg/kg/day was administered by intraperitoneal injection or gastric gavage, respectively, during TAC. Relative to the animals with TAC, edaravone reduced myocardial malonaldehyde level and increased superoxide dismutase activity. Protein level of the AT1 receptor was reduced and the AT2 receptor was upregulated, as evidenced by the reduced ratio of AT1 over AT2 receptor (0.57±0.2 vs 3.16±0.39, p<0.05 and less locally expressed AT1 receptor in the myocardium. Furthermore, the protein level of angiotensin converting enzyme 2 was upregulated. In coincidence with these changes, edaravone significantly decreased the populations of macrophages and myofibroblasts in the myocardium, which were accompanied by reduced levels of transforming growth factor beta 1 and Smad2/3. Collagen I synthesis was inhibited and collagen-rich fibrosis was attenuated. Relative to the TAC group, cardiac systolic function was preserved, as shown by increased left ventricular systolic pressure (204±51 vs 110±19

Angiotensin receptor blockers: Focus on cardiac and renal injury.

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Arumugam, Somasundaram; Sreedhar, Remya; Thandavarayan, Rajarajan A; Karuppagounder, Vengadeshprabhu; Krishnamurthy, Prasanna; Suzuki, Kenji; Nakamura, Masahiko; Watanabe, Kenichi

2016-04-01

Angiotensin II, an important component of renin angiotensin system, is a potent vasopressor and its actions are mostly mediated via angiotensin II type 1 receptor (AT1R) and role of AT2R in counterbalancing the actions of AT1R stimulation are under extensive research. In addition to its physiological actions, angiotensin II plays important roles in the pathogenesis of atherosclerosis, hypertension, left ventricular hypertrophy, and heart failure. The effects of angiotensin II can be blocked by either suppressing its production by blocking angiotensin converting enzyme or by antagonizing its actions on AT1R using angiotensin II receptor blockers (ARBs). Instead of the extensive use of ARBs in the treatment of various cardiovascular diseases, proper selection of a particular ARB is crucial as the clinical condition of individual patient is different and also their economic status would play an essential role in medication compliance. Thus a critical review of the proven and promising actions of ARBs against various pathological conditions will be of great importance for the clinicians as well as for the researchers. Copyright © 2016 Elsevier Inc. All rights reserved.

Angiotensin converting enzyme 1 in the median preoptic nucleus contributes to chronic intermittent hypoxia hypertension.

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Faulk, Katelynn E; Nedungadi, T Prashant; Cunningham, J Thomas

2017-05-01

Obstructive sleep apnea is associated with hypertension and cardiovascular disease. Chronic intermittent hypoxia is used to model the arterial hypoxemia seen in sleep apnea patients and is associated with increased sympathetic nerve activity and a sustained diurnal increase in blood pressure. The renin angiotensin system has been associated with hypertension seen in chronic intermittent hypoxia. Angiotensin converting enzyme 1, which cleaves angiotensin I to the active counterpart angiotensin II, is present within the central nervous system and has been shown to be regulated by AP-1 transcription factors, such as ΔFosB. Our previous study suggested that this transcriptional regulation in the median preoptic nucleus contributes to the sustained blood pressure seen following chronic intermittent hypoxia. Viral mediated delivery of a short hairpin RNA against angiotensin converting enzyme 1 in the median preoptic nucleus was used along with radio-telemetry measurements of blood pressure to test this hypothesis. FosB immunohistochemistry was utilized in order to assess the effects of angiotensin converting enzyme 1 knockdown on the activity of nuclei downstream from median preoptic nucleus. Angiotensin converting enzyme 1 knockdown within median preoptic nucleus significantly attenuated the sustained hypertension seen in chronic intermittent hypoxia. Angiotensin converting enzyme 1 seems to be partly responsible for regulating downstream regions involved in sympathetic and blood pressure control, such as the paraventricular nucleus and the rostral ventrolateral medulla. The data suggest that angiotensin converting enzyme 1 within median preoptic nucleus plays a critical role in the sustained hypertension seen in chronic intermittent hypoxia. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

Oral delivery of Angiotensin-converting enzyme 2 and Angiotensin-(1-7) bioencapsulated in plant cells attenuates pulmonary hypertension.

Science.gov (United States)

Shenoy, Vinayak; Kwon, Kwang-Chul; Rathinasabapathy, Anandharajan; Lin, Shina; Jin, Guiying; Song, Chunjuan; Shil, Pollob; Nair, Anand; Qi, Yanfei; Li, Qiuhong; Francis, Joseph; Katovich, Michael J; Daniell, Henry; Raizada, Mohan K

2014-12-01

Emerging evidences indicate that diminished activity of the vasoprotective axis of the renin-angiotensin system, constituting angiotensin-converting enzyme 2 (ACE2) and its enzymatic product, angiotensin-(1-7) [Ang-(1-7)] contribute to the pathogenesis of pulmonary hypertension (PH). However, long-term repetitive delivery of ACE2 or Ang-(1-7) would require enhanced protein stability and ease of administration to improve patient compliance. Chloroplast expression of therapeutic proteins enables their bioencapsulation within plant cells to protect against gastric enzymatic degradation and facilitates long-term storage at room temperature. Besides, fusion to a transmucosal carrier helps effective systemic absorption from the intestine on oral delivery. We hypothesized that bioencapsulating ACE2 or Ang-(1-7) fused to the cholera nontoxin B subunit would enable development of an oral delivery system that is effective in treating PH. PH was induced in male Sprague Dawley rats by monocrotaline administration. Subset of animals was simultaneously treated with bioencapsulaed ACE2 or Ang-(1-7) (prevention protocol). In a separate set of experiments, drug treatment was initiated after 2 weeks of PH induction (reversal protocol). Oral feeding of rats with bioencapsulated ACE2 or Ang-(1-7) prevented the development of monocrotaline-induced PH and improved associated cardiopulmonary pathophysiology. Furthermore, in the reversal protocol, oral ACE2 or Ang-(1-7) treatment significantly arrested disease progression, along with improvement in right heart function, and decrease in pulmonary vessel wall thickness. In addition, a combination therapy with ACE2 and Ang-(1-7) augmented the beneficial effects against monocrotaline-induced lung injury. Our study provides proof-of-concept for a novel low-cost oral ACE2 or Ang-(1-7) delivery system using transplastomic technology for pulmonary disease therapeutics. © 2014 American Heart Association, Inc.

Dietary sodium deprivation evokes activation of brain regional neurons and down-regulation of angiotensin II type 1 receptor and angiotensin-convertion enzyme mRNA expression.

Science.gov (United States)

Lu, B; Yang, X J; Chen, K; Yang, D J; Yan, J Q

2009-12-15

Previous studies have indicated that the renin-angiotensin-aldosterone system (RAAS) is implicated in the induction of sodium appetite in rats and that different dietary sodium intakes influence the mRNA expression of central and peripheral RAAS components. To determine whether dietary sodium deprivation activates regional brain neurons related to sodium appetite, and changes their gene expression of RAAS components of rats, the present study examined the c-Fos expression after chronic exposure to low sodium diet, and determined the relationship between plasma and brain angiotensin I (ANG I), angiotensin II (ANG II) and aldosterone (ALD) levels and the sodium ingestive behavior variations, as well as the effects of prolonged dietary sodium deprivation on ANG II type 1 (AT1) and ANG II type 2 (AT2) receptors and angiotensin-convertion enzyme (ACE) mRNA levels in the involved brain regions using the method of real-time polymerase chain reaction (PCR). Results showed that the Fos immunoreactivity (Fos-ir) expression in forebrain areas such as subfornical organ (SFO), paraventricular hypothalamic nuclei (PVN), supraoptic nucleus (SON) and organum vasculosum laminae terminalis (OVLT) all increased significantly and that the levels of ANG I, ANG II and ALD also increased in plasma and forebrain in rats fed with low sodium diet. In contrast, AT1, ACE mRNA in PVN, SON and OVLT decreased significantly in dietary sodium depleted rats, while AT2 mRNA expression did not change in the examined areas. These results suggest that many brain areas are activated by increased levels of plasma and/or brain ANG II and ALD, which underlies the elevated preference for hypertonic salt solution after prolonged exposure to low sodium diet, and that the regional AT1 and ACE mRNA are down-regulated after dietary sodium deprivation, which may be mediated by increased ANG II in plasma and/or brain tissue.

Renoprotective effects of angiotensin II receptor blockade in type 1 diabetic patients with diabetic nephropathy

DEFF Research Database (Denmark)

Andersen, S; Tarnow, L; Rossing, P

2000-01-01

BACKGROUND: Angiotensin I-converting enzyme (ACE) inhibitors reduce angiotensin II formation and induce bradykinin accumulation. Animal studies suggest that bradykinin may play a role for the effects of ACE inhibition on blood pressure and kidney function. Therefore, we compared the renal and hem...... inhibition is primarily caused by interference in the renin-angiotensin system. Our study suggest that losartan represents a valuable new drug in the treatment of hypertension and proteinuria in type 1 diabetic patients with diabetic nephropathy....... and hemodynamic effects of specific intervention in the renin-angiotensin system by blockade of the angiotensin II subtype-1 receptor to the effect of ACE inhibition. METHODS: A randomized, double-blind, cross-over trial was performed in 16 type 1 diabetic patients (10 men), age 42 +/- 2 years (mean +/- SEM...

Structural determinants for binding to angiotensin converting enzyme 2 (ACE2 and angiotensin receptors

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Daniel eClayton

2015-01-01

Full Text Available Angiotensin converting enzyme 2 (ACE2 is a zinc carboxypeptidase involved in the renin angiotensin system (RAS and inactivates the potent vasopressive peptide angiotensin II (Ang II by removing the C-terminal phenylalanine residue to yield Ang1-7. This conversion inactivates the vasoconstrictive action of Ang II and yields a peptide that acts as a vasodilatory molecule at the Mas receptor and potentially other receptors. Given the growing complexity of RAS and level of cross-talk between ligands and their corresponding enzymes and receptors, the design of molecules with selectivity for the major RAS binding partners to control cardiovascular tone is an on-going challenge. In previous studies we used single β-amino acid substitutions to modulate the structure of Ang II and its selectivity for ACE2, AT1R and angiotensin type 2 (AT2R receptor. We showed that modification at the C-terminus of Ang II generally resulted in more pronounced changes to secondary structure and ligand binding, and here we further explore this region for the potential to modulate ligand specificity. In this study, 1 a library of forty-seven peptides derived from the C-terminal tetra-peptide sequence (-IHPF of Ang II was synthesised and assessed for ACE2 binding, 2 the terminal group requirements for high affinity ACE2 binding were explored by and N- and C-terminal modification, 3 high affinity ACE2 binding chimeric AngII analogues were then synthesized and assessed, 4 the structure of the full-length Ang II analogues were assessed by circular dichroism, and 5 the Ang II analogues were assessed for AT1R/AT2R selectivity by cell-based assays. Studies on the C-terminus of Ang II demonstrated varied specificity at different residue positions for ACE2 binding and four Ang II chimeric peptides were identified as selective ligands for the AT2 receptor. Overall, these results provide insight into the residue and structural requirements for ACE2 binding and angiotensin receptor

Evidence of changes in alpha-1/AT1 receptor function generated by diet-induced obesity.

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Juarez, Esther; Tufiño, Cecilia; Querejeta, Enrique; Bracho-Valdes, Ismael; Bobadilla-Lugo, Rosa A

2017-11-01

To study whether hypercaloric diet-induced obesity deteriorates vascular contractility of rat aorta through functional changes in α 1 adrenergic and/or AT1 Angiotensin II receptors. Angiotensin II- or phenylephrine-induced contraction was tested on isolated aorta rings with and without endothelium from female Wistar rats fed for 7 weeks with hypercaloric diet or standard diet. Vascular expression of Angiotensin II Receptor type 1 (AT1R), Angiotensin II Receptor type 2 (AT2R), Cyclooxygenase-1 (COX-1), Cyclooxygenase-2 (COX-2), inducible Nitric Oxide Synthase (iNOS) and endothelial Nitric Oxide Synthase (eNOS), as well as blood pressure, glucose, insulin and angiotensin II blood levels were measured. Diet-induced obesity did not significantly change agonist-induced contractions (Emax and pD 2 hypercaloric diet vs standard diet n.s.d.) of both intact (e+) or endothelium free (e-) vessels but significantly decrease both phenylephrine and angiotensin II contraction (Emax p obesity did not change angiotensin II AT1, AT2 receptor proteins expression but reduced COX-1 and NOS2 ( p obesity produces alterations in vascular adrenergic and angiotensin II receptor dynamics that suggest an endothelium-dependent adrenergic/angiotensin II crosstalk. These changes reflect early-stage vascular responses to obesity.

Effects of angiotensin II type 1 receptor blocker on bones in mice with type 1 diabetes induced by streptozotocin.

Science.gov (United States)

Zhang, Yan; Diao, Teng-Yue; Gu, Sa-Sa; Wu, Shu-Yan; Gebru, Yoseph A; Chen, Xi; Wang, Jing-Yu; Ran, Shu; Wong, Man-Sau

2014-09-01

This study was performed to address the pathological roles of the skeletal renin-angiotensin system (RAS) in type 1 diabetes-induced osteoporosis and the effects of the angiotensin II type 1 receptor blocker losartan on bones in diabetic mice. Bone histomorphology was detected by H&E staining, Safranin O staining and X-ray radiography. Micro-CT was performed for the analysis of bone parameters. Gene and protein expression were determined by RT-PCR and immunoblotting. Type 1 diabetic mice displayed osteopenia phenotype, and losartan treatment had no osteoprotective effects on diabetic mice as shown by the reduction of bone mineral density and microarchitectural parameters at the proximal metaphysis of the tibia. The mRNA expression of AGT, renin receptor and ACE, and protein expression of renin and AT1R were markedly up-regulated in the bones of vehicle-treated diabetic mice compared to those of non-diabetic mice. The treatment with losartan further significantly increased the expression of AGT, renin, angiotensin II and AT1R, and reduced the expression of AT2R receptor as compared to those of diabetic mice. Local bone RAS functionally played a role in the development of type 1 diabetic osteoporosis, and losartan had no bone-sparing function in diabetes mice because of enhance skeletal RAS activity. © The Author(s) 2013.

Epitope mapping of the domains of human angiotensin converting enzyme.

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Kugaevskaya, Elena V; Kolesanova, Ekaterina F; Kozin, Sergey A; Veselovsky, Alexander V; Dedinsky, Ilya R; Elisseeva, Yulia E

2006-06-01

Somatic angiotensin converting enzyme (sACE), contains in its single chain two homologous domains (called N- and C-domains), each bearing a functional zinc-dependent active site. The present study aims to define the differences between two sACE domains and to localize experimentally revealed antigenic determinants (B-epitopes) in the recently determined three-dimensional structure of testicular tACE. The predicted linear antigenic determinants of human sACE were determined by peptide scanning ("PEPSCAN") approach. Essential difference was demonstrated between locations of the epitopes in the N- and C-domains. Comparison of arrangement of epitopes in the human domains with the corresponding sequences of some mammalian sACEs enabled to classify the revealed antigenic determinants as variable or conserved areas. The location of antigenic determinants with respect to various structural elements and to functionally important sites of the human sACE C-domain was estimated. The majority of antigenic sites of the C-domain were located at the irregular elements and at the boundaries of secondary structure elements. The data show structural differences between the sACE domains. The experimentally revealed antigenic determinants were in agreement with the recently determined crystal tACE structure. New potential applications are open to successfully produce mono-specific and group-specific antipeptide antibodies.

Safflor yellow B suppresses angiotensin II-mediated human umbilical vein cell injury via regulation of Bcl-2/p22phox expression

International Nuclear Information System (INIS)

Wang, Chaoyun; He, Yanhao; Yang, Ming; Sun, Hongliu; Zhang, Shuping; Wang, Chunhua

2013-01-01

Intracellular reactive oxygen species (ROS) are derived from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Angiotensin II (Ang II) can cause endothelial dysfunction by promoting intracellular ROS generation. Safflor yellow B (SYB) effectively inhibits ROS generation by upregulating Bcl-2 expression. In this study, we examined the effects of SYB on Ang II-induced injury to human umbilical vein endothelial cells (HUVECs), and elucidated the roles of NADPH oxidase and Bcl-2. We treated cultured HUVECs with Ang II, SYB, and Bcl-2 siRNA, and determined NADPH oxidase activity and ROS levels. Furthermore, cellular and mitochondrial physiological states were evaluated, and the expression levels of target proteins were analyzed. Ang II significantly enhanced intracellular ROS levels, caused mitochondrial membrane dysfunction, and decreased cell viability, leading to apoptosis. This was associated with increased expression of AT1R and p22 phox , increased NADPH oxidase activity, and an increased ratio of Bax/Bcl-2, leading to decreases in antioxidant enzyme activities, which were further strengthened after blocking Bcl-2. Compared to Ang II treatment alone, co-treatment with SYB significantly reversed HUVEC injury. Taken together, these results demonstrate that SYB could significantly protect endothelial cells from Ang II-induced cell damage, and that it does so by upregulating Bcl-2 expression and inhibiting ROS generation. - Highlights: • Angiotensin II depresses mitochondria physiological function. • Angiotensin II activates NADPH oxidase via up-regulating expresion of p22 phox . • Bcl-2 plays a pivotal role in improving mitochondria function and regulates ROS level. • Inhibitor of Bcl-2 promotes angiotensin II mediated HUVEC injury. • SYB attenuates angiotensin II mediated HUVEC injury via up regulating Bcl-2 expression

The ACE-2/Ang1-7/Mas cascade enhances bone structure and metabolism following angiotensin-II type 1 receptor blockade.

Science.gov (United States)

Abuohashish, Hatem M; Ahmed, Mohammed M; Sabry, Dina; Khattab, Mahmoud M; Al-Rejaie, Salim S

2017-07-15

The renin angiotensin system (RAS) regulates numerous systemic functions and is expressed locally in skeletal tissues. Angiotensin1-7 (Ang1-7) is a beneficial member of the RAS, and the therapeutic effects of a large number of angiotensin receptors blockers (ARBs) are mediated by an Ang1-7-dependent cascade. This study examines whether the reported osteo-preservative effects of losartan are mediated through the angiotensin converting enzyme2 (ACE-2)/Ang1-7/Mas pathway in ovariectomized (OVX) rats. Sham and OVX animals received losartan (10mg/kg/d p.o.) for 6 weeks. A specific Mas receptor blocker (A-779) was delivered via mini-osmotic pumps during the losartan treatment period. Serum and urine bone metabolism biomarker levels were measured. Bone trabecular and cortical morphometry were quantified in distal femurs, whereas mineral contents were estimated in ashed bones, serum and urine. Finally, the expression of RAS components, the receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG) was determined. Losartan significantly improved the elevated bone metabolism marker levels and altered trabecular and cortical structures in OVX animals, and restored normal urinary and skeletal mineral levels. Mas receptor inhibition significantly abolished all osteo-protective effects of losartan and enhanced the deleterious effects of OVX. Losartan enhanced OVX-induced up-regulation of ACE-1, AngII, angiotensin type 1 (AT 1 ) receptor and RANKL expression, and increased ACE-2, Ang1-7, Mas and OPG expression in OVX animals. However, A-779 significantly eradicated the effects of losartan on RAS components and RANKL/OPG expression. Thus, Ang1-7 are involved in the osteo-preservative effects of losartan via Mas receptor, which may add therapeutic value to this well-known antihypertensive agent. Copyright © 2017 Elsevier B.V. All rights reserved.

Glucose dependence of glycogen synthase activity regulation by GSK3 and MEK/ERK inhibitors and angiotensin-(1-7) action on these pathways in cultured human myotubes.

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Montori-Grau, Marta; Tarrats, Núria; Osorio-Conles, Oscar; Orozco, Anna; Serrano-Marco, Lucía; Vázquez-Carrera, Manuel; Gómez-Foix, Anna M

2013-05-01

Glycogen synthase (GS) is activated by glucose/glycogen depletion in skeletal muscle cells, but the contributing signaling pathways, including the chief GS regulator GSK3, have not been fully defined. The MEK/ERK pathway is known to regulate GSK3 and respond to glucose. The aim of this study was to elucidate the GSK3 and MEK/ERK pathway contribution to GS activation by glucose deprivation in cultured human myotubes. Moreover, we tested the glucose-dependence of GSK3 and MEK/ERK effects on GS and angiotensin (1-7) actions on these pathways. We show that glucose deprivation activated GS, but did not change phospho-GS (Ser640/1), GSK3β activity or activity-activating phosphorylation of ERK1/2. We then treated glucose-replete and -depleted cells with SB415286, U0126, LY294 and rapamycin to inhibit GSK3, MEK1/2, PI3K and mTOR, respectively. SB415286 activated GS and decreased the relative phospho-GS (Ser640/1) level, more in glucose-depleted than -replete cells. U0126 activated GS and reduced the phospho-GS (Ser640/1) content significantly in glucose-depleted cells, while GSK3β activity tended to increase. LY294 inactivated GS in glucose-depleted cells only, without affecting relative phospho-GS (Ser640/1) level. Rapamycin had no effect on GS activation. Angiotensin-(1-7) raised phospho-ERK1/2 but not phospho-GSK3β (Ser9) content, while it inactivated GS and increased GS phosphorylation on Ser640/1, in glucose-replete cells. In glucose-depleted cells, angiotensin-(1-7) effects on ERK1/2 and GS were reverted, while relative phospho-GSK3β (Ser9) content decreased. In conclusion, activation of GS by glucose deprivation is not due to GS Ser640/1 dephosphorylation, GSK3β or ERK1/2 regulation in cultured myotubes. However, glucose depletion enhances GS activation/Ser640/1 dephosphorylation due to both GSK3 and MEK/ERK inhibition. Angiotensin-(1-7) inactivates GS in glucose-replete cells in association with ERK1/2 activation, not with GSK3 regulation, and glucose

Dual repressive effect of angiotensin II-type 1 receptor blocker telmisartan on angiotensin II-induced and estradiol-induced uterine leiomyoma cell proliferation.

Science.gov (United States)

Isobe, Aki; Takeda, Takashi; Sakata, Masahiro; Miyake, Asako; Yamamoto, Toshiya; Minekawa, Ryoko; Nishimoto, Fumihito; Oskamoto, Yoko; Walker, Cheryl Lyn; Kimura, Tadashi

2008-02-01

Although uterine leiomyomas or fibroids are the most common gynecological benign tumor and greatly affect reproductive health and well-being, the pathophysiology and epidemiology of uterine leiomyomas are poorly understood. Elevated blood pressure has an independent, positive association with risk for clinically detected uterine leiomyoma. Angiotensin II (Ang II) is a key biological peptide in the renin-angiotensin system that regulates blood pressure. In this study, we investigated the potential role of Ang II (1-1000 nM) in the proliferation of rat ELT-3 leiomyoma cells in vitro. RT-PCR and western blot analysis with cell proliferation and DNA transfection assays were performed to determine the mechanism of action of Ang II. Ang II induced ELT-3 leiomyoma cell proliferation (P estradiol-induced cell proliferation (P < 0.01). AT(1)R, but not AT(2)R, plays a role in Ang II-induced ELT-3 cell proliferation. These experimental findings in vitro highlight the potential role of Ang II in the proliferation of leiomyoma cells.

A novel mechanism of angiotensin II-regulated placental vascular tone in the development of hypertension in preeclampsia.

Science.gov (United States)

Gao, Qinqin; Tang, Jiaqi; Li, Na; Zhou, Xiuwen; Li, Yongmei; Liu, Yanping; Wu, Jue; Yang, Yuxian; Shi, Ruixiu; He, Axin; Li, Xiang; Zhang, Yingying; Chen, Jie; Zhang, Lubo; Sun, Miao; Xu, Zhice

2017-05-09

The present study tested the hypothesis that angiotensin II plays a role in the regulation of placental vascular tone, which contributes to hypertension in preeclampsia. Functional and molecular assays were performed in large and micro placental and non-placental vessels from humans and animals. In human placental vessels, angiotensin II induced vasoconstrictions in 78.7% vessels in 155 tests, as referenced to KCl-induced contractions. In contrast, phenylephrine only produced contractions in 3.0% of 133 tests. In non-placental vessels, phenylephrine induced contractions in 76.0% of 67 tests, whereas angiotensin II failed to produce contractions in 75 tests. Similar results were obtained in animal placental and non-placental vessels. Compared with non-placental vessels, angiotensin II receptors and β-adrenoceptors were significantly increased in placental vessels. Compared to the vessels from normal pregnancy, angiotensin II-induced vasoconstrictions were significantly reduced in preeclamptic placentas, which was associated with a decrease in angiotensin II receptors. In addition, angiotensin II and angiotensin converting enzyme in the maternal-placenta circulation in preeclampsia were increased, whereas angiotensin I and angiotensin1-7 concentrations were unchanged. The study demonstrates a selective effect of angiotensin II in maintaining placental vessel tension, which may play an important role in development of hypertension in preeclampsia.

Angiotensin type 2 receptors

DEFF Research Database (Denmark)

Sumners, Colin; de Kloet, Annette D; Krause, Eric G

2015-01-01

In most situations, the angiotensin AT2-receptor (AT2R) mediates physiological actions opposing those mediated by the AT1-receptor (AT1R), including a vasorelaxant effect. Nevertheless, experimental evidence vastly supports that systemic application of AT2R-agonists is blood pressure neutral...

Purification and characterization of angiotensin-1 converting enzyme

African Journals Online (AJOL)

The Nemopilema nomurai hydrolysate was produced by the reaction of papain, and an angiotensin-Ι converting enzyme (ACE)-inhibitory peptide was purified by ... The infrared (IR), proton nuclear magnetic resonance spectroscopy (1H NMR), carbon nuclear magnetic resonance (13C NMR) and mass spectrometry (MS) ...

Troglitazone stimulates β-arrestin-dependent cardiomyocyte contractility via the angiotensin II type 1A receptor

International Nuclear Information System (INIS)

Tilley, Douglas G.; Nguyen, Anny D.; Rockman, Howard A.

2010-01-01

Peroxisome proliferator-activated receptor γ (PPARγ) agonists are commonly used to treat cardiovascular diseases, and are reported to have several effects on cardiovascular function that may be due to PPARγ-independent signaling events. Select angiotensin receptor blockers (ARBs) interact with and modulate PPARγ activity, thus we hypothesized that a PPARγ agonist may exert physiologic effects via the angiotensin II type 1 A receptor (AT1 A R). In AT1 A R-overexpressing HEK 293 cells, both angiotensin II (Ang II) and the PPARγ agonist troglitazone (Trog) enhanced AT1 A R internalization and recruitment of endogenous β-arrestin1/2 (βarr1/2) to the AT1 A R. A fluorescence assay to measure diacylglycerol (DAG) accumulation showed that although Ang II induced AT1 A R-G q protein-mediated DAG accumulation, Trog had no impact on DAG generation. Trog-mediated recruitment of βarr1/2 was selective to AT1 A R as the response was prevented by an ARB- and Trog-mediated βarr1/2 recruitment to β1-adrenergic receptor (β1AR) was not observed. In isolated mouse cardiomyocytes, Trog increased both % and rate of cell shortening to a similar extent as Ang II, effects which were blocked with an ARB. Additionally, these effects were found to be βarr2-dependent, as cardiomyocytes isolated from βarr2-KO mice showed blunted contractile responses to Trog. These findings show for the first time that the PPARγ agonist Trog acts at the AT1 A R to simultaneously block G q protein activation and induce the recruitment of βarr1/2, which leads to an increase in cardiomyocyte contractility.

Nephrin expression is reduced in human diabetic nephropathy: evidence for a distinct role for glycated albumin and angiotensin II.

Science.gov (United States)

Doublier, Sophie; Salvidio, Gennaro; Lupia, Enrico; Ruotsalainen, Vesa; Verzola, Daniela; Deferrari, Giacomo; Camussi, Giovanni

2003-04-01

We studied the distribution of nephrin in renal biopsies from 17 patients with diabetes and nephrotic syndrome (7 type 1 and 10 type 2 diabetes), 6 patients with diabetes and microalbuminuria (1 type 1 and 5 type 2 diabetes), and 10 normal subjects. Nephrin expression was semiquantitatively evaluated by measuring immunofluorescence intensity by digital image analysis. We found an extensive reduction of nephrin staining in both type 1 (67 +/- 9%; P < 0.001) and type 2 (65 +/- 10%; P < 0.001) diabetic patients with diabetes and nephrotic syndrome when compared with control subjects. The pattern of staining shifted from punctate/linear distribution to granular. In patients with microalbuminuria, the staining pattern of nephrin also showed granular distribution and reduction intensity of 69% in the patient with type 1 diabetes and of 62 +/- 4% (P < 0.001) in the patients with type 2 diabetes. In vitro studies on human cultured podocytes demonstrated that glycated albumin and angiotensin II reduced nephrin expression. Glycated albumin inhibited nephrin synthesis through the engagement of receptor for advanced glycation end products, whereas angiotensin II acted on cytoskeleton redistribution, inducing the shedding of nephrin. This study indicates that the alteration in nephrin expression is an early event in proteinuric patients with diabetes and suggests that glycated albumin and angiotensin II contribute to nephrin downregulation.

Methylation of Promoter Regions of Genes of the Human Intrauterine Renin Angiotensin System and Their Expression

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Shane D. Sykes

2015-01-01

Full Text Available The intrauterine renin angiotensin system (RAS is implicated in placentation and labour onset. Here we investigate whether promoter methylation of RAS genes changes with gestation or labour and if it affects gene expression. Early gestation amnion and placenta were studied, as were term amnion, decidua, and placenta collected before labour (at elective caesarean section or after spontaneous labour and delivery. The expression and degree of methylation of the prorenin receptor (ATP6AP2, angiotensin converting enzyme (ACE, angiotensin II type 1 receptor (AGTR1, and two proteases that can activate prorenin (kallikrein, KLK1, and cathepsin D, CTSD were measured by qPCR and a DNA methylation array. There was no effect of gestation or labour on the methylation of RAS genes and CTSD. Amnion and decidua displayed strong correlations between the percent hypermethylation of RAS genes and CTSD, suggestive of global methylation. There were no correlations between the degree of methylation and mRNA abundance of any genes studied. KLK1 was the most methylated gene and the proportion of hypermethylated KLK1 alleles was lower in placenta than decidua. The presence of intermediate methylated alleles of KLK1 in early gestation placenta and in amnion after labour suggests that KLK1 methylation is uniquely dynamic in these tissues.

Effect of the AT1-receptor antagonists losartan, irbesartan, and telmisartan on angiotensin II-induced facilitation of sympathetic neurotransmission in the rat mesenteric artery

NARCIS (Netherlands)

Balt, J. C.; Mathy, M. J.; Nap, A.; Pfaffendorf, M.; van Zwieten, P. A.

2001-01-01

SUMMARY: The effect of the AT1-receptor antagonists losartan, irbesartan, and telmisartan on angiotensin II (Ang II)-induced facilitation of noradrenergic neurotransmission was investigated in the isolated rat mesenteric artery under isometric conditions. Electrical field stimulation (2, 4, and 8

Expression of Angiotensin II Types 1 and 2 Receptors in Endometriotic Lesions.

Science.gov (United States)

Nakao, Takehiro; Chishima, Fumihisa; Sugitani, Masahiko; Tsujimura, Ryusuke; Hayashi, Chuyu; Yamamoto, Tatsuo

2017-01-01

The aim of this study was to evaluate the gene and protein expression of angiotensin type (AT) 1, AT2 receptors in endometriotic lesions and its relation to prostaglandin (PG) synthases. Endometriosis samples were obtained from 32 patients with endometriotic cysts. Endometrial tissues were obtained during operations for benign gynecological conditions. The expression of the AT1 and AT2 receptor mRNA and that of PG-endoperoxide synthase 2 and microsomal PGE2 synthase-1 (mPGES-1) was examined by quantitative RT-PCR. Immunohistochemical staining was performed for these receptors. AT1 and AT2 receptor proteins were mostly located in endometrial glandular epithelium and some stromal cells. Immunoreactivity of the receptor proteins was observed in both the eutopic endometrium and endometriotic lesions. The AT1/AT2 ratio in endometriotic cysts (median 7.29, range 1.88-187.60) was significantly increased compared with that in the eutopic endometrium in the proliferative-phase in controls (median 1.01, range 0.37-2.09, p < 0.001). There was a relationship between the AT1 mRNA expression and that of mPGES-1 mRNA in the endometriotic cysts (r = 0.394089, p < 0.05). There was a significant relationship between the mRNA expression of the AT2 receptor and that of mPGES-1 in eutopic endometrium of non-endometriotic control (r = 0.610714, p < 0.05). Renin-angiotensin system may play an important role in the pathophysiology of endometriosis. © 2016 S. Karger AG, Basel.

Blockade of AT1 type receptors for angiotensin II prevents cardiac microvascular fibrosis induced by chronic stress in Sprague-Dawley rats.

Science.gov (United States)

Firoozmand, Lília Taddeo; Sanches, Andrea; Damaceno-Rodrigues, Nilsa Regina; Perez, Juliana Dinéia; Aragão, Danielle Sanches; Rosa, Rodolfo Mattar; Marcondes, Fernanda Klein; Casarini, Dulce Elena; Caldini, Elia Garcia; Cunha, Tatiana Sousa

2018-04-20

To test the effects of chronic-stress on the cardiovascular system, the model of chronic mild unpredictable stress (CMS) has been widely used. The CMS protocol consists of the random, intermittent, and unpredictable exposure of laboratory animals to a variety of stressors, during 3 consecutive weeks. In this study, we tested the hypothesis that exposure to the CMS protocol leads to left ventricle microcirculatory remodeling that can be attenuated by angiotensin II receptor blockade. Male Sprague-Dawley rats were randomly assigned into four groups: Control, Stress, Control + losartan, and Stress + losartan (N = 6, each group, losartan: 20 mg/kg/day). The rats were euthanized 15 days after CMS exposure, and blood samples and left ventricle were collected. Rats submitted to CMS presented increased glycemia, corticosterone, noradrenaline and adrenaline concentration, and losartan reduced the concentration of the circulating amines. Cardiac angiotensin II, measured by high-performance liquid chromatography (HPLC), was significantly increased in the CMS group, and losartan treatment reduced it, while angiotensin 1-7 was significantly higher in the CMS losartan-treated group as compared with CMS. Histological analysis, verified by transmission electron microscopy, showed that rats exposed to CMS presented increased perivascular collagen and losartan effectively prevented the development of this process. Hence, CMS induced a state of microvascular disease, with increased perivascular collagen deposition, that may be the trigger for further development of cardiovascular disease. In this case, CMS fibrosis is associated with increased production of catecholamines and with a disruption of renin-angiotensin system balance, which can be prevented by angiotensin II receptor blockade.

C4d-negative antibody-mediated rejection with high anti-angiotensin II type I receptor antibodies in absence of donor-specific antibodies.

Science.gov (United States)

Fuss, Alexander; Hope, Christopher M; Deayton, Susan; Bennett, Greg Donald; Holdsworth, Rhonda; Carroll, Robert P; Coates, P Toby H

2015-07-01

Acute antibody-mediated rejection can occur in absence of circulating donor-specific antibodies. Agonistic antibodies targeting the anti-angiotensin II type 1 receptor (anti-AT1 R) are emerging as important non-human leucocyte antigen (HLA) antibodies. Elevated levels of anti-angiotensin II receptor antibodies were first observed in kidney transplant recipients with malignant hypertension and allograft rejection. They have now been studied in three separate kidney transplant populations and associate to frequency of rejection, severity of rejection and graft failure. We report 11 cases of biopsy-proven, Complement 4 fragment d (C4d)-negative, acute rejection occurring without circulating donor-specific anti-HLA antibodies. In eight cases, anti-angiotensin receptor antibodies were retrospectively examined. The remaining three subjects were identified from our centre's newly instituted routine anti-angiotensin receptor antibody screening. All subjects fulfilled Banff 2013 criteria for antibody-mediated rejection and all responded to anti-rejection therapy, which included plasma exchange and angiotensin receptor blocker therapy. These cases support the routine assessment of anti-AT1 R antibodies in kidney transplant recipients to identify subjects at risk. Further studies will need to determine optimal assessment protocol and the effectiveness of pre-emptive treatment with angiotensin receptor blockers. © 2015 Asian Pacific Society of Nephrology.

High-fat diet amplifies renal renin angiotensin system expression, blood pressure elevation, and renal dysfunction caused by Ceacam1 null deletion.

Science.gov (United States)

Li, Caixia; Culver, Silas A; Quadri, Syed; Ledford, Kelly L; Al-Share, Qusai Y; Ghadieh, Hilda E; Najjar, Sonia M; Siragy, Helmy M

2015-11-01

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAMl), a substrate of the insulin receptor tyrosine kinase, regulates insulin action by promoting insulin clearance. Global null mutation of Ceacam1 gene (Cc1(-/-)) results in features of the metabolic syndrome, including insulin resistance, hyperinsulinemia, visceral adiposity, elevated blood pressure, and albuminuria. It also causes activation of the renal renin-angiotensin system (RAS). In the current study, we tested the hypothesis that high-fat diet enhances the expression of RAS components. Three-month-old wild-type (Cc1(+/+)) and Cc1(-/-) mice were fed either a regular or a high-fat diet for 8 wk. At baseline under regular feeding conditions, Cc1(-/-) mice exhibited higher blood pressure, urine albumin-to-creatinine ratio (UACR), and renal expression of angiotensinogen, renin/prorenin, angiotensin-converting enzyme, (pro)renin receptor, angiotensin subtype AT1 receptor, angiotensin II, and elevated PI3K phosphorylation, as detected by p85α (Tyr(508)) immunostaining, inflammatory response, and the expression of collagen I and collagen III. In Cc1(+/+) mice, high-fat diet increased blood pressure, UACR, the expression of angiotensin-converting enzyme and angiotensin II, PI3K phosphorylation, inflammatory response, and the expression of collagen I and collagen III. In Cc1(-/-) mice, high-fat intake further amplified these parameters. Immunohistochemical staining showed increased p-PI3K p85α (Tyr(508)) expression in renal glomeruli, proximal, distal, and collecting tubules of Cc1(-/-) mice fed a high-fat diet. Together, this demonstrates that high-fat diet amplifies the permissive effect of Ceacam1 deletion on renal expression of all RAS components, PI3K phosphorylation, inflammation, and fibrosis. Copyright © 2015 the American Physiological Society.

Angiotensin II for the Treatment of Vasodilatory Shock.

Science.gov (United States)

Khanna, Ashish; English, Shane W; Wang, Xueyuan S; Ham, Kealy; Tumlin, James; Szerlip, Harold; Busse, Laurence W; Altaweel, Laith; Albertson, Timothy E; Mackey, Caleb; McCurdy, Michael T; Boldt, David W; Chock, Stefan; Young, Paul J; Krell, Kenneth; Wunderink, Richard G; Ostermann, Marlies; Murugan, Raghavan; Gong, Michelle N; Panwar, Rakshit; Hästbacka, Johanna; Favory, Raphael; Venkatesh, Balasubramanian; Thompson, B Taylor; Bellomo, Rinaldo; Jensen, Jeffrey; Kroll, Stew; Chawla, Lakhmir S; Tidmarsh, George F; Deane, Adam M

2017-08-03

Vasodilatory shock that does not respond to high-dose vasopressors is associated with high mortality. We investigated the effectiveness of angiotensin II for the treatment of patients with this condition. We randomly assigned patients with vasodilatory shock who were receiving more than 0.2 μg of norepinephrine per kilogram of body weight per minute or the equivalent dose of another vasopressor to receive infusions of either angiotensin II or placebo. The primary end point was a response with respect to mean arterial pressure at hour 3 after the start of infusion, with response defined as an increase from baseline of at least 10 mm Hg or an increase to at least 75 mm Hg, without an increase in the dose of background vasopressors. A total of 344 patients were assigned to one of the two regimens; 321 received a study intervention (163 received angiotensin II, and 158 received placebo) and were included in the analysis. The primary end point was reached by more patients in the angiotensin II group (114 of 163 patients, 69.9%) than in the placebo group (37 of 158 patients, 23.4%) (odds ratio, 7.95; 95% confidence interval [CI], 4.76 to 13.3; Pthe mean improvement in the cardiovascular Sequential Organ Failure Assessment (SOFA) score (scores range from 0 to 4, with higher scores indicating more severe dysfunction) was greater in the angiotensin II group than in the placebo group (-1.75 vs. -1.28, P=0.01). Serious adverse events were reported in 60.7% of the patients in the angiotensin II group and in 67.1% in the placebo group. Death by day 28 occurred in 75 of 163 patients (46%) in the angiotensin II group and in 85 of 158 patients (54%) in the placebo group (hazard ratio, 0.78; 95% CI, 0.57 to 1.07; P=0.12). Angiotensin II effectively increased blood pressure in patients with vasodilatory shock that did not respond to high doses of conventional vasopressors. (Funded by La Jolla Pharmaceutical Company; ATHOS-3 ClinicalTrials.gov number, NCT02338843 .).

Imidazole derivatives as angiotensin II AT1 receptor blockers: Benchmarks, drug-like calculations and quantitative structure-activity relationships modeling

Science.gov (United States)

Alloui, Mebarka; Belaidi, Salah; Othmani, Hasna; Jaidane, Nejm-Eddine; Hochlaf, Majdi

2018-03-01

We performed benchmark studies on the molecular geometry, electron properties and vibrational analysis of imidazole using semi-empirical, density functional theory and post Hartree-Fock methods. These studies validated the use of AM1 for the treatment of larger systems. Then, we treated the structural, physical and chemical relationships for a series of imidazole derivatives acting as angiotensin II AT1 receptor blockers using AM1. QSAR studies were done for these imidazole derivatives using a combination of various physicochemical descriptors. A multiple linear regression procedure was used to design the relationships between molecular descriptor and the activity of imidazole derivatives. Results validate the derived QSAR model.

Comparative biochemistry of renins and angiotensins in the vertebrates.

Science.gov (United States)

Nakajima, T; Khosla, M C; Sakakibara, S

1978-09-01

Comparative biochemistry of renins and angiotensins was discussed. Renin extracted from hog kidney was different from that from mouse submaxillary glands in immunoreactivity and carbohydrate content. Rat kidney renin was also different from hog kidney renin in the amino acid composition. The presence of big and big-big renins was pointed out immunochemically. These big renins were considered to be precursors of kidney renin. Angiotensins in mammalian and nonmammalian species produced by renal or extrarenal renin have been differentiated by some biochemical and pharmacological criteria. Some of these angiotensins were analyzed sequentially. The replacements of amino acid residues at positions 1, 5, and/or 9 of angiotensin I have been demonstrated in nonmammalian species. Specific pressor activities have been determined using synthetic angiotensins by a 4 point assay in rat. Specific pressor activities of various angiotensins were obtained from the dose-blood pressure-response curves using a single angiotensin sample per assay rat.

Activity of angiotensin-converting enzyme and risk of severe hypoglycaemia in type 1 diabetes mellitus

DEFF Research Database (Denmark)

Pedersen-Bjergaard, U; Agerholm-Larsen, Birgit; Pramming, S

2001-01-01

BACKGROUND: The insertion (I) allele of the angiotensin-converting-enzyme (ACE) gene occurs at increased frequency in endurance athletes. This association suggests that low ACE activity is favourable for performance in conditions with limited substrate availability. Such conditions occur in endur......BACKGROUND: The insertion (I) allele of the angiotensin-converting-enzyme (ACE) gene occurs at increased frequency in endurance athletes. This association suggests that low ACE activity is favourable for performance in conditions with limited substrate availability. Such conditions occur...... by diabetes history, degree of hypoglycaemia awareness, measurement of C-peptide, haemoglobin A(1c), and serum ACE concentrations, and determination of ACE genotype. FINDINGS: Patients with the DD genotype had a relative risk of severe hypoglycaemia in the preceding 2 years of 3.2 (95% CI 1.4-7.4) compared...

Induction of human adiponectin gene transcription by telmisartan, angiotensin receptor blocker, independently on PPAR-γ activation

International Nuclear Information System (INIS)

Moriuchi, Akie; Yamasaki, Hironori; Shimamura, Mika; Kita, Atsushi; Kuwahara, Hironaga; Fujishima, Keiichiro; Satoh, Tsuyoshi; Fukushima, Keiko; Fukushima, Tetsuya; Hayakawa, Takao; Mizuguchi, Hiroyuki; Nagayama, Yuji; Abiru, Norio; Kawasaki, Eiji; Eguchi, Katsumi

2007-01-01

Adiponectin, an adipose tissue-specific plasma protein, has been shown to ameliorate insulin resistance and inhibit the process of atherosclerosis. Recently, several reports have stated that angiotensin type 1 receptor blockers (ARBs), increase adiponectin plasma level, and ameliorate insulin resistance. Telmisartan, a subclass of ARBs, has been shown to be a partial agonist of the peroxisome proliferator-activated receptor (PPAR)-γ, and to increase the plasma adiponectin level. However, the transcriptional regulation of the human adiponectin gene by telmisartan has not been determined yet. To elucidate the effect of telmisartan on adiponectin, the stimulatory regulation of human adiponectin gene by telmisartan was investigated in 3T3-L1 adipocytes, utilizing adenovirus-mediated luciferase reporter gene-transferring technique. This study indicates that telmisartan may stimulate adiponectin transcription independent of PPAR-γ

Free Fatty Acids Activate Renin-Angiotensin System in 3T3-L1 Adipocytes through Nuclear Factor-kappa B Pathway

Directory of Open Access Journals (Sweden)

Jia Sun

2016-01-01

Full Text Available The activity of a local renin-angiotensin system (RAS in the adipose tissue is closely associated with obesity-related diseases. However, the mechanism of RAS activation in adipose tissue is still unknown. In the current study, we found that palmitic acid (PA, one kind of free fatty acid, induced the activity of RAS in 3T3-L1 adipocytes. In the presence of fetuin A (Fet A, PA upregulated the expression of angiotensinogen (AGT and angiotensin type 1 receptor (AT1R and stimulated the secretion of angiotensin II (ANG II in 3T3-L1 adipocytes. Moreover, the activation of RAS in 3T3-L1 adipocytes was blocked when we blocked Toll-like receptor 4 (TLR4 signaling pathway using TAK242 or NF-κB signaling pathway using BAY117082. Together, our results have identified critical molecular mechanisms linking PA/TLR4/NF-κB signaling pathway to the activity of the local renin-angiotensin system in adipose tissue.

Glucocorticoid effects on the programming of AT1b angiotensin receptor gene methylation and expression in the rat.

Directory of Open Access Journals (Sweden)

Irina Bogdarina

2010-02-01

Full Text Available Adverse events in pregnancy may 'programme' offspring for the later development of cardiovascular disease and hypertension. Previously, using a rodent model of programmed hypertension we have demonstrated the role of the renin-angiotensin system in this process. More recently we showed that a maternal low protein diet resulted in undermethylation of the At1b angiotensin receptor promoter and the early overexpression of this gene in the adrenal of offspring. Here, we investigate the hypothesis that maternal glucocorticoid modulates this effect on fetal DNA methylation and gene expression. We investigated whether treatment of rat dams with the 11beta-hydroxylase inhibitor metyrapone, could prevent the epigenetic and gene expression changes we observed. Offspring of mothers subjected to a low protein diet in pregnancy showed reduced adrenal Agtr1b methylation and increased adrenal gene expression as we observed previously. Treatment of mothers with metyrapone for the first 14 days of pregnancy reversed these changes and prevented the appearance of hypertension in the offspring at 4 weeks of age. As a control for non-specific effects of programmed hypertension we studied offspring of mothers treated with dexamethasone from day 15 of pregnancy and showed that, whilst they had raised blood pressure, they failed to show any evidence of Agtr1b methylation or increase in gene expression. We conclude that maternal glucocorticoid in early pregnancy may induce changes in methylation and expression of the Agtr1b gene as these are clearly reversed by an 11 beta-hydroxylase inhibitor. However in later pregnancy a converse effect with dexamethasone could not be demonstrated and this may reflect either an alternative mechanism of this glucocorticoid or a stage-specific influence.

Anthology of the renin-angiotensin system: a one hundred reference approach to angiotensin II antagonists.

Science.gov (United States)

Ménard, J

1993-04-01

To provide a historical overview of the renin-angiotensin system as a guide to the introduction of a new therapeutic pathway, non-peptide inhibition of a angiotensin II. One hundred references were selected as a personal preference, for their originality or for their potential impact on medicine. This review raises the following questions for future research. (1) Will the long-term cardiovascular effects of angiotensin converting enzyme (ACE) inhibition, angiotensin II antagonism and renin inhibition be similar or not, and dependent or independent of blood pressure levels? (2) What are the local-regional interactions between vasoconstrictor and vasodilator systems, and does the renin-angiotensin system synchronize these regional hemodynamic regulatory mechanisms? (3) If hypertension is the result of an interaction between genetic and environmental factors, do proteins secreted through constitutive pathways contribute to the genetic abnormality (prorenin, angiotensinogen, ACE) while regulated secretion (renin) and other regulatory mechanisms (angiotensin II receptors) provide biological support for the environmental effects?

The Angiotensin AT₂ Receptor

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Unger, Thomas; Steckelings, Ulrike M.; Dzau, Victor J.

2015-01-01

Since its discovery, 25 years ago, the angiotensin AT2 receptor (AT2R) has puzzled the scientific community because of its distinct -localization, regulation, signaling pathways, and biological effects separating it clearly from the classical features of the renin...... programs that can counterbalance pathological processes and enable recovery from disease. The AT2R has thus mutated from an "-enigmatic" receptor to a significant member of the "protective arm" of the RAS. The recent development of novel, small molecule- and peptide-derived AT2

Kinetic and structural characterization of amyloid-β peptide hydrolysis by human angiotensin-1-converting enzyme.

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Larmuth, Kate M; Masuyer, Geoffrey; Douglas, Ross G; Schwager, Sylva L; Acharya, K Ravi; Sturrock, Edward D

2016-03-01

Angiotensin-1-converting enzyme (ACE), a zinc metallopeptidase, consists of two homologous catalytic domains (N and C) with different substrate specificities. Here we report kinetic parameters of five different forms of human ACE with various amyloid beta (Aβ) substrates together with high resolution crystal structures of the N-domain in complex with Aβ fragments. For the physiological Aβ(1-16) peptide, a novel ACE cleavage site was found at His14-Gln15. Furthermore, Aβ(1-16) was preferentially cleaved by the individual N-domain; however, the presence of an inactive C-domain in full-length somatic ACE (sACE) greatly reduced enzyme activity and affected apparent selectivity. Two fluorogenic substrates, Aβ(4-10)Q and Aβ(4-10)Y, underwent endoproteolytic cleavage at the Asp7-Ser8 bond with all ACE constructs showing greater catalytic efficiency for Aβ(4-10)Y. Surprisingly, in contrast to Aβ(1-16) and Aβ(4-10)Q, sACE showed positive domain cooperativity and the double C-domain (CC-sACE) construct no cooperativity towards Aβ(4-10)Y. The structures of the Aβ peptide-ACE complexes revealed a common mode of peptide binding for both domains which principally targets the C-terminal P2' position to the S2' pocket and recognizes the main chain of the P1' peptide. It is likely that N-domain selectivity for the amyloid peptide is conferred through the N-domain specific S2' residue Thr358. Additionally, the N-domain can accommodate larger substrates through movement of the N-terminal helices, as suggested by the disorder of the hinge region in the crystal structures. Our findings are important for the design of domain selective inhibitors as the differences in domain selectivity are more pronounced with the truncated domains compared to the more physiological full-length forms. The atomic coordinates and structure factors for N-domain ACE with Aβ peptides 4-10 (5AM8), 10-16 (5AM9), 1-16 (5AMA), 35-42 (5AMB) and (4-10)Y (5AMC) complexes have been deposited in the

Reduced plasma levels of angiotensin-(1-7 and renin activity in preeclamptic patients are associated with the angiotensin I- converting enzyme deletion/deletion genotype

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E.P. Velloso

2007-04-01

Full Text Available The relationship between preeclampsia and the renin-angiotensin system (RAS is poorly understood. Angiotensin I-converting enzyme (ACE is a key RAS component and plays an important role in blood pressure homeostasis by generating angiotensin II (Ang II and inactivating the vasodilator angiotensin-(1-7 (Ang-(1-7. ACE (I/D polymorphism is characterized by the insertion (I or deletion (D of a 287-bp fragment, leading to changes in ACE activity. In the present study, ACE (I/D polymorphism was correlated with plasma Ang-(1-7 levels and several RAS components in both preeclamptic (N = 20 and normotensive pregnant women (N = 20. The percentage of the ACE DD genotype (60% in the preeclamptic group was higher than that for the control group (35%; however, this percentage was not statistically significant (Fisher exact test = 2.86, d.f. = 2, P = 0.260. The highest plasma ACE activity was observed in the ACE DD preeclamptic women (58.1 ± 5.06 vs 27.6 ± 3.25 nmol Hip-His Leu-1 min-1 mL-1 in DD control patients; P = 0.0005. Plasma renin activity was markedly reduced in preeclampsia (0.81 ± 0.2 vs 3.43 ± 0.8 ng Ang I mL plasma-1 h-1 in DD normotensive patients; P = 0.0012. A reduced plasma level of Ang-(1-7 was also observed in preeclamptic women (15.6 ± 1.3 vs 22.7 ± 2.5 pg/mL in the DD control group; P = 0.0146. In contrast, plasma Ang II levels were unchanged in preeclamptic patients. The selective changes in the RAS described in the present study suggest that the ACE DD genotype may be used as a marker for susceptibility to preeclampsia.

Reduced plasma levels of angiotensin-(1-7 and renin activity in preeclamptic patients are associated with the angiotensin I- converting enzyme deletion/deletion genotype

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E.P. Velloso

Full Text Available The relationship between preeclampsia and the renin-angiotensin system (RAS is poorly understood. Angiotensin I-converting enzyme (ACE is a key RAS component and plays an important role in blood pressure homeostasis by generating angiotensin II (Ang II and inactivating the vasodilator angiotensin-(1-7 (Ang-(1-7. ACE (I/D polymorphism is characterized by the insertion (I or deletion (D of a 287-bp fragment, leading to changes in ACE activity. In the present study, ACE (I/D polymorphism was correlated with plasma Ang-(1-7 levels and several RAS components in both preeclamptic (N = 20 and normotensive pregnant women (N = 20. The percentage of the ACE DD genotype (60% in the preeclamptic group was higher than that for the control group (35%; however, this percentage was not statistically significant (Fisher exact test = 2.86, d.f. = 2, P = 0.260. The highest plasma ACE activity was observed in the ACE DD preeclamptic women (58.1 ± 5.06 vs 27.6 ± 3.25 nmol Hip-His Leu-1 min-1 mL-1 in DD control patients; P = 0.0005. Plasma renin activity was markedly reduced in preeclampsia (0.81 ± 0.2 vs 3.43 ± 0.8 ng Ang I mL plasma-1 h-1 in DD normotensive patients; P = 0.0012. A reduced plasma level of Ang-(1-7 was also observed in preeclamptic women (15.6 ± 1.3 vs 22.7 ± 2.5 pg/mL in the DD control group; P = 0.0146. In contrast, plasma Ang II levels were unchanged in preeclamptic patients. The selective changes in the RAS described in the present study suggest that the ACE DD genotype may be used as a marker for susceptibility to preeclampsia.

Severe hypoglycaemia during pregnancy in women with type 1 diabetes: possible role of renin-angiotensin system activity?

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Nielsen, L Ringholm; Pedersen-Bjergaard, U; Thorsteinsson, B

2009-01-01

AIMS: To investigate whether increased risk of severe hypoglycaemia in early pregnancy is related to pregnancy-induced changes in renin-angiotensin system (RAS) activity in women with type 1 diabetes (T1DM). METHODS: Severe hypoglycaemic events the year preceding pregnancy were recorded...... retrospectively in 107 consecutive pregnant women with T1DM. Events during pregnancy were recorded prospectively. Measurements of ACE, renin and angiotensinogen were determined at 8, 14, 21, 27 and 33 weeks and postpartum. RESULTS: The rate of severe hypoglycaemia was 1.1 and 5.3 events/patient-year the year...... preceding pregnancy and postpartum ACE activity (relative rate of severe hypoglycaemia above versus below median ACE activity: 4.4 (CI: 1.7-11.9), p=0.003). No association was found between severe hypoglycaemia during pregnancy and renin angiotensin system activity at 8 weeks. CONCLUSIONS: In early...

Central administration of angiotensin IV rapidly enhances novel object recognition among mice.

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Paris, Jason J; Eans, Shainnel O; Mizrachi, Elisa; Reilley, Kate J; Ganno, Michelle L; McLaughlin, Jay P

2013-07-01

Angiotensin IV (Val(1)-Tyr(2)-Ile(3)-His(4)-Pro(5)-Phe(6)) has demonstrated potential cognitive-enhancing effects. The present investigation assessed and characterized: (1) dose-dependency of angiotensin IV's cognitive enhancement in a C57BL/6J mouse model of novel object recognition, (2) the time-course for these effects, (3) the identity of residues in the hexapeptide important to these effects and (4) the necessity of actions at angiotensin IV receptors for procognitive activity. Assessment of C57BL/6J mice in a novel object recognition task demonstrated that prior administration of angiotensin IV (0.1, 1.0, or 10.0, but not 0.01 nmol, i.c.v.) significantly enhanced novel object recognition in a dose-dependent manner. These effects were time dependent, with improved novel object recognition observed when angiotensin IV (0.1 nmol, i.c.v.) was administered 10 or 20, but not 30 min prior to the onset of the novel object recognition testing. An alanine scan of the angiotensin IV peptide revealed that replacement of the Val(1), Ile(3), His(4), or Phe(6) residues with Ala attenuated peptide-induced improvements in novel object recognition, whereas Tyr(2) or Pro(5) replacement did not significantly affect performance. Administration of the angiotensin IV receptor antagonist, divalinal-Ang IV (20 nmol, i.c.v.), reduced (but did not abolish) novel object recognition; however, this antagonist completely blocked the procognitive effects of angiotensin IV (0.1 nmol, i.c.v.) in this task. Rotorod testing demonstrated no locomotor effects with any angiotensin IV or divalinal-Ang IV dose tested. These data demonstrate that angiotensin IV produces a rapid enhancement of associative learning and memory performance in a mouse model that was dependent on the angiotensin IV receptor. Copyright © 2013 Elsevier Ltd. All rights reserved.

Angiotensin-converting enzyme activity and cognitive impairment during hypoglycaemia in healthy humans

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Pedersen-Bjergaard, Ulrik; Thomsen, Carsten E; Høgenhaven, Hans

2008-01-01

INTRODUCTION: In type 1 diabetes increased risk of severe hypoglycaemia is associated with high angiotensin-converting enzyme (ACE) activity. We tested in healthy humans the hypothesis that this association is explained by the reduced ability of subjects with high ACE activity to maintain normal...... cognitive function during hypoglycaemia. METHODS: Sixteen healthy volunteers selected by either particularly high or low serum ACE activity were subjected to hypoglycaemia (plasma glucose 2.7 mmol/L). Cognitive function was assessed by choice reaction tests. RESULTS: Despite a similar hypoglycaemic stimulus...... in the two groups, only the group with high ACE activity showed significant deterioration in cognitive performance during hypoglycaemia. In the high ACE group mean reaction time (MRT) in the most complex choice reaction task was prolonged and error rate (ER) was increased in contrast to the low ACE group...

Association of Angiotensin-Converting Enzyme Intron 16 Insertion/Deletion and Angiotensin II Type 1 Receptor A1166C Gene Polymorphisms with Preeclampsia in South East of Iran

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Saeedeh Salimi

2011-01-01

Full Text Available Some evidence suggests that a variety of genetic factors contributed in pathogenesis of the preeclampsia. The aim of this study was to assess the association between the angiotensin-converting enzyme (ACE I/D and angiotensin II type1 receptor A1166C polymorphisms with preeclampsia. This study was performed in 125 preeclamptic pregnant women and 132 controls. The I/D Polymorphism of the ACE gene was assessed by polymerase chain reaction and the A1166C Polymorphism of the AT1R gene was determined by restriction fragment length polymorphism. The genotype and allele frequencies of I/D polymorphism differed between two groups. The risk of preeclampsia was 3.2-fold in pregnant women with D allele (OR, 3.2 [95% CI, 1.1 to 3.8]; P=0.01. The distribution of the AT1R gene A1166C polymorphism was similar in affected and control groups. Our results supported that presence of the I/D polymorphism of ACE gene is a marker for the increased risk of preeclampsia.

Radioimmunoassay - renin - angiotensin. Principles of radioimmunoassay and their application in measuring renin and angiotensin

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Krause, D K; Hummerich, W; Poulsen, K [eds.

1978-01-01

Typical pitfalls such as impurity of 'standard', tracer damage, crossreactivity of antiserum, unspecific binding of protecting proteins, blank effects with negative results, charcoal stripping, invisible coprecipitate or uncertainty in the analysis of the calibration curve (graph, logit-log, polynormal or spline function) can occur in any type of radioimmunoassay; they are detailed in the general part of this book. The special position occupied by radioimmunological quantification of parameters of the renin-angiotensin system creates additional, even more serious problems. While the radioimmunological determination of the decapeptide angiotensin I no longer causes major obstacles, measurement of the biologically active octapeptide angiotensin II is still only possible in a few centers. The (indirect) determination of plasma renin is characterized by a situation where the enzyme renin may be clearly defined in theory as a specific 10-11-leucine-leucine-endopeptidase cleaving only a decapeptide, but the actual renin assay, however, measures various forms of renin and other angiotensin-forming (or angiotensin-destroying) enzymes at the same time.

Autonomic, locomotor and cardiac abnormalities in a mouse model of muscular dystrophy: targeting the renin-angiotensin system.

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Sabharwal, Rasna; Chapleau, Mark W

2014-04-01

New Findings What is the topic of this review? This symposium report summarizes autonomic, cardiac and skeletal muscle abnormalities in sarcoglycan-δ-deficient mice (Sgcd-/-), a mouse model of limb girdle muscular dystrophy, with emphasis on the roles of autonomic dysregulation and activation of the renin-angiotensin system at a young age. What advances does it highlight? The contributions of the autonomic nervous system and the renin-angiotensin system to the pathogenesis of muscular dystrophy are highlighted. Results demonstrate that autonomic dysregulation precedes and predicts later development of cardiac dysfunction in Sgcd-/- mice and that treatment of young Sgcd-/- mice with the angiotensin type 1 receptor antagonist losartan or with angiotensin-(1-7) abrogates the autonomic dysregulation, attenuates skeletal muscle pathology and increases spontaneous locomotor activity. Muscular dystrophies are a heterogeneous group of genetic muscle diseases characterized by muscle weakness and atrophy. Mutations in sarcoglycans and other subunits of the dystrophin-glycoprotein complex cause muscular dystrophy and dilated cardiomyopathy in animals and humans. Aberrant autonomic signalling is recognized in a variety of neuromuscular disorders. We hypothesized that activation of the renin-angiotensin system contributes to skeletal muscle and autonomic dysfunction in mice deficient in the sarcoglycan-δ (Sgcd) gene at a young age and that this early autonomic dysfunction contributes to the later development of left ventricular (LV) dysfunction and increased mortality. We demonstrated that young Sgcd-/- mice exhibit histopathological features of skeletal muscle dystrophy, decreased locomotor activity and severe autonomic dysregulation, but normal LV function. Autonomic regulation continued to deteriorate in Sgcd-/- mice with age and was accompanied by LV dysfunction and dilated cardiomyopathy at older ages. Autonomic dysregulation at a young age predicted later development of

Severe hypoglycaemia in type 1 diabetes: impact of the renin-angiotensin system and other risk factors

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Pedersen-Bjergaard, Ulrik

2009-01-01

this thesis was conducted to assess the significance of severe hypoglycaemia as a clinical problem in the type 1 diabetic population, to evaluate the impact of known risk factors on occurrence of severe hypoglycaemia, and to identify new markers that could contribute to improved prediction of, and inspire...... targets and thereby open for prevention of severe hypoglycaemia. Furthermore, subjects with elevated renin-angiotensin system activity and a high rate of severe hypoglycaemia might benefit from pharmacological blockade of the renin-angiotensin system by ACE inhibitors or angiotensin II receptor blockers...

Discovery of novel, potent and low-toxicity angiotensin II receptor type 1 (AT1) blockers: Design, synthesis and biological evaluation of 6-substituted aminocarbonyl benzimidazoles with a chiral center.

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Han, Xiao-Feng; He, Xing; Wang, Miao; Xu, Di; Hao, Li-Ping; Liang, Ai-Hua; Zhang, Jun; Zhou, Zhi-Ming

2015-10-20

Novel angiotensin II receptor type 1 (AT1) blockers bearing 6-substituted carbamoyl benzimidazoles with a chiral center were designed and synthesized as the first step to develop new antihypertensive agents and understand their pharmacodynamic and pharmacokinetic properties. The newly synthesized compounds were tested for their potential ability to displace [(125)I] Sar(1) Ile(8)-Ang II, which was specifically bound to human AT1 receptor. Radioligand binding assays revealed nanomolar affinity in several compounds under study. The IC50 values of nine ligands were higher than those of Losartan. The screening of decreased blood pressure in spontaneous hypertensive rats displayed that compound 8S (IC₅₀ = 5.0 nM) was equipotent with Losartan, whereas compounds 13R (IC₅₀ = 7.3 nM), 14R (IC₅₀ = 6.3 nM), and 14S (IC₅₀ = 3.5 nM) were slightly ahead of Losartan, and the most significant activity was demonstrated by compound 8R (IC₅₀ = 1.1 nM). Candidate 8R was identified for its excellent efficacy in antihypertension and fairly low toxicity based on plasma analyses, toxicology studies, and chronic oral tests. Finally, compound 8R exhibited strong and multiple interactions with target active sites of the theoretical AT1 receptor model in docking study. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Attenuation of the pressor response to exogenous angiotensin by angiotensin receptor blockers and benazepril hydrochloride in clinically normal cats.

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Jenkins, Tiffany L; Coleman, Amanda E; Schmiedt, Chad W; Brown, Scott A

2015-09-01

To compare the attenuation of the angiotensin I-induced blood pressure response by once-daily oral administration of various doses of angiotensin receptor blockers (irbesartan, telmisartan, and losartan), benazepril hydrochloride, or lactose monohydrate (placebo) for 8 days in clinically normal cats. 6 healthy cats (approx 17 months old) with surgically implanted arterial telemetric blood pressure-measuring catheters. Cats were administered orally the placebo or each of the drug treatments (benazepril [2.5 mg/cat], irbesartan [6 and 10 mg/kg], telmisartan [0.5, 1, and 3 mg/kg], and losartan [2.5 mg/kg]) once daily for 8 days in a crossover study. Approximately 90 minutes after capsule administration on day 8, each cat was anesthetized and arterial blood pressure measurements were recorded before and after IV administration of each of 4 boluses of angiotensin I (20, 100, 500, and 1,000 ng/kg). This protocol was repeated 24 hours after benazepril treatment and telmisartan (3 mg/kg) treatment. Differences in the angiotensin I-induced change in systolic arterial blood pressure (ΔSBP) among treatments were determined. At 90 minutes after capsule administration, only losartan did not significantly reduce ΔSBP in response to the 3 higher angiotensin doses, compared with placebo. Among drug treatments, telmisartan (3 mg/kg dosage) attenuated ΔSBP to a significantly greater degree than benazepril and all other treatments. At 24 hours, telmisartan was more effective than benazepril (mean ± SEM ΔSBP, 15.7 ± 1.9 mm Hg vs 55.9 ± 12.42 mm Hg, respectively). Results indicated that telmisartan administration may have advantages over benazepril administration for cats with renal or cardiovascular disease.

Exercise training modulates the hepatic renin-angiotensin system in fructose-fed rats.

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Frantz, Eliete Dalla Corte; Medeiros, Renata Frauches; Giori, Isabele Gomes; Lima, Juliana Bittencourt Silveira; Bento-Bernardes, Thais; Gaique, Thaiane Gadioli; Fernandes-Santos, Caroline; Fernandes, Tiago; Oliveira, Edilamar Menezes; Vieira, Carla Paulo; Conte-Junior, Carlos Adam; Oliveira, Karen Jesus; Nobrega, Antonio Claudio Lucas

2017-09-01

What is the central question of this study? What are the effects of exercise training on the hepatic renin-angiotensin system and their contribution to damage resulting from fructose overload in rats? What is the main finding and its importance? Exercise training attenuated the deleterious actions of the angiotensin-converting enzyme/angiotensin II/angiotensin II type 1 receptor axis and increased expression of the counter-regulatory (angiotensin-converting enzyme 2/angiotensin (1-7)/Mas receptor) axis in the liver. Therefore, our study provides evidence that exercise training modulates the hepatic renin-angiotensin system, which contributes to reducing the progression of metabolic dysfunction and non-alcoholic fatty liver disease in fructose-fed rats. The renin-angiotensin system (RAS) has been implicated in the development of metabolic syndrome. We investigated whether the hepatic RAS is modulated by exercise training and whether this modulation improves the deleterious effects of fructose overload in rats. Male Wistar rats were divided into (n = 8 each) control (CT), exercise control (CT-Ex), high-fructose (HFr) and exercise high-fructose (HFr-Ex) groups. Fructose-drinking rats received d-fructose (100 g l -1 ). After 2 weeks, CT-Ex and HFr-Ex rats were assigned to a treadmill training protocol at moderate intensity for 8 weeks (60 min day -1 , 4 days per week). We assessed body mass, glucose and lipid metabolism, hepatic histopathology, angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2) activity, the angiotensin concentration and the expression profile of proteins affecting the hepatic RAS, gluconeogenesis and inflammation. Neither fructose overload nor exercise training influenced body mass gain and serum ACE and ACE2 activity. The HFr group showed hyperinsulinaemia, but exercise training normalized this parameter. Exercise training was effective in preventing hepatic steatosis and in preventing triacylglycerol and

Mitochondrial uncoupling proteins regulate angiotensin-converting enzyme expression

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Dhamrait, Sukhbir S.; Maubaret, Cecilia; Pedersen-bjergaard, Ulrik

2016-01-01

Uncoupling proteins (UCPs) regulate mitochondrial function, and thus cellular metabolism. Angiotensin-converting enzyme (ACE) is the central component of endocrine and local tissue renin–angiotensin systems (RAS), which also regulate diverse aspects of whole-body metabolism and mitochondrial...... amongst UCP3-55C (rather than T) and UCP2 I (rather than D) allele carriers. RNA interference against UCP2 in human umbilical vein endothelial cells reduced UCP2 mRNA sixfold (P 

Mitochondrial uncoupling proteins regulate angiotensin-converting enzyme expression

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Dhamrait, Sukhbir S.; Maubaret, Cecilia; Pedersen-Bjergaard, Ulrik

2016-01-01

Uncoupling proteins (UCPs) regulate mitochondrial function, and thus cellular metabolism. Angiotensin-converting enzyme (ACE) is the central component of endocrine and local tissue renin-angiotensin systems (RAS), which also regulate diverse aspects of whole-body metabolism and mitochondrial...... amongst UCP3-55C (rather than T) and UCP2 I (rather than D) allele carriers. RNA interference against UCP2 in human umbilical vein endothelial cells reduced UCP2 mRNA sixfold (P 

Heme oxygenase-1 gene expression modulates angiotensin II-induced increase in blood pressure.

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Yang, Liming; Quan, Shuo; Nasjletti, Alberto; Laniado-Schwartzman, Michal; Abraham, Nader G

2004-06-01

The heme-heme oxygenase (HO) system has been implicated in the regulation of vascular reactivity and blood pressure. This study examines the notion that overexpression of HO decreases pressor responsiveness to angiotensin II (Ang II). Five-day-old Sprague-Dawley rats received an intraleft ventricular injection of approximately 5x10(9) cfu/mL of retroviruses containing human HO-1 sense (LSN-HHO-1), rat HO-1 antisense (LSN-RHO-1-AS), or control retrovirus (LXSN). Three months later, rats were instrumented with femoral arterial and venous catheters for mean arterial pressure (MAP) determination and Ang II administration, respectively. Rats injected with LSN-HHO-1, but not with LXSN, expressed human HO-1 mRNA and protein in several tissues. BP increased with administration of Ang II in rats expressing and not expressing human HO-1. However, the Ang II-induced pressor response (mm Hg) in LSN-HHO-1 rats (16+/-3, 27+/-3, and 38+/-3 at 0.5, 2, and 10 ng) was surpassed (PHHO-1 rats with the HO inhibitor tin mesoporphyrin (SnMP) enhanced (P<0.05) the Ang II-induced pressor response to a level not different from that observed in LXSN rats. Rats injected with LSN-RHO-1-AS showed a decrease in renal HO-1 protein expression and HO activity relative to control LXSN rats. Administration of Ang II (0.1 to 2 ng) caused small (4 to 5 mm Hg) but significant increases in MAP in rats injected with LSN-RHO-1-AS (P<0.05) compared with rats injected with LXSN. These data demonstrate that overexpression of HO-1 brings about a reduction in pressor responsiveness to Ang II, which is most likely due to increased generation of an HO-1 product, presumably CO, with the ability to inhibit vascular reactivity to constrictor stimuli.

Investigation into the Mechanism of Homo- and Heterodimerization of Angiotensin-Converting Enzyme.

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Abrie, J Albert; Moolman, Wessel J A; Cozier, Gyles E; Schwager, Sylva L; Acharya, K Ravi; Sturrock, Edward D

2018-04-01

Angiotensin-converting enzyme (ACE) plays a central role in the renin-angiotensin system (RAS), which is primarily responsible for blood pressure homeostasis. Studies have shown that ACE inhibitors yield cardiovascular benefits that cannot be entirely attributed to the inhibition of ACE catalytic activity. It is possible that these benefits are due to interactions between ACE and RAS receptors that mediate the protective arm of the RAS, such as angiotensin II receptor type 2 (AT 2 R) and the receptor MAS. Therefore, in this study, we investigated the molecular interactions of ACE, including ACE homodimerization and heterodimerization with AT 2 R and MAS, respectively. Molecular interactions were assessed by fluorescence resonance energy transfer and bimolecular fluorescence complementation in human embryonic kidney 293 cells and Chinese hamster ovary-K1 cells transfected with vectors encoding fluorophore-tagged proteins. The specificity of dimerization was verified by competition experiments using untagged proteins. These techniques were used to study several potential requirements for the germinal isoform of angiotensin-converting enzyme expressed in the testes (tACE) dimerization as well as the effect of ACE inhibitors on both somatic isoforms of angiotensin-converting enzyme expressed in the testes (sACE) and tACE dimerization. We demonstrated constitutive homodimerization of sACE and of both of its domains separately, as well as heterodimerization of both sACE and tACE with AT 2 R, but not MAS. In addition, we investigated both soluble sACE and the sACE N domain using size-exclusion chromatography-coupled small-angle X-ray scattering and we observed dimers in solution for both forms of the enzyme. Our results suggest that ACE homo- and heterodimerization does occur under physiologic conditions. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

Angiotensin II reduces cardiac AdipoR1 expression through AT1 receptor/ROS/ERK1/2/c-Myc pathway.

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Li Li

Full Text Available Adiponectin, an abundant adipose tissue-derived protein, exerts protective effect against cardiovascular disease. Adiponectin receptors (AdipoR1 and AdipoR2 mediate the beneficial effects of adiponectin on the cardiovascular system. However, the alteration of AdipoRs in cardiac remodeling is not fully elucidated. Here, we investigated the effect of angiotensin II (AngII on cardiac AdipoRs expression and explored the possible molecular mechanism. AngII infusion into rats induced cardiac hypertrophy, reduced AdipoR1 but not AdipoR2 expression, and attenuated the phosphorylations of adenosine monophosphate-activated protein kinase and acetyl coenzyme A carboxylase, and those effects were all reversed by losartan, an AngII type 1 (AT1 receptor blocker. AngII reduced expression of AdipoR1 mRNA and protein in cultured neonatal rat cardiomyocytes, which was abolished by losartan, but not by PD123319, an AT2 receptor antagonist. The antioxidants including reactive oxygen species (ROS scavenger NAC, NADPH oxidase inhibitor apocynin, Nox2 inhibitor peptide gp91 ds-tat, and mitochondrial electron transport chain complex I inhibitor rotenone attenuated AngII-induced production of ROS and phosphorylation of extracellular signal-regulated kinase (ERK 1/2. AngII-reduced AdipoR1 expression was reversed by pretreatment with NAC, apocynin, gp91 ds-tat, rotenone, and an ERK1/2 inhibitor PD98059. Chromatin immunoprecipitation assay demonstrated that AngII provoked the recruitment of c-Myc onto the promoter region of AdipoR1, which was attenuated by PD98059. Moreover, AngII-induced DNA binding activity of c-Myc was inhibited by losartan, NAC, apocynin, gp91 ds-tat, rotenone, and PD98059. c-Myc small interfering RNA abolished the inhibitory effect of AngII on AdipoR1 expression. Our results suggest that AngII inhibits cardiac AdipoR1 expression in vivo and in vitro and AT1 receptor/ROS/ERK1/2/c-Myc pathway is required for the downregulation of AdipoR1 induced by AngII.

Aldosterone downregulates delayed rectifier potassium currents through an angiotensin type 1 receptor-dependent mechanism.

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Lv, Yankun; Wang, Yanjun; Zhu, Xiaoran; Zhang, Hua

2018-01-01

We have previously shown that aldosterone downregulates delayed rectifier potassium currents (I Ks ) via activation of the mineralocorticoid receptor (MR) in adult guinea pig cardiomyocytes. Here, we investigate whether angiotensin II/angiotensin type 1 receptor (AngII/AT1R) and intracellular calcium also play a role in these effects. Ventricular cardiomyocytes were isolated from adult guinea pigs and incubated with aldosterone (1 μmol·L -1 ) either alone or in combination with enalapril (1 μmol·L -1 ), losartan (1 μmol·L -1 ), nimodipine (1 μmol·L -1 ), or BAPTA-AM (2.5 μmol·L -1 ) for 24 h. We used the conventional whole cell patch-clamp technique to record the I Ks component. In addition, we evaluated expression of the I Ks subunits KCNQ1 and KCNE1 using Western blotting. Our results showed that both enalapril and losartan, but not nimodipine or BAPTA-AM, completely reversed the aldosterone-induced inhibition of I Ks and its effects on KCNQ1/KCNE1 protein levels. Furthermore, we found that AngII/AT1R mediates the inhibitory effects of aldosterone on I Ks . Finally, the downregulation of I Ks induced by aldosterone did not occur secondarily to a change in intracellular calcium concentrations. Taken together, our findings demonstrate that crosstalk between MR and AT1R underlies the effects of aldosterone, and provide new insights into the mechanism underlying potassium channels.

Association studies suggest a key role for endothelin-1 in the pathogenesis of preeclampsia and the accompanying renin-angiotensin-aldosterone system suppression.

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Verdonk, Koen; Saleh, Langeza; Lankhorst, Stephanie; Smilde, J E Ilse; van Ingen, Manon M; Garrelds, Ingrid M; Friesema, Edith C H; Russcher, Henk; van den Meiracker, Anton H; Visser, Willy; Danser, A H Jan

2015-06-01

Women with preeclampsia display low renin-angiotensin-aldosterone system activity and a high antiangiogenic state, the latter characterized by high levels of soluble Fms-like tyrosine kinase (sFlt)-1 and reduced placental growth factor levels. To investigate whether renin-angiotensin-aldosterone system suppression in preeclampsia is because of this disturbed angiogenic balance, we measured mean arterial pressure, creatinine, endothelin-1 (ET-1), and renin-angiotensin-aldosterone system components in pregnant women with a high (≥85; n=38) or low (<85; n=65) soluble Fms-like tyrosine kinase-1/placental growth factor ratio. Plasma ET-1 levels were increased in women with a high ratio, whereas their plasma renin activity and plasma concentrations of renin, angiotensinogen, and aldosterone were decreased. Plasma renin activity-aldosterone relationships were identical in both the groups. Multiple regression analysis revealed that plasma renin concentration correlated independently with mean arterial pressure and plasma ET-1. Plasma ET-1 correlated positively with soluble Fms-like tyrosine kinase-1 and negatively with plasma renin concentration, and urinary protein correlated with plasma ET-1 and mean arterial pressure. Despite the lower plasma levels of renin and angiotensinogen in the high-ratio group, their urinary levels of these components were elevated. Correction for albumin revealed that this was because of increased glomerular filtration. Subcutaneous arteries obtained from patients with preeclampsia displayed an enhanced, AT2 receptor-mediated response to angiotensin II. In conclusion, a high antiangiogenic state associates with ET-1 activation, which together with the increased mean arterial pressure may underlie the parallel reductions in renin and aldosterone in preeclampsia. Because ET-1 also was a major determinant of urinary protein, our data reveal a key role for ET-1 in the pathogenesis of preeclampsia. Finally, the enhanced angiotensin responsiveness

Emerging Role of Angiotensin Type 2 Receptor (AT2R)/Akt/NO Pathway in Vascular Smooth Muscle Cell in the Hyperthyroidism

Science.gov (United States)

Carrillo-Sepúlveda, Maria Alícia; Ceravolo, Graziela S.; Furstenau, Cristina R.; Monteiro, Priscilla de Souza; Bruno-Fortes, Zuleica; Carvalho, Maria Helena; Laurindo, Francisco R.; Tostes, Rita C.; Webb, R. Clinton; Barreto-Chaves, Maria Luiza M.

2013-01-01

Hyperthyroidism is characterized by increased vascular relaxation and decreased vascular contraction and is associated with augmented levels of triiodothyronine (T3) that contribute to the diminished systemic vascular resistance found in this condition. T3 leads to augmented NO production via PI3K/Akt signaling pathway, which in turn causes vascular smooth muscle cell (VSMC) relaxation; however, the underlying mechanisms involved remain largely unknown. Evidence from human and animal studies demonstrates that the renin-angiotensin system (RAS) plays a crucial role in vascular function and also mediates some of cardiovascular effects found during hyperthyroidism. Thus, in this study, we hypothesized that type 2 angiotensin II receptor (AT2R), a key component of RAS vasodilatory actions, mediates T3 induced-decreased vascular contraction. Marked induction of AT2R expression was observed in aortas from T3-induced hyperthyroid rats (Hyper). These vessels showed decreased protein levels of the contractile apparatus: α-actin, calponin and phosphorylated myosin light chain (p-MLC). Vascular reactivity studies showed that denuded aortic rings from Hyper rats exhibited decreased maximal contractile response to angiotensin II (AngII), which was attenuated in aortic rings pre-incubated with an AT2R blocker. Further study showed that cultured VSMC stimulated with T3 (0.1 µmol/L) for 24 hours had increased AT2R gene and protein expression. Augmented NO levels and decreased p-MLC levels were found in VSMC stimulated with T3, both of which were reversed by a PI3K/Akt inhibitor and AT2R blocker. These findings indicate for the first time that the AT2R/Akt/NO pathway contributes to decreased contractile responses in rat aorta, promoted by T3, and this mechanism is independent from the endothelium. PMID:23637941

Emerging role of angiotensin type 2 receptor (AT2R/Akt/NO pathway in vascular smooth muscle cell in the hyperthyroidism.

Directory of Open Access Journals (Sweden)

Maria Alícia Carrillo-Sepúlveda

Full Text Available Hyperthyroidism is characterized by increased vascular relaxation and decreased vascular contraction and is associated with augmented levels of triiodothyronine (T3 that contribute to the diminished systemic vascular resistance found in this condition. T3 leads to augmented NO production via PI3K/Akt signaling pathway, which in turn causes vascular smooth muscle cell (VSMC relaxation; however, the underlying mechanisms involved remain largely unknown. Evidence from human and animal studies demonstrates that the renin-angiotensin system (RAS plays a crucial role in vascular function and also mediates some of cardiovascular effects found during hyperthyroidism. Thus, in this study, we hypothesized that type 2 angiotensin II receptor (AT2R, a key component of RAS vasodilatory actions, mediates T3 induced-decreased vascular contraction. Marked induction of AT2R expression was observed in aortas from T3-induced hyperthyroid rats (Hyper. These vessels showed decreased protein levels of the contractile apparatus: α-actin, calponin and phosphorylated myosin light chain (p-MLC. Vascular reactivity studies showed that denuded aortic rings from Hyper rats exhibited decreased maximal contractile response to angiotensin II (AngII, which was attenuated in aortic rings pre-incubated with an AT2R blocker. Further study showed that cultured VSMC stimulated with T3 (0.1 µmol/L for 24 hours had increased AT2R gene and protein expression. Augmented NO levels and decreased p-MLC levels were found in VSMC stimulated with T3, both of which were reversed by a PI3K/Akt inhibitor and AT2R blocker. These findings indicate for the first time that the AT2R/Akt/NO pathway contributes to decreased contractile responses in rat aorta, promoted by T3, and this mechanism is independent from the endothelium.

Pharmacodynamic Impact of Carboxylesterase 1 Gene Variants in Patients with Congestive Heart Failure Treated with Angiotensin-Converting Enzyme Inhibitors

DEFF Research Database (Denmark)

Nelveg-Kristensen, Karl Emil; Bie, Peter; Ferrero, Laura

2016-01-01

BACKGROUND: Variation in the carboxylesterase 1 gene (CES1) may contribute to the efficacy of ACEIs. Accordingly, we examined the impact of CES1 variants on plasma angiotensin II (ATII)/angiotensin I (ATI) ratio in patients with congestive heart failure (CHF) that underwent ACEI dose titrations. ...

Differential clinical profile of candesartan compared to other angiotensin receptor blockers

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Zimlichman R

2011-12-01

Full Text Available Relu Cernes1,2, Margarita Mashavi1,3, Reuven Zimlichman1,31The Brunner Institute for Cardiovascular Research, Wolfson Medical Center and Tel Aviv University, Tel Aviv, Israel; 2Department of Nephrology, Wolfson Medical Center, Holon, Israel; 3Department of Medicine, Wolfson Medical Center, Holon, IsraelAbstract: The advantages of blood pressure (BP control on the risks of heart failure and stroke are well established. The renin-angiotensin system plays an important role in volume homeostasis and BP regulation and is a target for several groups of antihypertensive drugs. Angiotensin II receptor blockers represent a major class of antihypertensive compounds. Candesartan cilexetil is an angiotensin II type 1 (AT[1] receptor antagonist (angiotensin receptor blocker [ARB] that inhibits the actions of angiotensin II on the renin-angiotensin-aldosterone system. Oral candesartan 8–32 mg once daily is recommended for the treatment of adult patients with hypertension. Clinical trials have demonstrated that candesartan cilexetil is an effective agent in reducing the risk of cardiovascular mortality, stroke, heart failure, arterial stiffness, renal failure, retinopathy, and migraine in different populations of adult patients including patients with coexisting type 2 diabetes, metabolic syndrome, or kidney impairment. Clinical evidence confirmed that candesartan cilexetil provides better antihypertensive efficacy than losartan and is at least as effective as telmisartan and valsartan. Candesartan cilexetil, one of the current market leaders in BP treatment, is a highly selective compound with high potency, a long duration of action, and a tolerability profile similar to placebo. The most important and recent data from clinical trials regarding candesartan cilexetil will be reviewed in this article.Keywords: angiotensin receptor blockers, candesartan, candesartan cilexetil, clinical trials, efficacy studies, safety, blood pressure

The Use of Angiotensin-I Converting Enzyme I/D Genetic Polymorphism as a Biomarker of Athletic Performance in Humans

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Maria Fernanda De Mello Costa

2012-10-01

Full Text Available Angiotensin II is a key regulator of blood pressure and cardiovascular function in mammals. The conversion of angiotensin into its active form is carried out by Angiotensin I-Converting Enzyme (ACE. The measurement of ACE concentration in plasma or serum, its enzymatic activity, and the correlation between an insertion/deletion (I/D genetic polymorphism of the ACE gene have been investigated as possible indicators of superior athletic performance in humans. In this context, other indicators of superior adaptation to exercise resulting in better athletic performance (such as ventricular hypertrophy, VO2 max, and competition results were mostly used to study the association between ACE I/D polymorphism and improved performance. Despite the fact that the existing literature presents little consensus, there is sufficient scientific evidence to warrant further investigation on the usage of ACE activity and the I/D ACE gene polymorphism as biomarkers of superior athletic performance in humans of specific ethnicities or in athletes involved in certain sports. In this sense, a biomarker would be a substance or genetic component that could be measured to provide a degree of certainty, or an indication, of the presence of a certain trait or characteristic that would be beneficial to the athlete’s performance. Difficulties in interpreting and comparing the results of scientific research on the topic arise from dissimilar protocols and variation in study design. This review aims to investigate the current literature on the use of ACE I/D polymorphism as a biomarker of performance in humans through the comparison of scientific publications.

Changes in angiotensin AT1 receptor mRNA levels in the rat brain after immobilization stress and inhibition of central nitric oxide synthase.

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Kiss, A; Jurkovicova, D; Jezova, D; Krizanova, O

2001-06-01

To study functional interactions between angiotensin II AT1 receptors and nitric oxide (NO) activity in different brain areas in rats exposed to immobilization stress. Central inhibition of nitric oxide synthase (NOS) was provided by intracerebroventricular (i.c.v.) administration of (N-omega-nitro-L-arginine-methylester) L-NAME and analysis of AT1 receptor mRNA was performed using semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) technique. The immobilization in prone position lasted 2 hrs and the rats were sacrificed 24 hr later. The hypothalamus, hippocampus, thalamus, and cortex were isolated from fresh brains. In the cortex, gene expression of AT1 receptors was unaffected either by L-NAME treatment, or by a single exposure to immobilization stress for 2 hours followed by 24 hours of rest. In the hippocampus, the repeated treatment with L-NAME increased mRNA levels of AT1 receptors approximately 9-times compared to those in the control (untreated) group. Immobilization also increased AT1 receptor mRNA levels in the hippocampus which was similar to that induced by the L-NAME. The increase of AT1 receptor mRNA levels in the hippocampus of immobilized rats was not further altered when the animals were pretreated with L-NAME. In control rats, exposure to immobilization resulted in a significant rise in mRNA levels coding for AT1 receptors in the hypothalamus, but not in the thalamus. L-NAME treatment showed a tendency of increase in AT1 receptor mRNA levels in the hypothalamus. Moreover, when animals treated with L-NAME were subjected to immobilization, a further increase in AT1 receptor mRNA levels was observed in the hypothalamus in comparison with corresponding controls. The present data indicate that a single immobilization stress results in increased gene expression of AT1 receptors in the hypothalamus and hippocampus. The rise in AT1 mRNA levels in the same brain structures after repeated treatment with L-NAME allow to suggest an

The non-biphenyl-tetrazole angiotensin AT1 receptor antagonist eprosartan is a unique and robust inverse agonist of the active state of the AT1 receptor.

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Takezako, Takanobu; Unal, Hamiyet; Karnik, Sadashiva S; Node, Koichi

2018-03-23

Conditions such as hypertension and renal allograft rejection are accompanied by chronic, agonist-independent, signalling by angiotensin II AT 1 receptors. The current treatment paradigm for these diseases entails the preferred use of inverse agonist AT 1 receptor blockers (ARBs). However, variability in the inverse agonist activities of common biphenyl-tetrazole ARBs for the active state of AT 1 receptors often leads to treatment failure. Therefore, characterization of robust inverse agonist ARBs for the active state of AT 1 receptors is necessary. To identify the robust inverse agonist for active state of AT 1 receptors and its molecular mechanism, we performed site-directed mutagenesis, competition binding assay, inositol phosphate production assay and molecular modelling for both ground-state wild-type AT 1 receptors and active-state N111G mutant AT 1 receptors. Although candesartan and telmisartan exhibited weaker inverse agonist activity for N111G- compared with WT-AT 1 receptors, only eprosartan exhibited robust inverse agonist activity for both N111G- and WT- AT 1 receptors. Specific ligand-receptor contacts for candesartan and telmisartan are altered in the active-state N111G- AT 1 receptors compared with the ground-state WT-AT 1 receptors, suggesting an explanation of their attenuated inverse agonist activity for the active state of AT 1 receptors. In contrast, interactions between eprosartan and N111G-AT 1 receptors were not significantly altered, and the inverse agonist activity of eprosartan was robust. Eprosartan may be a better therapeutic option than other ARBs. Comparative studies investigating eprosartan and other ARBs for the treatment of diseases caused by chronic, agonist-independent, AT 1 receptor activation are warranted. © 2018 The British Pharmacological Society.

The evolution of renin-angiotensin blockade: angiotensin-converting enzyme inhibitors as the starting point.

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Sica, Domenic A

2010-04-01

The renin-angiotensin system has been a target in the treatment of hypertension for close to three decades. Several medication classes that block specific aspects of this system have emerged as useful therapies, including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and, most recently, direct renin inhibitors. There has been a natural history to the development of each of these three drug classes, starting with their use as antihypertensive agents; thereafter, in each case they have been employed as end-organ protective agents. To date, there has been scant evidence to favor angiotensin receptor blockers or direct renin inhibitors over angiotensin-converting enzyme inhibitors in treating hypertension or in affording end-organ protection; thus, angiotensin-converting enzyme inhibitors remain the standard of care when renin-angiotensin system blockade is warranted.

Erratum Aldosterone synthase C-344T, angiotensin II type 1 receptor ...

Indian Academy of Sciences (India)

Aldosterone synthase C-344T, angiotensin II type 1 receptor A1166C and 11-β hydroxysteroid dehydrogenase G534A gene polymorphisms and essential hypertension in the population of Odisha, India. Manisha Patnaik, Pallabi Pati, Surendra N. Swain, Manoj K. Mohapatra, Bhagirathi Dwibedi, Shantanu K. Kar.

Does protein binding modulate the effect of angiotensin II receptor antagonists?

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Marc P Maillard

2001-03-01

Full Text Available IntroductionAngiotensin II AT 1-receptor antagonists are highly bound to plasma proteins (≥ 99%. With some antagonists, such as DuP-532, the protein binding was such that no efficacy of the drug could be demonstrated clinically. Whether protein binding interferes with the efficacy of other antagonists is not known. We have therefore investigated in vitro how plasma proteins may affect the antagonistic effect of different AT1-receptor antagonists.MethodsA radio-receptor binding assay was used to analyse the interaction between proteins and the ability of various angiotensin II (Ang II antagonists to block AT1-receptors. In addition, the Biacore technology, a new technique which enables the real-time monitoring of binding events between two molecules, was used to evaluate the dissociation rate constants of five AT1-receptor antagonists from human serum albumin.ResultsThe in vitro AT 1-antagonistic effects of different Ang II receptor antagonists were differentially affected by the presence of human plasma, with rightward shifts of the IC50 ranging from one to several orders of magnitude. The importance of the shift correlates with the dissociation rate constants of these drugs from albumin. Our experiments also show that the way that AT1-receptor antagonists bind to proteins differs from one compound to another. These results suggest that the interaction with plasma proteins appears to modulate the efficacy of some Ang II antagonists.ConclusionAlthough the high binding level of Ang II receptor antagonist to plasma proteins appears to be a feature common to this class of compounds, the kinetics and characteristics of this binding is of great importance. With some antagonists, protein binding interferes markedly with their efficacy to block AT1-receptors.

Molecule-specific Effects of Angiotensin II–Receptor Blockers Independent of the Renin–Angiotensin System

Czech Academy of Sciences Publication Activity Database

Kurtz, T. W.; Pravenec, Michal

2008-01-01

Roč. 21, č. 8 (2008), s. 852-859 ISSN 0895-7061 R&D Projects: GA MŠk(CZ) 1M0520; GA MZd(CZ) NR8545 Grant - others:EURATOOLS(XE) LSHG-CT-2005-019015; HHMI(US) 55005624 Institutional research plan: CEZ:AV0Z50110509 Keywords : angiotensin-receptor blockers * cardiovascular protection * renin-angiotensin system Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.122, year: 2008

Renal hemodynamics and renin-angiotensin system activity in humans with multifocal renal artery fibromuscular dysplasia.

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van Twist, Daan J L; Houben, Alphons J H M; de Haan, Michiel W; de Leeuw, Peter W; Kroon, Abraham A

2016-06-01

Fibromuscular dysplasia (FMD) is the second most common cause of renovascular hypertension. Nonetheless, knowledge on the renal microvasculature and renin-angiotensin system (RAS) activity in kidneys with FMD is scarce. Given the fairly good results of revascularization, we hypothesized that the renal microvasculature and RAS are relatively spared in kidneys with FMD. In 58 hypertensive patients with multifocal renal artery FMD (off medication) and 116 matched controls with essential hypertension, we measured renal blood flow (Xenon washout method) per kidney and drew blood samples from the aorta and both renal veins to determine renin secretion and glomerular filtration rate per kidney. We found that renal blood flow and glomerular filtration rate in FMD were comparable to those in controls. Although systemic renin levels were somewhat higher in FMD, renal renin secretion was not elevated. Moreover, in patients with unilateral FMD, no differences between the affected and unaffected kidney were observed with regard to renal blood flow, glomerular filtration rate, or renin secretion. In men, renin levels and renin secretion were higher as compared with women. The renal blood flow response to RAS modulation (by intrarenal infusion of angiotensin II, angiotensin-(1-7), an angiotensin II type 1 receptor blocker, or a nitric oxide synthase blocker) was also comparable between FMD and controls. Renal blood flow, glomerular filtration, and the response to vasoactive substances in kidneys with multifocal FMD are comparable to patients with essential hypertension, suggesting that microvascular function is relatively spared. Renin secretion was not increased and the response to RAS modulation was not affected in kidneys with FMD.

Functional and neurochemical characterization of angiotensin type 1A receptor-expressing neurons in the nucleus of the solitary tract of the mouse.

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Carter, D A; Choong, Y-T; Connelly, A A; Bassi, J K; Hunter, N O; Thongsepee, N; Llewellyn-Smith, I J; Fong, A Y; McDougall, S J; Allen, A M

2017-10-01

Angiotensin II acts via two main receptors within the central nervous system, with the type 1A receptor (AT 1A R) most widely expressed in adult neurons. Activation of the AT 1 R in the nucleus of the solitary tract (NTS), the principal nucleus receiving central synapses of viscerosensory afferents, modulates cardiovascular reflexes. Expression of the AT 1 R occurs in high density within the NTS of most mammals, including humans, but the fundamental electrophysiological and neurochemical characteristics of the AT 1A R-expressing NTS neurons are not known. To address this, we have used a transgenic mouse, in which the AT 1A R promoter drives expression of green fluorescent protein (GFP). Approximately one-third of AT 1A R-expressing neurons express the catecholamine-synthetic enzyme tyrosine hydroxylase (TH), and a subpopulation of these stained for the transcription factor paired-like homeobox 2b (Phox2b). A third group, comprising approximately two-thirds of the AT 1A R-expressing NTS neurons, showed Phox2b immunoreactivity alone. A fourth group in the ventral subnucleus expressed neither TH nor Phox2b. In whole cell recordings from slices in vitro, AT 1A R-GFP neurons exhibited voltage-activated potassium currents, including the transient outward current and the M-type potassium current. In two different mouse strains, both AT 1A R-GFP neurons and TH-GFP neurons showed similar AT 1A R-mediated depolarizing responses to superfusion with angiotensin II. These data provide a comprehensive description of AT 1A R-expressing neurons in the NTS and increase our understanding of the complex actions of this neuropeptide in the modulation of viscerosensory processing. Copyright © 2017 the American Physiological Society.

Angiotensin II modulates interleukin-1β-induced inflammatory gene expression in vascular smooth muscle cells via interfering with ERK-NF-κB crosstalk

International Nuclear Information System (INIS)

Xu, Shanqin; Zhi, Hui; Hou, Xiuyun; Jiang, Bingbing

2011-01-01

Highlights: → We examine how angiotensin II modulates ERK-NF-κB crosstalk and gene expression. → Angiotensin II suppresses IL-1β-induced prolonged ERK and NF-κB activation. → ERK-RSK1 signaling is required for IL-1β-induced prolonged NF-κB activation. → Angiotensin II modulates NF-κB responsive genes via regulating ERK-NF-κB crosstalk. → ERK-NF-κB crosstalk is a novel mechanism regulating inflammatory gene expression. -- Abstract: Angiotensin II is implicated in cardiovascular diseases, which is associated with a role in increasing vascular inflammation. The present study investigated how angiotensin II modulates vascular inflammatory signaling and expression of inducible nitric oxide synthase (iNOS) and vascular cell adhesion molecule (VCAM)-1. In cultured rat aortic vascular smooth muscle cells (VSMCs), angiotensin II suppressed interleukin-1β-induced prolonged phosphorylation of extracellular signal-regulated kinase (ERK) and ribosomal S6 kinase (RSK)-1, and nuclear translocation of nuclear factor (NF)-κB, leading to decreased iNOS but enhanced VCAM-1 expression, associated with an up-regulation of mitogen-activated protein kinase phosphatase-1 expression. Knock-down of RSK1 selectively down regulated interleukin-1β-induced iNOS expression without influencing VCAM-1 expression. In vivo experiments showed that interleukin-1β, iNOS, and VCAM-1 expression were detectable in the aortic arches of both wild-type and apolipoprotein E-deficient (ApoE -/- ) mice. VCAM-1 and iNOS expression were higher in ApoE -/- than in wild type mouse aortic arches. Angiotensin II infusion (3.2 mg/kg/day, for 6 days, via subcutaneous osmotic pump) in ApoE -/- mice enhanced endothelial and adventitial VCAM-1 and iNOS expression, but reduced medial smooth muscle iNOS expression associated with reduced phosphorylation of ERK and RSK-1. These results indicate that angiotensin II can differentially modulate inflammatory gene expression in aortic smooth muscle cells

Combined Angiotensin Receptor Modulation in the Management of Cardio-Metabolic Disorders

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Paulis, Ludovit; Foulquier, Sébastien; Namsolleck, Pawel

2016-01-01

Cardiovascular and metabolic disorders, such as hypertension, insulin resistance, dyslipidemia or obesity are linked with chronic low-grade inflammation and dysregulation of the renin-angiotensin system (RAS). Consequently, RAS inhibition by ACE inhibitors or angiotensin AT1 receptor (AT1R...... blockade abolishes the AT1R-linked RAS almost completely with subsequent risk of hypotension and hypotension-related events, i.e. syncope or renal dysfunction. Such complications might be especially prominent in patients with renal impairment or patients with isolated systolic hypertension and normal...

beta-Arrestin 1 and 2 stabilize the angiotensin II type I receptor in distinct high-affinity conformations

DEFF Research Database (Denmark)

Sanni, S J; Hansen, J T; Bonde, M M

2010-01-01

The angiotensin II type 1 (AT(1)) receptor belongs to family A of 7 transmembrane (7TM) receptors. The receptor has important roles in the cardiovascular system and is commonly used as a drug target in cardiovascular diseases. Interaction of 7TM receptors with G proteins or beta-arrestins often...

Imbalance between pulmonary angiotensin-converting enzyme and angiotensin-converting enzyme 2 activity in acute respiratory distress syndrome

NARCIS (Netherlands)

Wösten-van Asperen, Roelie M.; Bos, Albert P.; Bem, Reinout A.; Dierdorp, Barbara S.; Dekker, Tamara; van Goor, Harry; Kamilic, Jelena; van der Loos, Chris M.; van den Berg, Elske; Bruijn, Martijn; van Woensel, Job B.; Lutter, René

2013-01-01

Angiotensin-converting enzyme and its effector peptide angiotensin II have been implicated in the pathogenesis of acute respiratory distress syndrome. Recently, angiotensin-converting enzyme 2 was identified as the counter-regulatory enzyme of angiotensin-converting enzyme that converts angiotensin

Over-expression of angiotensin converting enzyme-1 augments cardiac hypertrophy in transgenic rats

NARCIS (Netherlands)

Tian, Xiao-Li; Pinto, Yigal Martin; Costerousse, Olivier; Franz, Wolfgang M.; Lippoldt, Andrea; Hoffmann, Sigrid; Unger, Thomas; Paul, Martin

2004-01-01

Increased cardiac angiotensin converting enzyme-1 (ACE1) is found in individuals who carry a deletion in intron 16 of ACE1 gene or in individuals who suffer from cardiac disorders, such as hypertrophy. However, whether a single increase in ACE1 expression leads to spontaneous cardiac defects remains

Angiotensin II type 1 and 2 receptors and lymphatic vessels modulate lung remodeling and fibrosis in systemic sclerosis and idiopathic pulmonary fibrosis.

Science.gov (United States)

Parra, Edwin Roger; Ruppert, Aline Domingos Pinto; Capelozzi, Vera Luiza

2014-01-01

To validate the importance of the angiotensin II receptor isotypes and the lymphatic vessels in systemic sclerosis and idiopathic pulmonary fibrosis. We examined angiotensin II type 1 and 2 receptors and lymphatic vessels in the pulmonary tissues obtained from open lung biopsies of 30 patients with systemic sclerosis and 28 patients with idiopathic pulmonary fibrosis. Their histologic patterns included cellular and fibrotic non-specific interstitial pneumonia for systemic sclerosis and usual interstitial pneumonia for idiopathic pulmonary fibrosis. We used immunohistochemistry and histomorphometry to evaluate the number of cells in the alveolar septae and the vessels stained by these markers. Survival curves were also used. We found a significantly increased percentage of septal and vessel cells immunostained for the angiotensin type 1 and 2 receptors in the systemic sclerosis and idiopathic pulmonary fibrosis patients compared with the controls. A similar percentage of angiotensin 2 receptor positive vessel cells was observed in fibrotic non-specific interstitial pneumonia and usual interstitial pneumonia. A significantly increased percentage of lymphatic vessels was present in the usual interstitial pneumonia group compared with the non-specific interstitial pneumonia and control groups. A Cox regression analysis showed a high risk of death for the patients with usual interstitial pneumonia and a high percentage of vessel cells immunostained for the angiotensin 2 receptor in the lymphatic vessels. We concluded that angiotensin II receptor expression in the lung parenchyma can potentially control organ remodeling and fibrosis, which suggests that strategies aimed at preventing high angiotensin 2 receptor expression may be used as potential therapeutic target in patients with pulmonary systemic sclerosis and idiopathic pulmonary fibrosis.

Recruitment of macrophages from the spleen contributes to myocardial fibrosis and hypertension induced by angiotensin II

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Ning-Ping Wang

2017-05-01

Full Text Available Introduction: The purpose of this study was to determine whether macrophages migrated from the spleen are associated with angiotensin II-induced cardiac fibrosis and hypertension. Methods: Sprague-Dawley rats were subjected to angiotensin II infusion in vehicle (500 ng/kg/min for up to four weeks. In splenectomy, the spleen was removed before angiotensin II infusion. In the angiotensin II AT1 receptor blockade, telmisartan was administered by gastric gavage (10 mg/kg/day during angiotensin II infusion. The heart and aorta were isolated for Western blot analysis and immunohistochemistry. Results: Angiotensin II infusion caused a significant reduction in the number of monocytes in the spleen through the AT1 receptor-activated monocyte chemoattractant protein-1. Comparison of angiotensin II infusion, splenectomy and telmisartan comparatively reduced the recruitment of macrophages into the heart. Associated with this change, transforming growth factor β1 expression and myofibroblast proliferation were inhibited, and Smad2/3 and collagen I/III were downregulated. Furthermore, interstitial/perivascular fibrosis was attenuated. These modifications occurred in coincidence with reduced blood pressure. At week 4, invasion of macrophages and myofibroblasts in the thoracic aorta was attenuated and expression of endothelial nitric oxide synthase was upregulated, along with a reduction in aortic fibrosis. Conclusions: These results suggest that macrophages when recruited into the heart and aorta from the spleen potentially contribute to angiotensin II-induced cardiac fibrosis and hypertension.

Angiotensin-(1-7)/Mas axis modulates fear memory and extinction in mice.

Science.gov (United States)

Lazaroni, Thiago Luiz do Nascimento; Bastos, Cristiane Perácio; Moraes, Márcio Flávio Dutra; Santos, Robson Souza; Pereira, Grace Schenatto

2016-01-01

Inappropriate defense-alerting reaction to fear is a common feature of neuropsychiatric diseases. Therefore, impairments in brain circuits, as well as in molecular pathways underlying the neurovegetative adjustments to fear may play an essential role on developing neuropsychiatric disorders. Here we tested the hypothesis that interfering with angiotensin-(1-7) [Ang-(1-7)]/Mas receptor axis homeostasis, which appears to be essential to arterial pressure control, would affect fear memory and extinction. Mas knockout (MasKO) mice, in FVB/N background, showed normal cued fear memory and extinction, but increased freezing in response to context. Next, as FVB/N has poor performance in contextual fear memory, we tested MasKO in mixed 129xC57BL/6 background. MasKO mice behaved similarly to wild-type (WT), but memory extinction was slower in contextual fear conditioning to a weak protocol (1CS/US). In addition, delayed extinction in MasKO mice was even more pronounced after a stronger protocol (3CS/US). We showed previously that Angiotensin II receptor AT1 antagonist, losantan, rescued object recognition memory deficit in MasKO mice. Here, losartan was also effective. Memory extinction was accelerated in MasKO mice after treatment with losartan. In conclusion, we showed for the first time that Ang-(1-7)/Mas axis may modulate fear memory extinction. Furthermore, we suggest MasKO mice as an animal model to study post-traumatic stress disorder (PTSD). Copyright © 2015 Elsevier Inc. All rights reserved.

The Impact of Age-Related Dysregulation of the Angiotensin System on Mitochondrial Redox Balance

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Ramya eVajapey

2014-11-01

Full Text Available Aging is associated with the accumulation of various deleterious changes in cells. According to the free radical and mitochondrial theory of aging, mitochondria initiate most of the deleterious changes in aging and govern life span. The failure of mitochondrial reduction-oxidation (redox homeostasis and the formation of excessive free radicals are tightly linked to dysregulation in the Renin Angiotensin System (RAS. A main rate-controlling step in RAS is renin, an enzyme that hydrolyzes angiotensinogen to generate angiotensin I. Angiotensin I is further converted to Angiotensin II (Ang II by angiotensin-converting enzyme (ACE. Ang II binds with equal affinity to two main angiotensin receptors—type 1 (AT1R and type 2 (AT2R. The binding of Ang II to AT1R activates NADPH oxidase, which leads to increased generation of cytoplasmic reactive oxygen species (ROS. This Ang II-AT1R–NADPH-ROS signal triggers the opening of mitochondrial KATP channels and mitochondrial ROS production in a positive feedback loop. Furthermore, RAS has been implicated in the decrease of many of ROS scavenging enzymes, thereby leading to detrimental levels of free radicals in the cell.AT2R is less understood, but evidence supports an anti-oxidative and mitochondria-protective function for AT2R. The overlap between age related changes in RAS and mitochondria, and the consequences of this overlap on age-related diseases are quite complex. RAS dysregulation has been implicated in many pathological conditions due to its contribution to mitochondrial dysfunction. Decreased age-related, renal and cardiac mitochondrial dysfunction was seen in patients treated with angiotensin receptor blockers. The aim of this review is to: (a report the most recent information elucidating the role of RAS in mitochondrial redox hemostasis and (b discuss the effect of age-related activation of RAS on generation of free radicals.

Angiotensin-(1-7)/Mas axis integrity is required for the expression of object recognition memory.

Science.gov (United States)

Lazaroni, Thiago L N; Raslan, Ana Cláudia S; Fontes, Walkiria R P; de Oliveira, Marilene L; Bader, Michael; Alenina, Natalia; Moraes, Márcio F D; Dos Santos, Robson A; Pereira, Grace S

2012-01-01

It has been shown that the brain has its own intrinsic renin-angiotensin system (RAS) and angiotensin-(1-7) (Ang-(1-7)) is particularly interesting, because it appears to counterbalance most of the Ang II effects. Ang-(1-7) exerts its biological function through activation of the G-protein-coupled receptor Mas. Interestingly, hippocampus is one of the regions with higher expression of Mas. However, the role of Ang-(1-7)/Mas axis in hippocampus-dependent memories is still poorly understood. Here we demonstrated that Mas ablation, as well as the blockade of Mas in the CA1-hippocampus, impaired object recognition memory (ORM). We also demonstrated that the blockade of Ang II receptors AT1, but not AT2, recovers ORM impairment of Mas-deficient mice. Considering that high concentrations of Ang-(1-7) may activate AT1 receptors, nonspecifically, we evaluate the levels of Ang-(1-7) and its main precursors Ang I and Ang II in the hippocampus of Mas-deficient mice. The Ang I and Ang II levels are unaltered in the whole hipocampus of MasKo. However, Ang-(1-7) concentration is increased in the whole hippocampus of MasKo mice, as well as in the CA1 area. Taken together, our findings suggest that the functionality of the Ang-(1-7)/Mas axis is essential for normal ORM processing. Copyright © 2011 Elsevier Inc. All rights reserved.

Local renin-angiotensin system contributes to hyperthyroidism-induced cardiac hypertrophy.

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Kobori, H; Ichihara, A; Miyashita, Y; Hayashi, M; Saruta, T

1999-01-01

We have reported previously that thyroid hormone activates the circulating and tissue renin-angiotensin systems without involving the sympathetic nervous system, which contributes to cardiac hypertrophy in hyperthyroidism. This study examined whether the circulating or tissue renin-angiotensin system plays the principal role in hyperthyroidism-induced cardiac hypertrophy. The circulating renin-angiotensin system in Sprague-Dawley rats was fixed by chronic angiotensin II infusion (40 ng/min, 28 days) via mini-osmotic pumps. Daily i.p. injection of thyroxine (0.1 mg/kg per day, 28 days) was used to mimic hyperthyroidism. Serum free tri-iodothyronine, plasma renin activity, plasma angiotensin II, cardiac renin and cardiac angiotensin II were measured with RIAs. The cardiac expression of renin mRNA was evaluated by semiquantitative reverse transcriptase-polymerase chain reaction. Plasma renin activity and plasma angiotensin II were kept constant in the angiotensin II and angiotensin II+thyroxine groups (0.12+/-0.03 and 0.15+/-0.03 microgram/h per liter, 126+/-5 and 130+/-5 ng/l respectively) (means+/-s.e.m.). Despite stabilization of the circulating renin-angiotensin system, thyroid hormone induced cardiac hypertrophy (5.0+/-0.5 vs 3.5+/-0.1 mg/g) in conjunction with the increases in cardiac expression of renin mRNA, cardiac renin and cardiac angiotensin II (74+/-2 vs 48+/-2%, 6.5+/-0.8 vs 3.8+/-0.4 ng/h per g, 231+/-30 vs 149+/-2 pg/g respectively). These results indicate that the local renin-angiotensin system plays the primary role in the development of hyperthyroidism-induced cardiac hypertrophy.

Angiotensin receptors in Dupuytren's disease: a target for pharmacological treatment?

Science.gov (United States)

Stephen, Christopher; Touil, Leila; Vaiude, Partha; Singh, Jaipaul; McKirdy, Stuart

2018-02-01

Attempts at the pharmacological treatment of Dupuytren's disease have so far been unsuccessful, and the disease is not yet fully understood on a cellular level. The Renin-Angiotensin System has long been understood to play a circulating hormonal role. However, there is much evidence showing Angiotensin II to play a local role in wound healing and fibrosis, with ACE inhibitors being widely used as an anti-fibrotic agent in renal and cardiac disease. This study was designed to investigate the presence of Angiotensin II receptors 1 (AT1) and 2 (AT2) in Dupuytren's tissue to form a basis for further study into the pharmacological treatment of this condition. Tissue was harvested from 11 patients undergoing surgery for Dupuytren's disease. Each specimen was processed into frozen sections and immunostaining was employed to identify AT1 and AT2 receptors. Immunostaining for AT1 receptors was mildly positive in one patient and negative in all the remaining patients. However, all specimens stained extensively for AT2 receptors. This suggests that the expression of AT2 receptors is more prominent than AT1 receptors in Dupuytren's disease. These findings have opened a new avenue for future research involving ACE inhibitors, AT2 agonists, and AT2 antagonists in Dupuytren's disease.

Keeping pace with ACE: are ACE inhibitors and angiotensin II type 1 receptor antagonists potential doping agents?

Science.gov (United States)

Wang, Pei; Fedoruk, Matthew N; Rupert, Jim L

2008-01-01

In the decade since the angiotensin-converting enzyme (ACE) gene was first proposed to be a 'human gene for physical performance', there have been numerous studies examining the effects of ACE genotype on physical performance phenotypes such as aerobic capacity, muscle function, trainability, and athletic status. While the results are variable and sometimes inconsistent, and corroborating phenotypic data limited, carriers of the ACE 'insertion' allele (the presence of an alu repeat element in intron 16 of the gene) have been reported to have higher maximum oxygen uptake (VO2max), greater response to training, and increased muscle efficiency when compared with individuals carrying the 'deletion' allele (absence of the alu repeat). Furthermore, the insertion allele has been reported to be over-represented in elite athletes from a variety of populations representing a number of endurance sports. The mechanism by which the ACE insertion genotype could potentiate physical performance is unknown. The presence of the ACE insertion allele has been associated with lower ACE activity (ACEplasma) in number of studies, suggesting that individuals with an innate tendency to have lower ACE levels respond better to training and are at an advantage in endurance sporting events. This could be due to lower levels of angiotensin II (the vasoconstrictor converted to active form by ACE), higher levels of bradykinin (a vasodilator degraded by ACE) or some combination of the two phenotypes. Observations that individuals carrying the ACE insertion allele (and presumably lower ACEplasma) have an enhanced response to training or are over-represented amongst elite athletes raises the intriguing question: would individuals with artificially lowered ACEplasma have similar training or performance potential? As there are a number of drugs (i.e. ACE inhibitors and angiotensin II type 1 receptor antagonists [angiotensin receptor blockers--ARBs]) that have the ability to either reduce ACEplasma

Local Bone Marrow Renin-Angiotensin System and Atherosclerosis

Directory of Open Access Journals (Sweden)

Yavuz Beyazit

2011-01-01

Full Text Available Local hematopoietic bone marrow (BM renin-angiotensin system (RAS affects the growth, production, proliferation differentiation, and function of hematopoietic cells. Angiotensin II (Ang II, the dominant effector peptide of the RAS, regulates cellular growth in a wide variety of tissues in pathobiological states. RAS, especially Ang II and Ang II type 1 receptor (AT1R, has considerable proinflammatory and proatherogenic effects on the vessel wall, causing progression of atherosclerosis. Recent investigations, by analyzing several BM chimeric mice whose BM cells were positive or negative for AT1R, disclosed that AT1R in BM cells participates in the pathogenesis of atherosclerosis. Therefore, AT1R blocking not only in vascular cells but also in the BM could be an important therapeutic approach to prevent atherosclerosis. The aim of this paper is to review the function of local BM RAS in the pathogenesis of atherosclerosis.

Expression of genes of the cardiac and renal renin-angiotensin systems in preterm piglets: is this system a suitable target for therapeutic intervention?

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Kim, Eleanor; Eiby, Yvonne; Lumbers, Eugenie; Boyce, Amanda; Gibson, Karen; Lingwood, Barbara

2015-10-01

The newborn circulating, cardiac and renal renin-angiotensin systems (RASs) are essential for blood pressure control, and for cardiac and renal development. If cardiac and renal RASs are immature this may contribute to cardiovascular compromise in preterm infants. This study measured mRNA expression of cardiac and renal RAS components in preterm, glucocorticoid (GC) exposed preterm, and term piglets. Renal and cardiac RAS mRNA levels were measured using real-time polymerase chain reaction (PCR). Genes studied were: (pro)renin receptor, renin, angiotensinogen, angiotensin converting enzyme (ACE), ACE2, angiotensin type 1 receptor (AT1R) and angiotensin type 2 receptor (AT2R). All the genes studied were expressed in the kidney; neither renin nor AT2R mRNA were detected in the heart. There were no gestational changes in (pro)renin receptor, renin, ACE or AT1R mRNA levels. Right ventricular angiotensinogen mRNA levels in females were lower in preterm animals than at term, and GC exposure increased levels in male piglets. Renal angiotensinogen mRNA levels in female term piglets were lower than females from both preterm groups, and lower than male term piglets. Left ventricular ACE2 mRNA expression was lower in GC treated preterm piglets. Renal AT2R mRNA abundance was highest in GC treated preterm piglets, and the AT1R/AT2R ratio was increased at term. Preterm cardiac and renal RAS mRNA levels were similar to term piglets, suggesting that immaturity of these RASs does not contribute to preterm cardiovascular compromise. Since preterm expression of both renal and cardiac angiotensin II-AT1R is similar to term animals, cardiovascular dysfunction in the sick preterm human neonate might be effectively treated by agents acting on their RASs. © The Author(s), 2015.

Potentiation of the actions of bradykinin by angiotensin I-converting enzyme inhibitors. The role of expressed human bradykinin B2 receptors and angiotensin I-converting enzyme in CHO cells.

Science.gov (United States)

Minshall, R D; Tan, F; Nakamura, F; Rabito, S F; Becker, R P; Marcic, B; Erdös, E G

1997-11-01

Part of the beneficial effects of angiotensin I-converting enzyme (ACE) inhibitors are due to augmenting the actions of bradykinin (BK). We studied this effect of enalaprilat on the binding of [3H]BK to Chinese hamster ovary (CHO) cells stably transfected to express the human BK B2 receptor alone (CHO-3B) or in combination with ACE (CHO-15AB). In CHO-15AB cells, enalaprilat (1 mumol/L) increased the total number of low-affinity [3H]BK binding sites on the cells at 37 degrees C, but not at 4 degrees C, from 18.4 +/- 4.3 to 40.3 +/- 11.9 fmol/10(6) cells (P potentiated the release of [3H]arachidonic acid and the liberation of inositol 1,4,5-trisphosphate (IP3) induced by BK and [Hyp3-Tyr(Me)8]BK. Moreover, enalaprilat (1 mumol/L) completely and immediately restored the response of the B2 receptor, desensitized by the agonist (1 mumol/L [Hyp3-Tyr(Me)8]BK); this effect was blocked by the antagonist, HOE 140. Finally, enalaprilat, but not the prodrug enalapril, decreased internalization of the receptor from 70 +/- 9% to 45 +/- 9% (P desensitization, and decrease internalization, thereby potentiating BK beyond blocking its hydrolysis.

Impact of Angiotensin Type 1A Receptors in Principal Cells of the Collecting Duct on Blood Pressure and Hypertension.

Science.gov (United States)

Chen, Daian; Stegbauer, Johannes; Sparks, Matthew A; Kohan, Donald; Griffiths, Robert; Herrera, Marcela; Gurley, Susan B; Coffman, Thomas M

2016-06-01

The main actions of the renin-angiotensin system to control blood pressure (BP) are mediated by the angiotensin type 1 receptors (AT1Rs). The major murine AT1R isoform, AT1AR, is expressed throughout the nephron, including the collecting duct in both principal and intercalated cells. Principal cells play the major role in sodium and water reabsorption. Although aldosterone is considered to be the dominant regulator of sodium reabsorption by principal cells, recent studies suggest a role for direct actions of AT1R. To specifically examine the contributions of AT1AR in principal cells to BP regulation and the development of hypertension in vivo, we generated inbred 129/SvEv mice with deletion of AT1AR from principal cells (PCKO). At baseline, we found that BPs measured by radiotelemetry were similar between PCKOs and controls. During 1-week of low-salt diet (hypertension, there was a modest but significant attenuation of hypertension in PCKOs (163±6 mm Hg) compared with controls (178±2 mm Hg; Phypertension and epithelial sodium channel activation. © 2016 American Heart Association, Inc.

Aspirin suppresses cardiac fibroblast proliferation and collagen formation through downregulation of angiotensin type 1 receptor transcription

International Nuclear Information System (INIS)

Wang, Xianwei; Lu, Jingjun; Khaidakov, Magomed; Mitra, Sona; Ding, Zufeng; Raina, Sameer; Goyal, Tanu; Mehta, Jawahar L.

2012-01-01

Aspirin (acetyl salicylic acid, ASA) is a common drug used for its analgesic and antipyretic effects. Recent studies show that ASA not only blocks cyclooxygenase, but also inhibits NADPH oxidase and resultant reactive oxygen species (ROS) generation, a pathway that underlies pathogenesis of several ailments, including hypertension and tissue remodeling after injury. In these disease states, angiotensin II (Ang II) activates NADPH oxidase via its type 1 receptor (AT1R) and leads to fibroblast growth and collagen synthesis. In this study, we examined if ASA would inhibit NADPH oxidase activation, upregulation of AT1R transcription, and subsequent collagen generation in mouse cardiac fibroblasts challenged with Ang II. Mouse heart fibroblasts were isolated and treated with Ang II with or without ASA. As expected, Ang II induced AT1R expression, and stimulated cardiac fibroblast growth and collagen synthesis. The AT1R blocker losartan attenuated these effects of Ang II. Similarly to losartan, ASA, and its SA moiety suppressed Ang II-mediated AT1R transcription and fibroblast proliferation as well as expression of collagens and MMPs. ASA also suppressed the expression of NADPH oxidase subunits (p22 phox , p47 phox , p67 phox , NOX2 and NOX4) and ROS generation. ASA did not affect total NF-κB p65, but inhibited its phosphorylation and activation. These observations suggest that ASA inhibits Ang II-induced NADPH oxidase expression, NF-κB activation and AT1R transcription in cardiac fibroblasts, and fibroblast proliferation and collagen expression. The critical role of NADPH oxidase activity in stimulation of AT1R transcription became apparent in experiments where ASA also inhibited AT1R transcription in cardiac fibroblasts challenged with H 2 O 2 . Since SA had similar effect as ASA on AT1R expression, we suggest that ASA's effect is mediated by its SA moiety. -- Highlights: ► Aspirin in therapeutic concentrations decreases mouse cardiac fibroblast growth and collagen

Aspirin suppresses cardiac fibroblast proliferation and collagen formation through downregulation of angiotensin type 1 receptor transcription

Energy Technology Data Exchange (ETDEWEB)

Wang, Xianwei, E-mail: XWang2@UAMS.edu; Lu, Jingjun; Khaidakov, Magomed; Mitra, Sona; Ding, Zufeng; Raina, Sameer; Goyal, Tanu; Mehta, Jawahar L., E-mail: MehtaJL@UAMS.edu

2012-03-15

Aspirin (acetyl salicylic acid, ASA) is a common drug used for its analgesic and antipyretic effects. Recent studies show that ASA not only blocks cyclooxygenase, but also inhibits NADPH oxidase and resultant reactive oxygen species (ROS) generation, a pathway that underlies pathogenesis of several ailments, including hypertension and tissue remodeling after injury. In these disease states, angiotensin II (Ang II) activates NADPH oxidase via its type 1 receptor (AT1R) and leads to fibroblast growth and collagen synthesis. In this study, we examined if ASA would inhibit NADPH oxidase activation, upregulation of AT1R transcription, and subsequent collagen generation in mouse cardiac fibroblasts challenged with Ang II. Mouse heart fibroblasts were isolated and treated with Ang II with or without ASA. As expected, Ang II induced AT1R expression, and stimulated cardiac fibroblast growth and collagen synthesis. The AT1R blocker losartan attenuated these effects of Ang II. Similarly to losartan, ASA, and its SA moiety suppressed Ang II-mediated AT1R transcription and fibroblast proliferation as well as expression of collagens and MMPs. ASA also suppressed the expression of NADPH oxidase subunits (p22{sup phox}, p47{sup phox}, p67{sup phox}, NOX2 and NOX4) and ROS generation. ASA did not affect total NF-κB p65, but inhibited its phosphorylation and activation. These observations suggest that ASA inhibits Ang II-induced NADPH oxidase expression, NF-κB activation and AT1R transcription in cardiac fibroblasts, and fibroblast proliferation and collagen expression. The critical role of NADPH oxidase activity in stimulation of AT1R transcription became apparent in experiments where ASA also inhibited AT1R transcription in cardiac fibroblasts challenged with H{sub 2}O{sub 2}. Since SA had similar effect as ASA on AT1R expression, we suggest that ASA's effect is mediated by its SA moiety. -- Highlights: ► Aspirin in therapeutic concentrations decreases mouse cardiac

Auto-inhibitory regulation of angiotensin II functionality in hamster aorta during the early phases of dyslipidemia.

Science.gov (United States)

Pereira, Priscila Cristina; Pernomian, Larissa; Côco, Hariane; Gomes, Mayara Santos; Franco, João José; Marchi, Kátia Colombo; Hipólito, Ulisses Vilela; Uyemura, Sergio Akira; Tirapelli, Carlos Renato; de Oliveira, Ana Maria

2016-06-15

Emerging data point the crosstalk between dyslipidemia and renin-angiotensin system (RAS). Advanced dyslipidemia is described to induce RAS activation in the vasculature. However, the interplay between early dyslipidemia and the RAS remains unexplored. Knowing that hamsters and humans have a similar lipid profile, we investigated the effects of early and advanced dyslipidemia on angiotensin II-induced contraction. Cumulative concentration-response curves for angiotensin II (1.0pmol/l to 1.0µmol/l) were obtained in the hamster thoracic aorta. We also investigated the modulatory action of NAD(P)H oxidase on angiotensin II-induced contraction using ML171 (Nox-1 inhibitor, 0.5µmol/l) and VAS2870 (Nox-4 inhibitor, 5µmol/l). Early dyslipidemia was detected in hamsters treated with a cholesterol-rich diet for 15 days. Early dyslipidemia decreased the contraction induced by angiotensin II and the concentration of Nox-4-derived hydrogen peroxide. Advanced dyslipidemia, observed in hamsters treated with cholesterol-rich diet for 30 days, restored the contractile response induced by angiotensin II by compensatory mechanism that involves Nox-4-mediated oxidative stress. The hyporresponsiveness to angiotensin II may be an auto-inhibitory regulation of the angiotensinergic function during early dyslipidemia in an attempt to reduce the effects of the upregulation of the vascular RAS during the advanced stages of atherogenesis. The recovery of vascular angiotensin II functionality during the advanced phases of dyslipidemia is the result of the upregulation of redox-pro-inflammatory pathway that might be most likely involved in atherogenesis progression rather than in the recovery of vascular function. Taken together, our findings show the early phase of dyslipidemia may be the most favorable moment for effective atheroprotective therapeutic interventions. Copyright © 2016 Elsevier B.V. All rights reserved.

Association between angiotensin II receptor gene polymorphism and serum angiotensin converting enzyme (SACE) activity in patients with sarcoidosis.

Science.gov (United States)

Takemoto, Y; Sakatani, M; Takami, S; Tachibana, T; Higaki, J; Ogihara, T; Miki, T; Katsuya, T; Tsuchiyama, T; Yoshida, A; Yu, H; Tanio, Y; Ueda, E

1998-06-01

Serum angiotensin converting enzyme (SACE) is considered to reflect disease activity in sarcoidosis. SACE activity is increased in many patients with active sarcoid lesions. The mechanism for the increased SACE activity in this disease has not been clarified. ACE insertion/deletion (I/D) gene polymorphism has been reported to have an association with SACE levels in sarcoidosis, but no evidence of an association between angiotensin II receptor gene polymorphism and SACE in this disease has been found. A study of the association of angiotensin II receptor gene polymorphisms with sarcoidosis was therefore undertaken. ACE (I/D), angiotensin II type 1 receptor (AGTR1), and angiotensin II type 2 receptor (AGTR2) gene polymorphisms were investigated by polymerase chain reaction (PCR) and SACE levels were measured in three groups of patients: those with sarcoidosis or tuberculosis and normal controls. There was no difference in allele frequency of AGTR1 and AGTR2 polymorphism among the three groups. Neither AGTR1 nor AGTR2 polymorphisms were associated with sarcoidosis. SACE activity was higher in patients with sarcoidosis with the AGTR1 A/C genotype than in others. However, this tendency was not detected in patients with tuberculosis. The AGTR1 allele C is associated with high activity of SACE in patients with sarcoidosis. It is another predisposing factor for high levels of SACE in patients with sarcoidosis and is considered to be an independent factor from the ACE D allele for high levels of SACE in sarcoidosis. This fact could be one of the explanations for the increased SACE activity in sarcoidosis.

Angiotensin II facilitates breast cancer cell migration and metastasis.

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Sylvie Rodrigues-Ferreira

Full Text Available Breast cancer metastasis is a leading cause of death by malignancy in women worldwide. Efforts are being made to further characterize the rate-limiting steps of cancer metastasis, i.e. extravasation of circulating tumor cells and colonization of secondary organs. In this study, we investigated whether angiotensin II, a major vasoactive peptide both produced locally and released in the bloodstream, may trigger activating signals that contribute to cancer cell extravasation and metastasis. We used an experimental in vivo model of cancer metastasis in which bioluminescent breast tumor cells (D3H2LN were injected intra-cardiacally into nude mice in order to recapitulate the late and essential steps of metastatic dissemination. Real-time intravital imaging studies revealed that angiotensin II accelerates the formation of metastatic foci at secondary sites. Pre-treatment of cancer cells with the peptide increases the number of mice with metastases, as well as the number and size of metastases per mouse. In vitro, angiotensin II contributes to each sequential step of cancer metastasis by promoting cancer cell adhesion to endothelial cells, trans-endothelial migration and tumor cell migration across extracellular matrix. At the molecular level, a total of 102 genes differentially expressed following angiotensin II pre-treatment were identified by comparative DNA microarray. Angiotensin II regulates two groups of connected genes related to its precursor angiotensinogen. Among those, up-regulated MMP2/MMP9 and ICAM1 stand at the crossroad of a network of genes involved in cell adhesion, migration and invasion. Our data suggest that targeting angiotensin II production or action may represent a valuable therapeutic option to prevent metastatic progression of invasive breast tumors.

Interaction of a non-peptide agonist with angiotensin II AT1 receptor mutants

DEFF Research Database (Denmark)

Costa-Neto, Claudio M; Miyakawa, Ayumi A; Pesquero, João B

2002-01-01

and inositol phosphate turnover assays in COS-7 cells transiently transfected with the wild-type and mutant forms of the receptor. Mutant receptors bore modifications in the extracellular region: T88H, Y92H, G1961, G196W, and D278E. Compound L-162,313 displaced [125I]-Sar1,Leu8-AngII from the mutants G196I...... and G196W with IC50 values similar to that of the wild-type. The affinity was, however, slightly affected by the D278E mutation and more significantly by the T88H and Y92H mutations. In inositol phosphate turnover assays, the ability of L-162,313 to trigger the activation cascade was compared...... with that of angiotensin II. These assays showed that the G196W mutant reached a relative maximum activation exceeding that of the wild-type receptor; the efficacy was slightly reduced in the G1961 mutant and further reduced in the T88H, Y92H, and D278E mutants. Our data suggest that residues of the extracellular domain...

Regulation of the renin-angiotensin-aldosterone system in fibromyalgia.

Science.gov (United States)

Maliszewski, Anne M; Goldenberg, Don L; Hurwitz, Shelley; Adler, Gail K

2002-07-01

To assess the function of the renin-angiotensin-aldosterone (RAA) system in women with fibromyalgia (FM) compared to healthy women. Women with FM [n = 14, age 41.0+/-7.2 yrs, body mass index (BMI) 26.4+/-5.4 kg/m2] and healthy women (n = 13, age 40.0+/-7.7 yrs, BMI 25.0+/-5.0 kg/m2) were placed on a low sodium diet (10 mEq sodium/day) for 5 days. After being supine and fasting overnight, subjects received an intravenous infusion of angiotensin II at successive doses of 1, 3, and 10 ng/kg/min for 45 min per dose. Blood pressure (BP), plasma renin activity (PRA), aldosterone, and cortisol were measured at baseline and after each dose of angiotensin II. Prior to sodium restriction, women with FM completed the Hopkins Symptom Checklist-90, which included a question grading the extent of dizziness/faintness on a scale of 0 (none) to 4 (extremely). After dietary sodium restriction, baseline PRA, aldosterone, and supine BP were similar in healthy women and women with FM. Aldosterone and BP rose in response to infused angiotensin II; these responses did not differ significantly between healthy women and women with FM. In women with FM, symptoms of dizziness correlated inversely with BMI (r = -0.81, p < 0.001) and the systolic BP response to 10 ng/kg/min angiotensin II (r = -0.81, p < 0.001). The functioning of the RAA system, including the vascular response to angiotensin II, was intact in women with FM compared to healthy women. However, women with FM who complained of dizziness had a blunted vascular response to angiotensin II. This blunted vascular response may indicate intravascular volume depletion in women with symptoms of dizziness.

Focus on Brain Angiotensin III and Aminopeptidase A in the Control of Hypertension

Directory of Open Access Journals (Sweden)

John W. Wright

2012-01-01

Full Text Available The classic renin-angiotensin system (RAS was initially described as a hormone system designed to mediate cardiovascular and body water regulation. The discovery of a brain RAS composed of the necessary functional components (angiotensinogen, peptidases, angiotensins, and specific receptor proteins independent of the peripheral system significantly expanded the possible physiological and pharmacological functions of this system. This paper first describes the enzymatic pathways resulting in active angiotensin ligands and their interaction with AT1, AT2, and mas receptor subtypes. Recent evidence points to important contributions by brain angiotensin III (AngIII and aminopeptidases A (APA and N (APN in sustaining hypertension. Next, we discuss current approaches to the treatment of hypertension followed by novel strategies that focus on limiting the binding of AngII and AngIII to the AT1 receptor subtype by influencing the activity of APA and APN. We conclude with thoughts concerning future treatment approaches to controlling hypertension and hypotension.

Analysis of angiotensin II binding to human platelets: Differences in young and old subjects

International Nuclear Information System (INIS)

Siebers, M.J.; Goodfriend, T.L.; Ball, D.; Elliott, M.E.

1990-01-01

We examined the binding of radiolabeled angiotensin II (AII) to human platelets to characterize the apparent increase in AII receptors observed in older subjects. At 22 degrees C, the amount of radioactivity associated with platelets from older subjects increased continuously for more than 2 hours. The same amount of radioactivity was displaced by addition of unlabeled AII at 30 min and 60 min. In the presence of phenylarsine oxide, in the cold, or when labeled antagonist was the ligand, binding came to equilibrium by 30 min. High pressure liquid chromatography demonstrated that 125 I-AII was the major radioactive compound in the supernatant and platelets after incubation, but the platelets also contained radiolabeled AII fragments. Thus, some degradation accompanied interaction of AII and platelets. Phenylarsine oxide did not prevent degradation of bound AII, suggesting that degradation precedes internalization. On average, maximum binding was greater in older subjects whether platelets were incubated with 125 I-AII alone, with 125 I-AII and phenylarsine oxide to prevent internalization, or when the competitive inhibitor 125 I-sar1,ile8-AII was the radioligand. Variability of binding among subjects also increased with age. Thus, platelets bind, degrade, and internalize AII, and the three processes occur to a greater extent in platelets from some, but not all older subjects

Imbalance between pulmonary angiotensin-converting enzyme and angiotensin-converting enzyme 2 activity in acute respiratory distress syndrome

NARCIS (Netherlands)

Wosten-van Asperen, Roelie M.; Bos, Albert; Bem, Reinout A.; Dierdorp, Barbara S.; Dekker, Tamara; van Goor, Harry; Kamilic, Jelena; van der Loos, Chris M.; van den Berg, Elske; Bruijn, Martijn; van Woensel, Job B.; Lutter, Rene

2013-01-01

Objective: Angiotensin-converting enzyme and its effector peptide angiotensin II have been implicated in the pathogenesis of acute respiratory distress syndrome. Recently, angiotensin-converting enzyme 2 was identified as the counter-regulatory enzyme of angiotensin-converting enzyme that converts

The absence of protective effect of candesartan and angiotensin IV in the moderate brain injury in rats

International Nuclear Information System (INIS)

Nasser, M.; Botelle, L.; Javellaud, J.; Oudart, N.; Achard, J-M

2012-01-01

Background: angiotensin receptor blockers (ARB) are protective in various models of experimental ischemic stroke. This protective effect is mediated by the stimulation of non-AT1 receptors by angiotensin II and angiotensin IV. Since traumatic brain injury shares with ischemic cerebral injury several common mechanisms, we examined if a pretreatment with the ARB candesartan, or a post-treatment with angiotensin IV are also protective in a rat model of blunt traumatic brain injury (TBI). Methods :adults Sprague Dawley rats were treated for five days with candesartan (0.5 mg/kg/day) or saline by gavage prior to the induction of diffuse moderate TBI using the impact-acceleration model. Two others groups of rats were treated by a daily intraperitoneal injection of angiotensin IV (1.5 mg/kg/day) or saline for five days following TBI. Overall neurological insult were assessed daily by measuring the neurological score. Sensitive deficits (scotch test) and sensorimotor deficits (beam-walking test) were evaluated daily from day 1 to 7 and at day 15; cognitive impairment (object recognition test) was evaluated at day 15. Results : TBI induced significant sensitive and sensorimotor deficits that were maximal at day 1 and spontaneously improved with time. At day 15, traumatised animals had a marked alteration of the working memory. Neither treatment with candesartan, angiotensin IV or with erythropoietin decreased the severity of the initial sensorimotor deficits, nor accelerate the recovery rate. Candesartan, angiotensin IV had likewise no protective effect on the cognitive deficit evaluated to day 15. Conclusion: pretreatment with candesartan and post-treatment with angiotensin IV are both ineffective to protect against sensorimotor and c ognitive impairment in a rat model of impact-acceleration TBI. (author)

Between-patient differences in the renal response to renin-angiotensin system intervention : clue to optimising renoprotective therapy?

NARCIS (Netherlands)

Laverman, GD; de Zeeuw, D; Navis, G

2002-01-01

Renin-angiotensin-aldosterone system (RAAS) blockade with angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin II (Ang II), AT(1)-receptor blockers (ARB) is the cornerstone of renoprotective therapy. Still, the number of patients with end-stage renal disease is increasing worldwide,

Local renin–angiotensin system contributes to hyperthyroidism-induced cardiac hypertrophy

Science.gov (United States)

Kobori, H; Ichihara, A; Miyashita, Y; Hayashi, M; Saruta, T

2008-01-01

We have reported previously that thyroid hormone activates the circulating and tissue renin–angiotensin systems without involving the sympathetic nervous system, which contributes to cardiac hypertrophy in hyperthyroidism. This study examined whether the circulating or tissue renin–angiotensin system plays the principal role in hyperthyroidism-induced cardiac hypertrophy. The circulating renin–angiotensin system in Sprague–Dawley rats was fixed by chronic angiotensin II infusion (40 ng/ min, 28 days) via mini-osmotic pumps. Daily i.p. injection of thyroxine (0·1 mg/kg per day, 28 days) was used to mimic hyperthyroidism. Serum free tri-iodothyronine, plasma renin activity, plasma angiotensin II, cardiac renin and cardiac angiotensin II were measured with RIAs. The cardiac expression of renin mRNA was evaluated by semiquantitative reverse transcriptase-polymerase chain reaction. Plasma renin activity and plasma angiotensin II were kept constant in the angiotensin II and angiotensin II+thyroxine groups (0·12 ± 0·03 and 0·15 ± 0·03 μg/h per liter, 126 ± 5 and 130 ± 5 ng/l respectively) (means ± s.e.m.). Despite stabilization of the circulating renin–angiotensin system, thyroid hormone induced cardiac hypertrophy (5·0 ± 0·5 vs 3·5 ± 0·1 mg/g) in conjunction with the increases in cardiac expression of renin mRNA, cardiac renin and cardiac angiotensin II (74 ± 2 vs 48 ± 2%, 6·5 ± 0·8 vs 3·8 ± 0·4 ng/h per g, 231 ± 30 vs 149 ± 2 pg/g respectively). These results indicate that the local renin–angiotensin system plays the primary role in the development of hyperthyroidism-induced cardiac hypertrophy. PMID:9854175

Renin-Angiotensin Inhibitors Decrease Recurrence after Transurethral Resection of Bladder Tumor in Patients with Nonmuscle Invasive Bladder Cancer.

Science.gov (United States)

Blute, Michael L; Rushmer, Timothy J; Shi, Fangfang; Fuller, Benjamin J; Abel, E Jason; Jarrard, David F; Downs, Tracy M

2015-11-01

Prior reports suggest that renin-angiotensin system inhibition may decrease nonmuscle invasive bladder cancer recurrence. We evaluated whether angiotensin converting enzyme inhibitor or angiotensin receptor blocker treatment at initial surgery was associated with decreased recurrence or progression in patients with nonmuscle invasive bladder cancer. Using an institutional bladder cancer database we identified 340 patients with data available on initial transurethral resection of bladder tumor. Progression was defined as an increase to stage T2. Cox proportional hazards models were used to evaluate associations with recurrence-free and progression-free survival. Median patient age was 69.6 years. During a median followup of 3 years (IQR 1.3-6.1) 200 patients (59%) had recurrence and 14 (4.1%) had stage progression. Of those patients 143 were receiving angiotensin converting enzyme inhibitor/angiotensin receptor blockers at the time of the first transurethral resection. On univariate analysis factors associated with improved recurrence-free survival included carcinoma in situ (p = 0.040), bacillus Calmette-Guérin therapy (p = 0.003) and angiotensin converting enzyme inhibitor/angiotensin receptor blocker therapy (p = 0.009). Multivariate analysis demonstrated that patients treated with bacillus Calmette-Guérin therapy (HR 0.68, 95% CI 0.47-0.87, p = 0.002) or angiotensin converting enzyme inhibitor/angiotensin receptor blocker therapy (HR 0.61, 95% CI 0.45-0.84, p = 0.005) were less likely to experience tumor recurrence. The 5-year recurrence-free survival rate was 45.6% for patients treated with angiotensin converting enzyme inhibitor/angiotensin receptor blockers and 28.1% in those not treated with angiotensin converting enzyme inhibitor/angiotensin receptor blockers (p = 0.009). Subgroup analysis was performed to evaluate nonmuscle invasive bladder cancer pathology (Ta, T1 and carcinoma in situ) in 85 patients on bacillus Calmette-Guérin therapy alone and in

Renin-angiotensin system inhibitors, angiotensin I-converting enzyme gene insertion/deletion polymorphism, and cancer: The Rotterdam study

NARCIS (Netherlands)

R. van der Knaap (Ronald); C. Siemes (Claire); J.W.W. Coebergh (Jan Willem); P. Tikka-Kleemola (Päivi); A. Hofman (Albert); B.H.Ch. Stricker (Bruno)

2008-01-01

textabstractBACKGROUND. Angiotensin I-converting enzyme (ACE) inhibitors, angiotensin II antagonists, and the ACE insertion/deletion (I/D) gene polymorphism all influence serum angiotensin II action. Because angiotensin II levels have been associated with cancer, the objective of the current

Targeting Renin–Angiotensin System Against Alzheimer’s Disease

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Abadi Kahsu Gebre

2018-04-01

Full Text Available Renin Angiotensin System (RAS is a hormonal system that regulates blood pressure and fluid balance through a coordinated action of renal, cardiovascular, and central nervous systems. In addition to its hemodynamic regulatory role, RAS involves in many brain activities, including memory acquisition and consolidation. This review has summarized the involvement of RAS in the pathology of Alzheimer’s disease (AD, and the outcomes of treatment with RAS inhibitors. We have discussed the effect of brain RAS in the amyloid plaque (Aβ deposition, oxidative stress, neuroinflammation, and vascular pathology which are directly and indirectly associated with AD. Angiotensin II (AngII via AT1 receptor is reported to increase brain Aβ level via different mechanisms including increasing amyloid precursor protein (APP mRNA, β-secretase activity, and presenilin expression. Similarly, it was associated with tau phosphorylation, and reactive oxygen species generation. However, these effects are counterbalanced by Ang II mediated AT2 signaling. The protective effect observed with angiotensin receptor blockers (ARBs and angiotensin converting enzyme inhibitors (ACEIs could be as the result of inhibition of Ang II signaling. ARBs also offer additional benefit by shifting the effect of Ang II toward AT2 receptor. To conclude, targeting RAS in the brain may benefit patients with AD though it still requires further in depth understanding.

The angiotensin II type 2 receptor agonist Compound 21 is protective in experimental diabetes-associated atherosclerosis

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Chow, Bryna S M; Koulis, Christine; Krishnaswamy, Pooja

2016-01-01

AIMS/HYPOTHESIS: Angiotensin II is well-recognised to be a key mediator in driving the pathological events of diabetes-associated atherosclerosis via signalling through its angiotensin II type 1 receptor (AT1R) subtype. However, its actions via the angiotensin II type 2 receptor (AT2R) subtype...... are still poorly understood. This study is the first to investigate the role of the novel selective AT2R agonist, Compound 21 (C21) in an experimental model of diabetes-associated atherosclerosis (DAA). METHODS: Streptozotocin-induced diabetic Apoe-knockout mice were treated with vehicle (0.1 mol/l citrate...

Epistatic effects of polymorphisms in genes from the renin-angiotensin, bradykinin, and fibrinolytic systems on plasma t-PA and PAI-1 levels

NARCIS (Netherlands)

Asselbergs, Folkert W.; Williams, Scott M.; Hebert, Patricia R.; Coffey, Christopher S.; Hillege, Hans L.; Navis, Gerjan; Vaughan, Douglas E.; van Gilst, Wiek H.; Moore, Jason H.

Tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1) directly influence thrombus formation and degradation and thereby risk for arterial thrombosis. Activation of the renin-angiotensin system has been linked to the production of PAI-1 expression via the angiotensin II

A local renal renin-angiotensin system activation via renal uptake of prorenin and angiotensinogen in diabetic rats.

Science.gov (United States)

Tojo, Akihiro; Kinugasa, Satoshi; Fujita, Toshiro; Wilcox, Christopher S

2016-01-01

The mechanism of activation of local renal renin-angiotensin system (RAS) has not been clarified in diabetes mellitus (DM). We hypothesized that the local renal RAS will be activated via increased glomerular filtration and tubular uptake of prorenin and angiotensinogen in diabetic kidney with microalbuminuria. Streptozotocin (STZ)-induced DM and control rats were injected with human prorenin and subsequently with human angiotensinogen. Human prorenin uptake was increased in podocytes, proximal tubules, macula densa, and cortical collecting ducts of DM rats where prorenin receptor (PRR) was expressed. Co-immunoprecipitation of kidney homogenates in DM rats revealed binding of human prorenin to the PRR and to megalin. The renal uptake of human angiotensinogen was increased in DM rats at the same nephron sites as prorenin. Angiotensin-converting enzyme was increased in podocytes, but decreased in the proximal tubules in DM rats, which may have contributed to unchanged renal levels of angiotensin despite increased angiotensinogen. The systolic blood pressure increased more after the injection of 20 μg of angiotensinogen in DM rats than in controls, accompanied by an increased uptake of human angiotensinogen in the vascular endothelium. In conclusion, endocytic uptake of prorenin and angiotensinogen in the kidney and vasculature in DM rats was contributed to increased tissue RAS and their pressor response to angiotensinogen.

The renin–angiotensin system and diabetes: An update

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Antônio Ribeiro-Oliveira Jr

2008-08-01

Full Text Available Antônio Ribeiro-Oliveira Jr1, Anelise Impeliziere Nogueira1, Regina Maria Pereira2, Walkiria Wingester Vilas Boas3, Robson Augusto Souza dos Santos4, Ana Cristina Simões e Silva51Laboratório de Endocrinologia, Departamento de Clínica Médica, 2Departamento de Ciências Biológicas, Centro Universitário de Belo Horizonte, UNIBH, Belo Horizonte, MG, Brazil; 3Hospital Life Center, Belo Horizonte, MG, Brazil; 4Laboratório de Hipertensão, Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas, UFMG, Belo Horizonte, MG, Brazil; 5Departamento de Pediatria, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG, Belo Horizonte, MG, BrazilAbstract: In the past few years the classical concept of the renin–angiotensin system (RAS has experienced substantial conceptual changes. The identification of the renin/prorenin receptor, the angiotensin-converting enzyme homologue ACE2 as an angiotensin peptide processing enzyme, Mas as a receptor for Ang-(1-7 and the possibility of signaling through ACE, have contributed to switch our understanding of the RAS from the classical limited-proteolysis linear cascade to a cascade with multiple mediators, multiple receptors, and multi-functional enzymes. In this review we will focus on the recent findings related to RAS and, in particular, on its role in diabetes by discussing possible interactions between RAS mediators, endothelium function, and insulin signaling transduction pathways as well as the putative role of ACE2-Ang-(1-7-Mas axis in disease pathogenesis.Keywords: renin–angiotensin system, diabetes, angiotensin II, angiotensin-(1-7, insulin, endothelium

Evidence that the angiotensin at 2-receptor agonist compound 21 is also a low affinity thromboxane TXA2-receptor antagonist

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Fredgart, M.; Leurgans, T.; Stenelo, M.

2015-01-01

Objective: The objective of this study was to test whether Compound 21 (C21), a high-affinity, non-peptide angiotensinAT2-receptor agonist, is also an antagonist of thromboxane A2 (TXA2) receptors thus reducing both vasoconstriction and platelet aggregation. Design and method: Binding of C21...... to the TXA2 receptor was determined by TBXA2R Arrestin Biosensor Assay. Mouse mesenteric arteries were mounted in wire myographs, and responses to increasing concentrations of C21 (1nM- 10muM) were recorded during submaximal contractions with 0.1muM U46619 (TXA2 analogue) or 1muMphenylephrine. To control for......AT2-receptor specificity, arteries were pre-incubated with the AT2-receptor antagonist PD123319 (10muM), or mesenteric arteries from AT2-receptor knock-out (AT2R-/y) mice were used. An inhibitory effect of C21 (100nM - 10muM) on U46619 (0,3muM) induced platelet aggregation was examined in whole human...

Angiotensin II Type 1 Receptor Mechanoactivation Involves RGS5 (Regulator of G Protein Signaling 5) in Skeletal Muscle Arteries: Impaired Trafficking of RGS5 in Hypertension.

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Hong, Kwangseok; Li, Min; Nourian, Zahra; Meininger, Gerald A; Hill, Michael A

2017-12-01

Studies suggest that arteriolar pressure-induced vasoconstriction can be initiated by GPCRs (G protein-coupled receptors), including the AT 1 R (angiotensin II type 1 receptor). This raises the question, are such mechanisms regulated by negative feedback? The present studies examined whether RGS (regulators of G protein signaling) proteins in vascular smooth muscle cells are colocalized with the AT 1 R when activated by mechanical stress or angiotensin II and whether this modulates AT 1 R-mediated vasoconstriction. To determine whether activation of the AT 1 R recruits RGS5, an in situ proximity ligation assay was performed in primary cultures of cremaster muscle arteriolar vascular smooth muscle cells treated with angiotensin II or hypotonic solution in the absence or presence of candesartan (an AT 1 R blocker). Proximity ligation assay results revealed a concentration-dependent increase in trafficking/translocation of RGS5 toward the activated AT 1 R, which was attenuated by candesartan. In intact arterioles, knockdown of RGS5 enhanced constriction to angiotensin II and augmented myogenic responses to increased intraluminal pressure. Myogenic constriction was attenuated to a higher degree by candesartan in RGS5 siRNA-transfected arterioles, consistent with RGS5 contributing to downregulation of AT 1 R-mediated signaling. Further, translocation of RGS5 was impaired in vascular smooth muscle cells of spontaneously hypertensive rats. This is consistent with dysregulated (RGS5-mediated) AT 1 R signaling that could contribute to excessive vasoconstriction in hypertension. In intact vessels, candesartan reduced myogenic vasoconstriction to a greater extent in spontaneously hypertensive rats compared with controls. Collectively, these findings suggest that AT 1 R activation results in translocation of RGS5 toward the plasma membrane, limiting AT 1 R-mediated vasoconstriction through its role in G q/11 protein-dependent signaling. © 2017 American Heart Association, Inc.

Effects of angiotensin (1-7 on nephrosis of the mice with metabolic syndrome induced by high-salt and high-fat diet

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Nan ZHU

2013-11-01

Full Text Available Objective 　To establish a metabolic syndrome model of C57BL/6 mice by high-salt and high-fat diet, and investigate the effects of angiotensin converting enzyme 2 (ACE 2 and angiotensin (1-7 on renal damage in mice. Methods　Fifty-six male C57BL/6 mice were randomly divided into 7 groups (8 each, and fed with normal diet (0.3% NaCl, 10% fat, high-salt diet (8% NaCl, 10% fat, high-fat diet (0.3% NaCl, 60% fat, high-salt and high-fat diet (8% NaCl, 60% fat, high-salt and high-fat diet with enalapril 20mg/(kg•d, with valsartan 50mg/(kg•d, and with valsartan 50mg/(kg•d plus Mas receptor antagonist (A-779 150ng/(kg•d, respectively for 16 weeks. Basal metabolic index including blood pressure, body weight, blood glucose and urinary albumin excretion rate (UAER were tested. After intraperitoneal anesthesia with chloral hydrate, the blood was collected from the carotid artery. Serum angiotensin Ⅱ and angiotensin (1-7 levels were detected by ELISA; Western blotting was performed to evaluate the expression of ACE 2 protein and collagen Ⅲ in renal tissue; renal pathological changes were observed by HE and Masson staining. Results　The blood pressure, ratio of visceral fat weight/body weight, blood lipid, blood glucose and UAER increased significantly in the C57BL/6 mice fed with high-salt and high-fat diet for 16 weeks, and the renal fibrosis change was obvious, serum angiotensin Ⅱ level increased, expressions of ACE 2 and angiotensin (1-7 decreased significantly in the renal tissue. In different intervention groups, valsartan obviously alleviated the abnormal metabolism, ameliorated renal injury, promoted the expression of ACE2 and angiotensin (1-7 in the kidney and serum. However, no significant change was observed in the groups with intervention of enalapril or valsartan+A-779 compared with non-intervention group. Conclusions　High-salt and high-fat diet can be used to successfully establish the model of metabolic syndrome in C57BL/6

Angiotensin peptides in the non-gravid uterus: Paracrine actions beyond circulation.

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Casalechi, Maíra; Dela Cruz, Cynthia; Lima, Luiza C; Maciel, Luciana P; Pereira, Virgínia M; Reis, Fernando M

2018-03-01

The renin-angiotensin system (RAS) involves a complex network of precursors, peptides, enzymes and receptors comprising a systemic (endocrine) and a local (paracrine/autocrine) system. The local RAS plays important roles in tissue modulation and may operate independently of or in close interaction with the circulatory RAS, acting in a complementary fashion. Angiotensin (Ang) II, its receptor AT 1 and Ang-(1-7) expression in the endometrium vary with menstrual cycle, and stromal cell decidualization in vitro is accompanied by local synthesis of angiotensinogen and prorenin. Mas receptor is unlikely to undergo marked changes accompanying the cyclic ovarian steroid hormone fluctuations. Studies investigating the functional relevance of the RAS in the non-gravid uterus show a number of paracrine effects beyond circulation and suggest that RAS peptides may be involved in the pathophysiology of proliferative and fibrotic diseases. Endometrial cancer is associated with increased expression of Ang II, Ang-converting enzyme 1 and AT 1 in the tumoral tissue compared to neighboring non-neoplastic endometrium, and also with a gene polymorphism that enhances AT 1 signal. Ang II induces human endometrial cells to transdifferentiate into cells with myofibroblast phenotype and to synthetize extracellular matrix components that might contribute to endometrial fibrosis. Altogether, these findings point to a fully operating RAS within the uterus, but since many concepts rely on preliminary evidence further studies are needed to clarify the role of the local RAS in uterine physiology and pathophysiology. Copyright © 2018 Elsevier Inc. All rights reserved.

Role of the renin-angiotensin system in hepatic fibrosis and portal hypertension.

Science.gov (United States)

Shim, Kwang Yong; Eom, Young Woo; Kim, Moon Young; Kang, Seong Hee; Baik, Soon Koo

2018-05-01

The renin-angiotensin system (RAS) is an important regulator of cirrhosis and portal hypertension. As hepatic fibrosis progresses, levels of the RAS components angiotensin (Ang) II, Ang-(1-7), angiotensin-converting enzyme (ACE), and Ang II type 1 receptor (AT1R) are increased. The primary effector Ang II regulates vasoconstriction, sodium homoeostasis, fibrosis, cell proliferation, and inflammation in various diseases, including liver cirrhosis, through the ACE/Ang II/AT1R axis in the classical RAS. The ACE2/Ang-(1-7)/Mas receptor and ACE2/Ang-(1-9)/AT2R axes make up the alternative RAS and promote vasodilation, antigrowth, proapoptotic, and anti-inflammatory effects; thus, countering the effects of the classical RAS axis to reduce hepatic fibrogenesis and portal hypertension. Patients with portal hypertension have been treated with RAS antagonists such as ACE inhibitors, Ang receptor blockers, and aldosterone antagonists, with very promising hemodynamic results. In this review, we examine the RAS, its roles in hepatic fibrosis and portal hypertension, and current therapeutic approaches based on the use of RAS antagonists in patients with portal hypertension.

Angiotensin, transforming growth factor β and aortic dilatation in Marfan syndrome: Of mice and humans

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Christopher Yu

2018-03-01

Full Text Available Marfan syndrome is consequent upon mutations in FBN1, which encodes the extracellular matrix microfibrillar protein fibrillin-1. The phenotype is characterised by development of thoracic aortic aneurysm. Current understanding of the pathogenesis of aneurysms in Marfan syndrome focuses upon abnormal vascular smooth muscle cell signalling through the transforming growth factor beta (TGFβ pathway. Angiotensin II (Ang II can directly induce aortic dilatation and also influence TGFβ synthesis and signalling. It has been hypothesised that antagonism of Ang II signalling may protect against aortic dilatation in Marfan syndrome. Experimental studies have been supportive of this hypothesis, however results from multiple clinical trials are conflicting. This paper examines current knowledge about the interactions of Ang II and TGFβ signalling in the vasculature, and critically interprets the experimental and clinical findings against these signalling interactions. Keywords: Aneurysm, Angiotensin blocker, Cell Signalling, Clinical trial

Angiotensin-converting enzyme and angiotensin II receptor subtype 2 genotypes in type 1 diabetes and severe hypoglycaemia requiring emergency treatment: a case cohort study

DEFF Research Database (Denmark)

Pedersen-Bjergaard, Ulrik; Nielsen, Søren L; Akram, Kamran

2009-01-01

AIMS: In type 1 diabetes, individual susceptibility to severe hypoglycaemia is likely to be influenced by genetic factors. We have previously reported an association of the deletion (D-) allele of the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism and the A-allele of th...

Splanchnic blood flow and hepatic glucose production in exercising humans

DEFF Research Database (Denmark)

Bergeron, R; Kjaer, M; Simonsen, L

2001-01-01

The study examined the implication of the renin-angiotensin system (RAS) in regulation of splanchnic blood flow and glucose production in exercising humans. Subjects cycled for 40 min at 50% maximal O(2) consumption (VO(2 max)) followed by 30 min at 70% VO(2 max) either with [angiotensin-converti......The study examined the implication of the renin-angiotensin system (RAS) in regulation of splanchnic blood flow and glucose production in exercising humans. Subjects cycled for 40 min at 50% maximal O(2) consumption (VO(2 max)) followed by 30 min at 70% VO(2 max) either with [angiotensin......-converting enzyme (ACE) blockade] or without (control) administration of the ACE inhibitor enalapril (10 mg iv). Splanchnic blood flow was estimated by indocyanine green, and splanchnic substrate exchange was determined by the arteriohepatic venous difference. Exercise led to an approximately 20-fold increase (P ...-blockade group vs. the control group, hormones, metabolites, VO(2), and RER followed the same pattern of changes in ACE-blockade and control groups during exercise. Splanchnic blood flow (at rest: 1.67 +/- 0.12, ACE blockade; 1.59 +/- 0.18 l/min, control) decreased during moderate exercise (0.78 +/- 0.07, ACE...

Associations between the deletion polymorphism of the angiotensin 1-converting enzyme gene and ocular signs of primary open-angle glaucoma

NARCIS (Netherlands)

Bunce, Catey; Hitchings, Roger A.; van Duijn, Cornelia M.; de Jong, Paulus T. V. M.; Vingerling, Johannes R.

2005-01-01

Primary open-angle glaucoma (POAG) is a leading cause of blindness. High intraocular pressure (IOP) has been shown to be a key risk factor for POAG. Topical application of angiotensin 1-converting enzyme (ACE) inhibitors has been shown to lower IOP, and angiotensin-induced increase in vascular tone

Inhibition of angiotensin II-induced facilitation of sympathetic neurotransmission in the pithed rat: a comparison between losartan, irbesartan, telmisartan, and captopril

NARCIS (Netherlands)

Balt, J. C.; Mathy, M. J.; Pfaffendorf, M.; van Zwieten, P. A.

2001-01-01

Numerous studies have shown that angiotensin II enhances sympathetic nervous transmission. The objective of the present study was to quantify the inhibitory effect of the angiotensin II type 1 (AT1) receptor blockers losartan, irbesartan and telmisartan and the angiotensin converting enzyme (ACE)

Renin angiotensin system and cardiac hypertrophy after sinoaortic denervation in rats

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Aline Cristina Piratello

2010-01-01

Full Text Available OBJECTIVE: The aim of this study was to evaluate the role of angiotensin I, II and 1-7 on left ventricular hypertrophy of Wistar and spontaneously hypertensive rats submitted to sinoaortic denervation. METHODS: Ten weeks after sinoaortic denervation, hemodynamic and morphofunctional parameters were analyzed, and the left ventricle was dissected for biochemical analyses. RESULTS: Hypertensive groups (controls and denervated showed an increase on mean blood pressure compared with normotensive ones (controls and denervated. Blood pressure variability was higher in denervated groups than in their respective controls. Left ventricular mass and collagen content were increased in the normotensive denervated and in both spontaneously hypertensive groups compared with Wistar controls. Both hypertensive groups presented a higher concentration of angiotensin II than Wistar controls, whereas angiotensin 1-7 concentration was decreased in the hypertensive denervated group in relation to the Wistar groups. There was no difference in angiotensin I concentration among groups. CONCLUSION: Our results suggest that not only blood pressure variability and reduced baroreflex sensitivity but also elevated levels of angiotensin II and a reduced concentration of angiotensin 1-7 may contribute to the development of left ventricular hypertrophy. These data indicate that baroreflex dysfunction associated with changes in the renin angiotensin system may be predictive factors of left ventricular hypertrophy and cardiac failure.

Association of renin-angiotensin system genes polymorphism with progression of diabetic nephropathy in patients with type 1 diabetes mellitus

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Ilić Vesna

2014-01-01

Full Text Available Background/Aim. Diabetic nephropathy (DN as a major microvascular complication of diabetes mellitus (DM include a progressive increase in urinary albumin excretion in association with an increase in blood pressure and to end stage renal failure. Hypertension connected with renin-angiotensin system (RAS hyperactivity and corresponding genotypes, angiotensinogen (AGT, angiotensine-converting enzyme (ACE and angiotensin II type 1 receptor (AT1R, predispose the increasing risk of DN. The aim of this study was to assess the distribution of AGT, ACE and AT1R gene polymorphisms in patients with type 1 DM according to the level of DN and patients clinical characteristics. Methods. The study included 79 type 1 diabetic patients. Inclusion criteria were: age between 20-40, duration of diabetes > 5 years, and no other severe diseases. Clinical characteristics were gained from interviewing the patients. Polymorphism was detected by polymerase chain reaction (PCR and restriction fragment length polymorphism using restriction enzymes Psy I (Tth 111 I and Hae III. Results. The patients with proteinuria compared with normo- and microalbuminuric patients, highly differed in age, diabetes duration, blood pressure level, hypertension, rethynopathy and urinary albumin excretion values (p < 0.001. No statistically significant difference between the groups was found for the ACE and AT1R gene polymorphisms distribution. The presence of TT genotype of the M235T polymorphism was significantly higher in the group with proteinuria (p < 0.05. The patients with hypertension raised nephropathy 5.2 times higher (OR = 5.20, p < 0.05 while carriers of TT allel developed nephropathy 28.38 times higher (OR = 28.389, p < 0.01 than those with MM genotype. Conclusion. Increased association of hypertension and TT angiotensinogen gene polymorphism in patients with diabetes mellitus with proteinuria could be a significant marker of diabetic nephropathy.

Rcan1-1L overexpression induces mitochondrial autophagy and improves cell survival in angiotensin II-exposed cardiomyocytes

International Nuclear Information System (INIS)

Duan, Hongyan; Li, Yongqiang; Yan, Lijie; Yang, Haitao; Wu, Jintao; Qian, Peng; Li, Bing; Wang, Shanling

2015-01-01

Mitochondrial autophagy is an important adaptive stress response and can be modulated by various key molecules. A previous study found that the regulator of calcineurin 1-1L (Rcan1-1L) may regulate mitochondrial autophagy and cause mitochondria degradation in neurocytes. However, the effect of Rcan1-1L on cardiomyocytes has not been determined. In the present study, we aimed to investigate the role of Rcan1-1L in angiotensin II (Ang II)-exposed human cardiomyocytes. Above all, Human adult cardiac myocytes (HACMs) were exposed to 200 nmol/L Ang II for 4 days. Enhanced H 2 O 2 production, cytochrome C release and mitochondrial permeability were observed in these cells, which were blocked by valsartan. Consistently, Ang II exposure significantly reduced cardiomyocyte viability. However, transfection of Rcan1-1L vector promoted cell viability and ameliorated the apoptosis caused by Ang II. Rcan1-1L clearly promoted mitochondrial autophagy in HACMs, with elevated autophagy protein (ATG) 5 and light chain 3 (LC3) expression. Transient mitochondrial biogenesis and reduced cytochrome C release was also induced by Rcan1-1L. Additionally, Rcan1-1L significantly inhibited calcineurin/nuclear factor of activated T cells (NFAT) signaling. We thus conclude that Rcan1-1L may play a protective role in Ang II-treated cardiomyocytes through the induction of mitochondrial autophagy, and may be an alternative method of cardiac protection. - Highlights: • Transfection of Rcan1-1L into HACMs promoted cell viability and reduced apoptosis. • Transfection of Rcan1-1L promoted mitochondrial autophagy in HACMs. • Rcan1-1L inhibited the calcineurin/nuclear factor of activated T cells signaling

Rcan1-1L overexpression induces mitochondrial autophagy and improves cell survival in angiotensin II-exposed cardiomyocytes

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Duan, Hongyan; Li, Yongqiang; Yan, Lijie; Yang, Haitao; Wu, Jintao; Qian, Peng; Li, Bing; Wang, Shanling, E-mail: shanglingwang@126.com

2015-07-01

Mitochondrial autophagy is an important adaptive stress response and can be modulated by various key molecules. A previous study found that the regulator of calcineurin 1-1L (Rcan1-1L) may regulate mitochondrial autophagy and cause mitochondria degradation in neurocytes. However, the effect of Rcan1-1L on cardiomyocytes has not been determined. In the present study, we aimed to investigate the role of Rcan1-1L in angiotensin II (Ang II)-exposed human cardiomyocytes. Above all, Human adult cardiac myocytes (HACMs) were exposed to 200 nmol/L Ang II for 4 days. Enhanced H{sub 2}O{sub 2} production, cytochrome C release and mitochondrial permeability were observed in these cells, which were blocked by valsartan. Consistently, Ang II exposure significantly reduced cardiomyocyte viability. However, transfection of Rcan1-1L vector promoted cell viability and ameliorated the apoptosis caused by Ang II. Rcan1-1L clearly promoted mitochondrial autophagy in HACMs, with elevated autophagy protein (ATG) 5 and light chain 3 (LC3) expression. Transient mitochondrial biogenesis and reduced cytochrome C release was also induced by Rcan1-1L. Additionally, Rcan1-1L significantly inhibited calcineurin/nuclear factor of activated T cells (NFAT) signaling. We thus conclude that Rcan1-1L may play a protective role in Ang II-treated cardiomyocytes through the induction of mitochondrial autophagy, and may be an alternative method of cardiac protection. - Highlights: • Transfection of Rcan1-1L into HACMs promoted cell viability and reduced apoptosis. • Transfection of Rcan1-1L promoted mitochondrial autophagy in HACMs. • Rcan1-1L inhibited the calcineurin/nuclear factor of activated T cells signaling.

Angiotensin II and Renal Tubular Ion Transport

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Patricia Valles

2005-01-01

Evidence for the regulation of H+-ATPase activity in vivo and in vitro by trafficking/exocytosis has been provided. An additional level of H+-ATPase regulation via protein synthesis may be important as well. Recently, we have shown that both aldosterone and angiotensin II provide such a mechanism of regulation in vivo at the level of the medullary collecting tubule. Interestingly, in this part of the nephron, the effects of aldosterone and angiotensin II are not sodium dependent, whereas in the cortical collecting duct, both aldosterone and angiotensin II, by contrast, affect H+ secretion by sodium-dependent mechanisms.

Impact of angiotensin II on skeletal muscle metabolism and function in mice: contribution of IGF-1, Sirtuin-1 and PGC-1α.

Science.gov (United States)

Kackstein, Katharina; Teren, Andrej; Matsumoto, Yasuharu; Mangner, Norman; Möbius-Winkler, Sven; Linke, Axel; Schuler, Gerhard; Punkt, Karla; Adams, Volker

2013-05-01

Activation of the renin-angiotensin-aldosterone system and increased levels of angiotensin II (Ang-II) occurs in numerous cardiovascular diseases such as chronic heart failure (CHF). Another hallmark in CHF is a reduced exercise tolerance with impaired skeletal muscle function. The aim of this study was to investigate in an animal model the impact of Ang-II on skeletal muscle function and concomitant molecular alterations. Mice were infused with Ang-II for 4 weeks. Subsequently, skeletal muscle function of the soleus muscle was assessed. Expression of selected proteins was quantified by qRT-PCR and Western blot. Infusion of Ang-II resulted in a 33% reduction of contractile force, despite a lack of changes in muscle weight. At the molecular level an increased expression of NAD(P)H oxidase and a reduced expression of Sirt1, PGC-1α and IGF-1 were noticed. No change was evident for the ubiquitin E3-ligases MuRF1 and MafBx and α-sarcomeric actin expression. Cytophotometrical analysis of the soleus muscle revealed a metabolic shift toward a glycolytic profile. This study provides direct evidence of Ang-II-mediated, metabolic deterioration of skeletal muscle function despite preserved muscle mass. One may speculate that the Ang-II-mediated loss of muscle force is due to an activation of NAD(P)H oxidase expression and a subsequent ROS-induced down regulation of IGF-1, PGC-1α and Sirt1. Copyright © 2012 Elsevier GmbH. All rights reserved.

Angiotensin and bradykinin interactions with phospholipids

International Nuclear Information System (INIS)

Elliott, M.E.; Goodfriend, T.L.

1979-01-01

Reversible interactions were demonstrated between some phospholipids and some polypeptides related to angiotensin and bradykinin. The extent of the interaction was dependent on the structures of the lipid and peptide. The naturally occurring compounds that interacted most avidly were cardiolipin and (des-Asp 1 )-angiotensins. The apparent dissociation constant of this complex in chloroform was 10 -5 M. The complex contained more than one cardiolipin molecule/molecule of peptide. Kinins interacted most strongly with lecithin. The phospholipids altered the chromatographic behaviour of radioiodinated derivatives of the polypeptides, and solubilized radioactive and unlabeled polypeptides in chloroform. In aqueous media, cardiolipin suspensions preferentially bound (des-Asp 1 )-angiotensin II, and inhibited its binding by antibody. The interactions were sensitive to pH and cations in the aqueous phase, and were reversed by some reagents added to the organic phase. These interactions have direct implications for binding reactions of peptides in vitro, and may bear upon the actions of the hormones in vivo. (Auth.)

The mechanisms behind decreased internalization of angiotensin II type 1 receptor.

Science.gov (United States)

Bian, Jingwei; Zhang, Suli; Yi, Ming; Yue, Mingming; Liu, Huirong

2018-04-01

The internalization of angiotensin II type 1 receptor (AT 1 R) plays an important role in maintaining cardiovascular homeostasis. Decreased receptor internalization is closely related to cardiovascular diseases induced by the abnormal activation of AT 1 R, such as hypertension. However, the mechanism behind reduced AT 1 R internalization is not fully understood. This review focuses on four parts of the receptor internalization process (the combination of agonists and receptors, receptor phosphorylation, endocytosis, and recycling) and summarizes the possible mechanisms by which AT 1 R internalization is reduced based on these four parts of the process. (1) The agonist has a large molecular weight or a stronger ability to hydrolyze phosphatidylinositol 4,5-bisphosphate (PtdIns (4,5) P 2 ), which can increase the consumption of PtdIns (4,5) P 2 . (2) AT 1 R phosphorylation is weakened because of an abnormal function of phosphorylated kinase or changes in phospho-barcoding and GPCR-β-arrestin complex conformation. (3) The abnormal formation of vesicles or AT 1 R heterodimers with fewer endocytic receptors results in less AT 1 R endocytosis. (4) The enhanced activity and upregulated expression of small GTP-binding protein 4 (Rab4) and 11 (Rab11), which regulate receptor recycling, and phosphatidylinositol 3-kinase increase AT 1 R recycling. In addition, lower expression of AT 1 R-associated protein (ATRAP) or higher expression of AT 1 R-associated protein 1 (ARAP1) can reduce receptor internalization. Copyright © 2018 Elsevier Inc. All rights reserved.

Perioperative changes of serum cortisol and plasma angiotensin II levels in patients undergoing thoracotomy for malignancy

International Nuclear Information System (INIS)

Tian Runhua; Lun Limin; Li Yusheng; Yu Yunyun; Li Xin; Zheng Chunxi

2006-01-01

Objective: To investigate the perioperative changes of serum stress hormones cortisol and plasma angiotensin II in patients undergoing thoracotomy for malignancy. Methods: Serum cortisol and plasma angiotensin II levels were measured with RIA repeatedly in 35 thoracotomy patients operated for malignancy before operation, 1 h after starting operation, at the end of operation, and one day later, Heart rate and blood pressure were constantly monitored during operation. Results: The serum levels of cortisol and plasma angiotensin-II rose gradually during operation with significant differences among the measurements (P < 0. 001 -0.05), No age-difference for the measurements was observed except for a higher systolic pressure in patients over 60. Heart rates at 1 h were positively correlated with 1 h angiotensin-II levels. Heart rates at the end of operation were positively correlated with the cortisol and angiotensin-II levels at that time. Conclusion: The serum levels of these stress hormones rose significantly during the operation. Stress responses in older patients were adequate, yet the higher levels of stress hormones might bring more adverse effect in elderly people, especially cognition impairment. Smooth anaesthesia and adequate post-operative analgesia would lessen the stress effect, providing more ideal recovery, especially for the older patients. (authors)

Heart Failure Therapeutics on the Basis of a Biased Ligand of the Angiotensin-2 Type 1 Receptor Rationale and Design of the BLAST-AHF Study (Biased Ligand of the Angiotensin Receptor Study in Acute Heart Failure)

NARCIS (Netherlands)

Felker, G. Michael; Butler, Javed; Collins, Sean P.; Cotter, Gad; Davison, Beth A.; Ezekowitz, Justin A.; Filippatos, Gerasimos; Levy, Phillip D.; Metra, Marco; Ponikowski, Piotr; Soergel, David G.; Teerlink, John R.; Violin, Jonathan D.; Voors, Adriaan A.; Pang, Peter S.

The BLAST-AHF (Biased Ligand of the Angiotensin Receptor Study in Acute Heart Failure) study is designed to test the efficacy and safety of TRV027, a novel biased ligand of the angiotensin-2 type 1 receptor, in patients with acute heart failure (AHF). AHF remains a major public health problem, and

Renin angiotensin system and gender differences in dopaminergic degeneration

Directory of Open Access Journals (Sweden)

Rodriguez-Perez Ana I

2011-08-01

Full Text Available Abstract Background There are sex differences in dopaminergic degeneration. Men are approximately two times as likely as premenopausal women of the same age to develop Parkinson's disease (PD. It has been shown that the local renin angiotensin system (RAS plays a prominent role in sex differences in the development of chronic renal and cardiovascular diseases, and there is a local RAS in the substantia nigra and dopaminergic cell loss is enhanced by angiotensin via type 1 (AT1 receptors. Results In the present study, we observed that intrastriatal injection of 6-hydroxydopamine induced a marked loss of dopaminergic neurons in the substantia nigra of male rats, which was significantly higher than the loss induced in ovariectomized female rats given estrogen implants (i.e. rats with estrogen. However, the loss of dopaminergic neurons was significantly lower in male rats treated with the AT1 antagonist candesartan, and similar to that observed in female rats with estrogen. The involvement of the RAS in gender differences in dopaminergic degeneration was confirmed with AT1a-null mice lesioned with the dopaminergic neurotoxin MPTP. Significantly higher expression of AT1 receptors, angiotensin converting enzyme activity, and NADPH-oxidase complex activity, and much lower levels of AT2 receptors were observed in male rats than in female rats with estrogen. Conclusions The results suggest that brain RAS plays a major role in the increased risk of developing PD in men, and that manipulation of brain RAS may be an efficient approach for neuroprotective treatment of PD in men, without the feminizing effects of estrogen.

Evidence for Heterodimerization and Functional Interaction of the Angiotensin Type 2 Receptor and the Receptor MAS.

Science.gov (United States)

Leonhardt, Julia; Villela, Daniel C; Teichmann, Anke; Münter, Lisa-Marie; Mayer, Magnus C; Mardahl, Maibritt; Kirsch, Sebastian; Namsolleck, Pawel; Lucht, Kristin; Benz, Verena; Alenina, Natalia; Daniell, Nicholas; Horiuchi, Masatsugu; Iwai, Masaru; Multhaup, Gerhard; Schülein, Ralf; Bader, Michael; Santos, Robson A; Unger, Thomas; Steckelings, Ulrike Muscha

2017-06-01

The angiotensin type 2 receptor (AT2R) and the receptor MAS are receptors of the protective arm of the renin-angiotensin system. They mediate strikingly similar actions. Moreover, in various studies, AT2R antagonists blocked the effects of MAS agonists and vice versa. Such cross-inhibition may indicate heterodimerization of these receptors. Therefore, this study investigated the molecular and functional interplay between MAS and the AT2R. Molecular interactions were assessed by fluorescence resonance energy transfer and by cross correlation spectroscopy in human embryonic kidney-293 cells transfected with vectors encoding fluorophore-tagged MAS or AT2R. Functional interaction of AT2R and MAS was studied in astrocytes with CX3C chemokine receptor-1 messenger RNA expression as readout. Coexpression of fluorophore-tagged AT2R and MAS resulted in a fluorescence resonance energy transfer efficiency of 10.8 ± 0.8%, indicating that AT2R and MAS are capable to form heterodimers. Heterodimerization was verified by competition experiments using untagged AT2R and MAS. Specificity of dimerization of AT2R and MAS was supported by lack of dimerization with the transient receptor potential cation channel, subfamily C-member 6. Dimerization of the AT2R was abolished when it was mutated at cysteine residue 35. AT2R and MAS stimulation with the respective agonists, Compound 21 or angiotensin-(1-7), significantly induced CX3C chemokine receptor-1 messenger RNA expression. Effects of each agonist were blocked by an AT2R antagonist (PD123319) and also by a MAS antagonist (A-779). Knockout of a single of these receptors made astrocytes unresponsive for both agonists. Our results suggest that MAS and the AT2R form heterodimers and that-at least in astrocytes-both receptors functionally depend on each other. © 2017 American Heart Association, Inc.

Effects of angiotensin II receptor blockade on cerebral, cardiovascular, counter-regulatory, and symptomatic responses during hypoglycaemia in patients with type 1 diabetes

DEFF Research Database (Denmark)

Færch, Louise H; Thorsteinsson, Birger; Tarnow, Lise

2015-01-01

INTRODUCTION: High spontaneous activity of the renin-angiotensin system (RAS) results in more pronounced cognitive impairment and more prolonged QTc interval during hypoglycaemia in type 1 diabetes. We tested whether angiotensin II receptor blockade improves cerebral and cardiovascular function d...

Role of Mas receptor in renal blood flow response to angiotensin-(1-7) in ovariectomized estradiol treated rats.

Science.gov (United States)

Saberi, Shadan; Dehghani, Aghdas; Nematbakhsh, Mehdi

2016-01-01

The angiotensin 1-7 (Ang 1-7), is abundantly produced in kidneys and antagonizes the function of angiotensin II through Mas receptor (MasR) or other unknown mechanisms. In the current study, the role of MasR and steroid hormone estrogen on renal blood flow response to Ang 1-7 administration was investigated in ovariectomized (OV) female rats. OV female Wistar-rats received estradiol (500 μg/kg/week) or vehicle for two weeks. In the day of the experiment, the animals were anesthetized, cannulated, and the responses including mean arterial pressure, renal blood flow (RBF), and renal vascular resistance at the constant level of renal perfusion pressure to graded infusion of Ang 1-7 at 0, 100 and 300 ng/kg/min were determined in OV and OV estradiol-treated (OVE) rats, treated with vehicle or MasR antagonist; A779. RBF response to Ang 1-7 infusion increased dose-dependently in vehicle (Pdose <0.001) and A779-treated (Pdose <0.01) animals. However, when MasR was blocked, the RBF response to Ang 1-7 significantly increased in OV animals compared with OVE rats (P<0.05). When estradiol was limited by ovariectomy, A779 increased RBF response to Ang 1-7 administration, while this response was attenuated in OVE animals.

Tissue Renin-Angiotensin Systems: A Unifying Hypothesis of Metabolic Disease

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Jeppe eSkov

2014-02-01

Full Text Available The actions of angiotensin peptides are diverse and locally acting tissue renin-angiotensin systems (RAS are present in almost all tissues of the body. An activated RAS strongly correlates to metabolic disease (e.g. diabetes and its complications and blockers of RAS have been demonstrated to prevent diabetes in humans.Hyperglycemia, obesity, hypertension, and cortisol are well-known risk factors of metabolic disease and all stimulate tissue RAS whereas glucagon-like peptide-1, vitamin D, and aerobic exercise are inhibitors of tissue RAS and to some extent can prevent metabolic disease. Furthermore, an activated tissue RAS deteriorates the same risk factors creating a system with several positive feedback pathways. The primary effector hormone of the RAS, angiotensin II, stimulates reactive oxygen species, induces tissue damage, and can be associated to most diabetic complications. Based on these observations we hypothesize that an activated tissue RAS is the principle cause of metabolic syndrome and type 2 diabetes, and additionally is mediating the majority of the metabolic complications. The involvement of positive feedback pathways may create a self-reinforcing state and explain why metabolic disease initiate and progress. The hypothesis plausibly unify the major predictors of metabolic disease and places tissue RAS regulation in the center of metabolic control.

Enhanced activity of an angiotensin-(1-7) neuropeptidase in glucocorticoid-induced fetal programming.

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Marshall, Allyson C; Shaltout, Hossam A; Pirro, Nancy T; Rose, James C; Diz, Debra I; Chappell, Mark C

2014-02-01

We previously identified angiotensin converting enzyme (ACE) and an endopeptidase activity that degraded angiotensin-(1-7) [Ang-(1-7)] to Ang-(1-5) and Ang-(1-4), respectively, in the cerebrospinal fluid (CSF) of 6-month old male sheep. The present study undertook a more comprehensive analysis of the CSF peptidase that converts Ang-(1-7) to Ang-(1-4) in control and in utero betamethasone-exposed sheep (BMX). Characterization of the Ang-(1-7) peptidase revealed that the thiol agents 4-aminophenylmercuric acetate (APMA) and p-chloromercuribenzoic acid (PCMB), as well as the metallo-chelators o-phenanthroline and EDTA essentially abolished the enzyme activity. Additional inhibitors for serine, aspartyl, and cysteine proteases, as well as selective inhibitors against the endopeptidases neprilysin, neurolysin, prolyl and thimet oligopeptidases did not attenuate enzymatic activity. Competition studies against the peptidase revealed similar IC50s for Ang-(1-7) (5μM) and Ang II (3μM), but lower values for Ala(1)-Ang-(1-7) and Ang-(2-7) of 1.8 and 2.0μM, respectively. In contrast, bradykinin exhibited a 6-fold higher IC50 (32μM) than Ang-(1-7) while neurotensin was a poor competitor. Mean arterial pressure (78±1 vs. 94±2mmHg, N=4-5, Pfetal programming. Copyright © 2013 Elsevier Inc. All rights reserved.

Activation of Central PPAR-γ Attenuates Angiotensin II-Induced Hypertension

Science.gov (United States)

Yu, Yang; Xue, Bao-Jian; Wei, Shun-Guang; Zhang, Zhi-Hua; Beltz, Terry G; Guo, Fang; Johnson, Alan Kim; Felder, Robert B

2015-01-01

Inflammation and renin-angiotensin system activity in the brain contribute to hypertension through effects on fluid intake, vasopressin release, and sympathetic nerve activity. We recently reported that activation of brain peroxisome proliferator-activated receptor (PPAR)-γ in heart failure rats reduced inflammation and renin-angiotensin system activity in the hypothalamic paraventricular nucleus and ameliorated the peripheral manifestations of heart failure. We hypothesized that activation of brain PPAR-γ might have beneficial effects in angiotensin II-induced hypertension. Sprague-Dawley rats received a 2-week subcutaneous infusion of angiotensin II (120 ng/kg/min) combined with a continuous intracerebroventricular infusion of vehicle, the PPAR-γ agonist pioglitazone (3 nmol/h) or the PPAR-γ antagonist GW9662 (7 nmol/h). Angiotensin II+vehicle rats had increased mean blood pressure, increased sympathetic drive as indicated by the mean blood pressure response to ganglionic blockade, and increased water consumption. PPAR-γ mRNA in subfornical organ and hypothalamic paraventricular nucleus was unchanged, but PPAR-γ DNA binding activity was reduced. mRNA for interleukin-1β, tumor necrosis factor-α, cyclooxygenase-2 and angiotensin II type-1 receptor was augmented in both nuclei, and hypothalamic paraventricular nucleus neuronal activity was increased. The plasma vasopressin response to a 6-hour water restriction also increased. These responses to angiotensin II were exacerbated by GW9662 and ameliorated by pioglitazone, which increased PPAR-γ mRNA and PPAR-γ DNA binding activity in subfornical organ and hypothalamic paraventricular nucleus. Pioglitazone and GW9662 had no effects on control rats. The results suggest that activating brain PPAR-γ to reduce central inflammation and brain renin-angiotensin system activity may be a useful adjunct in the treatment of angiotensin II-dependent hypertension. PMID:26101342

Angiotensin type 1a receptors in the paraventricular nucleus of the hypothalamus protect against diet-induced obesity

Science.gov (United States)

de Kloet, Annette D.; Pati, Dipanwita; Wang, Lei; Hiller, Helmut; Sumners, Colin; Frazier, Charles J.; Seeley, Randy J.; Herman, James P.; Woods, Stephen C.; Krause, Eric G.

2013-01-01

Obesity is associated with increased levels of angiotensin-II (Ang-II), which activates angiotensin type-1a receptors (AT1a) to influence cardiovascular function and energy homeostasis. To test the hypothesis that specific AT1a within the brain control these processes, we utilized the Cre/lox system to delete AT1a from the paraventricular nucleus of the hypothalamus (PVN) of mice. PVN AT1a deletion did not affect body mass or adiposity when mice were maintained on standard chow. However, maintenance on a high-fat diet revealed a gene by environment interaction whereby mice lacking AT1a in the PVN had increased food intake and decreased energy expenditure that augmented body mass and adiposity relative to controls. Despite this increased adiposity, PVN AT1a deletion reduced systolic blood pressure, suggesting that this receptor population mediates the positive correlation between adiposity and blood pressure. Gene expression studies revealed that PVN AT1a deletion decreased hypothalamic expression of corticotrophin-releasing hormone and oxytocin, neuropeptides known to control food intake and sympathetic nervous system activity. Whole cell patch clamp recordings confirmed that PVN AT1a deletion eliminates responsiveness of PVN parvocellular neurons to Ang-II, and suggest that Ang-II responsiveness is increased in obese wild-type mice. Central inflammation is associated with metabolic and cardiovascular disorders and PVN AT1a deletion reduced indices of hypothalamic inflammation. Collectively, these studies demonstrate that PVN AT1a regulate energy balance during environmental challenges that promote metabolic and cardiovascular pathologies. The implication is that the elevated Ang-II that accompanies obesity serves as a negative feedback signal that activates PVN neurons to alleviate weight gain. PMID:23486953

Acute ethanol intake induces superoxide anion generation and mitogen-activated protein kinase phosphorylation in rat aorta: A role for angiotensin type 1 receptor

Energy Technology Data Exchange (ETDEWEB)

Yogi, Alvaro; Callera, Glaucia E. [Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ontario (Canada); Mecawi, André S. [Department of Physiology, Faculty of Medicine of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, SP (Brazil); Batalhão, Marcelo E.; Carnio, Evelin C. [Department of General and Specialized Nursing, College of Nursing of Ribeirão Preto, USP, São Paulo (Brazil); Antunes-Rodrigues, José [Department of Physiology, Faculty of Medicine of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, SP (Brazil); Queiroz, Regina H. [Department of Clinical, Toxicological and Food Science Analysis, Faculty of Pharmaceutical Sciences, USP, São Paulo (Brazil); Touyz, Rhian M. [Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ontario (Canada); Tirapelli, Carlos R., E-mail: crtirapelli@eerp.usp.br [Department of Psychiatric Nursing and Human Sciences, Laboratory of Pharmacology, College of Nursing of Ribeirão Preto, USP, Ribeirão Preto, SP (Brazil)

2012-11-01

Ethanol intake is associated with increase in blood pressure, through unknown mechanisms. We hypothesized that acute ethanol intake enhances vascular oxidative stress and induces vascular dysfunction through renin–angiotensin system (RAS) activation. Ethanol (1 g/kg; p.o. gavage) effects were assessed within 30 min in male Wistar rats. The transient decrease in blood pressure induced by ethanol was not affected by the previous administration of losartan (10 mg/kg; p.o. gavage), a selective AT{sub 1} receptor antagonist. Acute ethanol intake increased plasma renin activity (PRA), angiotensin converting enzyme (ACE) activity, plasma angiotensin I (ANG I) and angiotensin II (ANG II) levels. Ethanol induced systemic and vascular oxidative stress, evidenced by increased plasma thiobarbituric acid-reacting substances (TBARS) levels, NAD(P)H oxidase‐mediated vascular generation of superoxide anion and p47phox translocation (cytosol to membrane). These effects were prevented by losartan. Isolated aortas from ethanol-treated rats displayed increased p38MAPK and SAPK/JNK phosphorylation. Losartan inhibited ethanol-induced increase in the phosphorylation of these kinases. Ethanol intake decreased acetylcholine-induced relaxation and increased phenylephrine-induced contraction in endothelium-intact aortas. Ethanol significantly decreased plasma and aortic nitrate levels. These changes in vascular reactivity and in the end product of endogenous nitric oxide metabolism were not affected by losartan. Our study provides novel evidence that acute ethanol intake stimulates RAS activity and induces vascular oxidative stress and redox-signaling activation through AT{sub 1}-dependent mechanisms. These findings highlight the importance of RAS in acute ethanol-induced oxidative damage. -- Highlights: ► Acute ethanol intake stimulates RAS activity and vascular oxidative stress. ► RAS plays a role in acute ethanol-induced oxidative damage via AT{sub 1} receptor activation. �

Renal graft failure after addition of an angiotensin II receptor antagonist to an angiotensin-converting enzyme inhibitor

DEFF Research Database (Denmark)

Kamper, Anne-Lise; Nielsen, Arne Høj; Baekgaard, Niels

2002-01-01

Combined treatment with an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin II (Ang II) receptor blocker (ARB) has been suggested in order to achieve a more complete blockade of the renin-angiotensin-aldosterone system in cardiovascular and renal disease. The present report descri...

The Expression of MTUS1/ATIP and Its Major Isoforms, ATIP1 and ATIP3, in Human Prostate Cancer

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Louis, Simon N.S., E-mail: simonnsl@unimelb.edu.au; Chow, Laurie T.C.; Varghayee, Naghmeh; Rezmann, Linda A.; Frauman, Albert G.; Louis, William J. [Clinical Pharmacology and Therapeutics Unit, Department of Medicine, University of Melbourne, Austin Health, Heidelberg 3084, Victoria (Australia)

2011-10-11

Angiotensin II (Ang II), the main effector of the renin angiotensin system, acts upon two distinct transmembrane receptors, the Ang II type 1 and the type 2 (AT{sub 2}-) receptor, to induce promotion and inhibition of ERK2 phosphorylation. The AT{sub 2}-receptor, through an interaction with its putative signaling partner MTUS1/ATIP (AT{sub 2}-receptor interacting protein), inhibits the mitogenic effects of EGF in prostate cancer cell lines representing both early and late stage disease. This is the first report on the expression of ATIP in normal and malignant human prostatic biopsies. The expression of ATIP and its major isoforms, ATIP1 and ATIP3, in normal prostatic cells and three prostate cancer cell lines was examined using QPCR and immunohistochemistry. Human biopsies containing benign prostatic hyperplasia (BPH), high grade prostatic intraepithelial neoplasia (HGPIN) and well, moderately and poorly differentiated prostate cancer were also examined. Overall, ATIP1 and ATIP3 mRNA expression was increased in malignant compared to normal tissues and cell lines. ATIP immunostaining was low or absent in both the basal and columnar epithelial cell layers surrounding BPH acini; however, it was observed in high concentration in neoplastic epithelial cells of HGPIN and was clearly evident in cytoplasms of malignant cells in all prostate cancer grades. ATIP immunostaining was also identified in the cytoplasms of LNCaP and PC3 prostate cancer cells. As the AT{sub 2}-receptor/ATIP inhibitory signaling pathway exists in malignant cells in all grades of prostate cancer, enhancement of this pathway may be a therapeutic target even after the development of androgen-independence.

The Expression of MTUS1/ATIP and Its Major Isoforms, ATIP1 and ATIP3, in Human Prostate Cancer

International Nuclear Information System (INIS)

Louis, Simon N.S.; Chow, Laurie T.C.; Varghayee, Naghmeh; Rezmann, Linda A.; Frauman, Albert G.; Louis, William J.

2011-01-01

Angiotensin II (Ang II), the main effector of the renin angiotensin system, acts upon two distinct transmembrane receptors, the Ang II type 1 and the type 2 (AT 2 -) receptor, to induce promotion and inhibition of ERK2 phosphorylation. The AT 2 -receptor, through an interaction with its putative signaling partner MTUS1/ATIP (AT 2 -receptor interacting protein), inhibits the mitogenic effects of EGF in prostate cancer cell lines representing both early and late stage disease. This is the first report on the expression of ATIP in normal and malignant human prostatic biopsies. The expression of ATIP and its major isoforms, ATIP1 and ATIP3, in normal prostatic cells and three prostate cancer cell lines was examined using QPCR and immunohistochemistry. Human biopsies containing benign prostatic hyperplasia (BPH), high grade prostatic intraepithelial neoplasia (HGPIN) and well, moderately and poorly differentiated prostate cancer were also examined. Overall, ATIP1 and ATIP3 mRNA expression was increased in malignant compared to normal tissues and cell lines. ATIP immunostaining was low or absent in both the basal and columnar epithelial cell layers surrounding BPH acini; however, it was observed in high concentration in neoplastic epithelial cells of HGPIN and was clearly evident in cytoplasms of malignant cells in all prostate cancer grades. ATIP immunostaining was also identified in the cytoplasms of LNCaP and PC3 prostate cancer cells. As the AT 2 -receptor/ATIP inhibitory signaling pathway exists in malignant cells in all grades of prostate cancer, enhancement of this pathway may be a therapeutic target even after the development of androgen-independence

Prediction of severe hypoglycaemia by angiotensin-converting enzyme activity and genotype in type 1 diabetes

DEFF Research Database (Denmark)

Pedersen-Bjerggaard, U.; Agerholm-Larsen, B.; Pramming, S.

2003-01-01

AIMS/HYPOTHESIS: We have previously shown a strong relationship between high angiotensin-converting enzyme (ACE) activity, presence of the deletion (D) allele of the ACEgene and recall of severe hypoglycaemic events in patients with Type 1 diabetes. This study was carried out to assess...... this relationship prospectively. METHODS: We followed 171 adult outpatients with Type 1 diabetes in a one-year observational study with the recording of severe hypoglycaemia. Participants were characterised by serum ACE activity and ACE genotype and not treated with ACE inhibitors or angiotensin II receptor...... antagonists. RESULTS: There was a positive relationship between serum ACE activity and rate of severe hypoglycaemia with a 2.7 times higher rate in the fourth quartile of ACE activity compared to the first quartile (p=0.0007). A similar relationship was observed for the subset of episodes with coma (2.9 times...

Molecular Mechanisms Underlying Renin-Angiotensin-Aldosterone System Mediated Regulation of BK Channels

Directory of Open Access Journals (Sweden)

Zhen-Ye Zhang

2017-09-01

Full Text Available Large-conductance calcium-activated potassium channels (BK channels belong to a family of Ca2+-sensitive voltage-dependent potassium channels and play a vital role in various physiological activities in the human body. The renin-angiotensin-aldosterone system is acknowledged as being vital in the body's hormone system and plays a fundamental role in the maintenance of water and electrolyte balance and blood pressure regulation. There is growing evidence that the renin-angiotensin-aldosterone system has profound influences on the expression and bioactivity of BK channels. In this review, we focus on the molecular mechanisms underlying the regulation of BK channels mediated by the renin-angiotensin-aldosterone system and its potential as a target for clinical drugs.

Angiotensin II type 2 receptors and cardiac hypertrophy in women with hypertrophic cardiomyopathy

NARCIS (Netherlands)

J. Deinum (Jacob); J.M. van Gool (Jeanette); M.J.M. Kofflard (Marcel); A.H.J. Danser (Jan); F.J. ten Cate (Folkert)

2001-01-01

textabstractThe development of left ventricular hypertrophy in subjects with hypertrophic cardiomyopathy (HCM) is variable, suggesting a role for modifying factors such as angiotensin II. Angiotensin II mediates both trophic and antitrophic effects, via angiotensin II type 1

Genetically determined angiotensin converting enzyme level and myocardial tolerance to ischemia

OpenAIRE

Messadi, Erij; Vincent, Marie-Pascale; Griol-Charhbili, Violaine; Mandet, Chantal; Colucci, Juliana; Krege, John H.; Bruneval, Patrick; Bouby, Nadine; Smithies, Oliver; Alhenc-Gelas, François; Richer, Christine

2010-01-01

Angiotensin I-converting enzyme (ACE; kininase II) levels in humans are genetically determined. ACE levels have been linked to risk of myocardial infarction, but the association has been inconsistent, and the causality underlying it remains undocumented. We tested the hypothesis that genetic variation in ACE levels influences myocardial tolerance to ischemia. We studied ischemia-reperfusion injury in mice bearing 1 (ACE1c), 2 (ACE2c, wild type), or 3 (ACE3c) functional copies of the ACE gene ...

Increased expression of endothelin ET(B) and angiotensin AT(1) receptors in peripheral resistance arteries of patients with suspected acute coronary syndrome

DEFF Research Database (Denmark)

Dimitrijevic, Ivan; Ekelund, Ulf; Edvinsson, Lars

2009-01-01

of arterial vasoconstrictor endothelin (ET) and angiotensin (AT) receptors. Our aim was to investigate if the arterial expressions of these receptors are changed in patients with suspected but ruled out acute coronary syndrome (ACS). Small subcutaneous arteries (diameter of 100 microm) were surgically removed...... in the regulation of coronary tone and in the development of atherosclerosis, and may be related to increased cardiovascular risk....

Role of Mas receptor in renal blood flow response to angiotensin (1-7) in male and female rats.

Science.gov (United States)

Nematbakhsh, Mehdi; Safari, Tahereh

2014-01-01

Epidemiologic and clinical studies have shown that progression of renal disease in male is faster than that in female. However, the exact mechanisms are not well recognized. Angiotensin (1-7) (Ang 1-7) receptor, called "Mas", is an element in the depressor arm of renin angiotensin system (RAS), and its expression is enhanced in females. We test the hypothesis that Mas receptor (MasR) blockade (A779) attenuates renal blood flow (RBF) in response to infusion of graded doses of Ang 1-7 in female rats. Male and female Wistar rats were anesthetized and catheterized. Then, the mean arterial pressure (MAP), RBF, and controlled renal perfusion pressure (RPP) responses to infusion of graded doses of Ang 1-7 (100-1000 ng/kg/min i.v.) with and without A779 were measured in the animals. Basal MAP, RPP, RBF, and renal vascular resistance (RVR) were not significantly different between the two groups. After Ang 1-7 administration, RPP was controlled at a constant level. However, RBF increased in a dose-related manner in response to Ang 1-7 infusion in both male and female rats (Pdoserenal diseases.

Adverse cardiac effects of exogenous angiotensin 1-7 in rats with subtotal nephrectomy are prevented by ACE inhibition.

Directory of Open Access Journals (Sweden)

Louise M Burrell

Full Text Available We previously reported that exogenous angiotensin (Ang 1-7 has adverse cardiac effects in experimental kidney failure due to its action to increase cardiac angiotensin converting enzyme (ACE activity. This study investigated if the addition of an ACE inhibitor (ACEi to Ang 1-7 infusion would unmask any beneficial effects of Ang 1-7 on the heart in experimental kidney failure. Male Sprague-Dawley rats underwent subtotal nephrectomy (STNx and were treated with vehicle, the ACEi ramipril (oral 1mg/kg/day, Ang 1-7 (subcutaneous 24 μg/kg/h or dual therapy (all groups, n = 12. A control group (n = 10 of sham-operated rats were also studied. STNx led to hypertension, renal impairment, cardiac hypertrophy and fibrosis, and increased both left ventricular ACE2 activity and ACE binding. STNx was not associated with changes in plasma levels of ACE, ACE2 or angiotensin peptides. Ramipril reduced blood pressure, improved cardiac hypertrophy and fibrosis and inhibited cardiac ACE. Ang 1-7 infusion increased blood pressure, cardiac interstitial fibrosis and cardiac ACE binding compared to untreated STNx rats. Although in STNx rats, the addition of ACEi to Ang 1-7 prevented any deleterious cardiac effects of Ang 1-7, a limitation of the study is that the large increase in plasma Ang 1-7 with ramipril may have masked any effect of infused Ang 1-7.

Vascular Type 1A Angiotensin II Receptors Control BP by Regulating Renal Blood Flow and Urinary Sodium Excretion.

Science.gov (United States)

Sparks, Matthew A; Stegbauer, Johannes; Chen, Daian; Gomez, Jose A; Griffiths, Robert C; Azad, Hooman A; Herrera, Marcela; Gurley, Susan B; Coffman, Thomas M

2015-12-01

Inappropriate activation of the type 1A angiotensin (AT1A) receptor contributes to the pathogenesis of hypertension and its associated complications. To define the role for actions of vascular AT1A receptors in BP regulation and hypertension pathogenesis, we generated mice with cell-specific deletion of AT1A receptors in smooth muscle cells (SMKO mice) using Loxp technology and Cre transgenes with robust expression in both conductance and resistance arteries. We found that elimination of AT1A receptors from vascular smooth muscle cells (VSMCs) caused a modest (approximately 7 mmHg) yet significant reduction in baseline BP and exaggerated sodium sensitivity in mice. Additionally, the severity of angiotensin II (Ang II)-dependent hypertension was dramatically attenuated in SMKO mice, and this protection against hypertension was associated with enhanced urinary excretion of sodium. Despite the lower BP, acute vasoconstrictor responses to Ang II in the systemic vasculature were largely preserved (approximately 80% of control levels) in SMKO mice because of exaggerated activity of the sympathetic nervous system rather than residual actions of AT1B receptors. In contrast, Ang II-dependent responses in the renal circulation were almost completely eliminated in SMKO mice (approximately 5%-10% of control levels). These findings suggest that direct actions of AT1A receptors in VSMCs are essential for regulation of renal blood flow by Ang II and highlight the capacity of Ang II-dependent vascular responses in the kidney to effect natriuresis and BP control. Copyright © 2015 by the American Society of Nephrology.

Living high training low induces physiological cardiac hypertrophy accompanied by down-regulation and redistribution of the renin-angiotensin system

Science.gov (United States)

Shi, Wei; Meszaros, J Gary; Zeng, Shao-ju; Sun, Ying-yu; Zuo, Ming-xue

2013-01-01

Aim: Living high training low” (LHTL) is an exercise-training protocol that refers living in hypoxia stress and training at normal level of O2. In this study, we investigated whether LHTL caused physiological heart hypertrophy accompanied by changes of biomarkers in renin-angiotensin system in rats. Methods: Adult male SD rats were randomly assigned into 4 groups, and trained on living low-sedentary (LLS, control), living low-training low (LLTL), living high-sedentary (LHS) and living high-training low (LHTL) protocols, respectively, for 4 weeks. Hematological parameters, hemodynamic measurement, heart hypertrophy and plasma angiotensin II (Ang II) level of the rats were measured. The gene and protein expression of angiotensin-converting enzyme (ACE), angiotensinogen (AGT) and angiotensin II receptor I (AT1) in heart tissue was assessed using RT-PCR and immunohistochemistry, respectively. Results: LLTL, LHS and LHTL significantly improved cardiac function, increased hemoglobin concentration and RBC. At the molecular level, LLTL, LHS and LHTL significantly decreased the expression of ACE, AGT and AT1 genes, but increased the expression of ACE and AT1 proteins in heart tissue. Moreover, ACE and AT1 protein expression was significantly increased in the endocardium, but unchanged in the epicardium. Conclusion: LHTL training protocol suppresses ACE, AGT and AT1 gene expression in heart tissue, but increases ACE and AT1 protein expression specifically in the endocardium, suggesting that the physiological heart hypertrophy induced by LHTL is regulated by region-specific expression of renin-angiotensin system components. PMID:23377552

Angiotensin II prevents hypoxic pulmonary hypertension and vascular changes in rat

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Rabinovitch, M.; Mullen, M.; Rosenberg, H.C.; Maruyama, K.; O'Brodovich, H.; Olley, P.M.

1988-01-01

Angiotensin II, a vasoconstrictor, has been previously demonstrated to produce a secondary vasodilatation due to release of prostaglandins. Because of this effect, the authors investigated whether infusion of exogenous angiotensin II via miniosmopumps in rats during a 1-wk exposure to chronic hypobaric hypoxia might prevent pulmonary hypertension, right ventricular hypertrophy, and vascular changes. They instrumented the rats with indwelling cardiovascular catheters and compared the hemodynamic and structural response in animals given angiotensin II, indomethacin in addition to angiotensin II (to block prostaglandin production), or saline with or without indomethacin. They then determine whether angiotensin II infusion also prevents acute hypoxic pulmonary vasoconstriction. They observed that exogenous angiotensin II infusion abolished the rise in pulmonary artery pressure, the right ventricular hypertrophy, and the vascular changes induced during chronic hypoxia in control saline-infused rats with or without indomethacin. The protective effects of angiotensin II was lost when indomethacin was given to block prostaglandin synthesis. During acute hypoxia, both antiotensin II and prostacyclin infusion similarly prevented the rise in pulmonary artery pressure observed in saline-infused rats and in rats given indomethacin or saralasin in addition to angiotensin II. Thus exogenous angiotensin II infusion prevents chronic hypoxic pulmonary hypertension, associated right ventricular hypertrophy, and vascular changes and blocks acute hypoxic pulmonary hypertension, and this is likely related to its ability to release vasodilator prostaglandins

Spiral CT during pharmacoangiography with angiotensin II in patients with pancreatic disease. Technique and diagnostic efficacy

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Kuroda, C.; Mihara, N.; Hosomi, N.; Inoue, E.; Fujita, M. [Osaka Medical Center for Cancer and Cardiovascular Diseases (Japan). Dept. of Diagnostic Radiology; Ohigashi, H.; Ishikawa, O. [Osaka Medical Center for Cancer and Cardiovascular Diseases (Japan). Dept. of Surgery; Nakaizumi, A. [Osaka Medical Center for Cancer and Cardiovascular Deseases (Japan). Dept. of Internal Medicine; Ishiguro, S. [Osaka Medical Center for Cancer and Cardiovascular Diseases (Japan). Dept. of Pathology

1998-03-01

Purpose: To compare the diagnostic efficacy of pancreatic pharmacoangiographic CT using angiotensin II with conventional angiographic CT. Material and Methods: Eighteen patients with space-occupying pancreatic disease were examined in this study. Pharmacoangiographic CT was performed with a 1-3-{mu}/6-ml solution of angiotensin II injected through a catheter into the celiac artery during spiral CT. Results: In 17 of the 18 (94%) patients, the area of pancreatic parenchymal enhancement was the same or larger at pharmacoangiographic CT than at conventional angiographic CT. The attenuation value of the pancreatic parenchyma was significantly increased at pharmacoangiographic CT (p=0.0010). Although the attenuation value of tumors was also increased on images obtained after the injection of angiotensin II, the tumor-to-pancreas contrast was significantly greater at pharmacoangiographic CT (p=0.0479). The mean differences in attenuation between tumor and pancreas at angiographic CT with and without angiotensin II were respectively 182 HU and 115 HU. Conclusion: Pharmacoangiographic CT with angiotensin II proved superior to conventional angiographic CT in the diagnosis of pancreatic disease. We therefore recommend it as a supplementary technique at the angiographic examination of patients with suspected pancreatic tumor. (orig.).

Pharmacological properties of angiotensin II antagonists: Examining all the therapeutic implications

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Thomas Unger

2001-06-01

Full Text Available Angiotensin II (Ang II, the effector peptide of the renin-angiotensin system (RAS, exerts a variety of actions in physiological blood pressure and body fluid regulation, and is implicated as a major pathogenic factor in the development of cardiovascular disease. Inhibition of the RAS, via treatment with the angiotensin-converting enzyme inhibitors (ACE-I, or more recently the Ang II AT1-receptor blockers (ARBs, has been used as a therapeutic approach to the treatment of hypertension and other cardiovascular dysfunction. Evidence from animal and clinical studies shows that the antihypertensive and overall organ-protective actions of the ARBs are similar to those of ACE-I. However, as the ARBs selectively block the AT1-receptor, which is responsible for the known cardiovascular actions of Ang II, leave the AT2-receptor unopposed and do not interfere with the breakdown of bradykinin, there is the potential for beneficial effects in hypertensive patients with cardiovascular diseases such as left ventricular hypertrophy. Furthermore, there may be additional benefits when the ARBs are combined with ACE-I in such patients. Animal studies contribute to the elucidation and understanding of the role of AT1- and AT2-receptors in the cardiovascular system, and may help in the design of clinical studies aimed at investigating the effects of ACE-I, ARBs, and their combination, on cardiovascular outcomes in hypertensive patients.

Pharmacological properties of angiotensin II antagonists: examining all the therapeutic implications

Directory of Open Access Journals (Sweden)

Thomas Unger

2001-06-01

Full Text Available Angiotensin II (Ang II, the effector peptide of the renin-angiotensin system (RAS, exerts a variety of actions in physiological blood pressure and body fluid regulation, and is implicated as a major pathogenic factor in the development of cardiovascular disease. Inhibition of the RAS, via treatment with the angiotensin-converting enzyme inhibitors (ACE-I, or more recently the Ang II AT1-receptor blockers (ARBs, has been used as a therapeutic approach to the treatment of hypertension and other cardiovascular dysfunction. Evidence from animal and clinical studies shows that the antihypertensive and overall organ-protective actions of the ARBs are similar to those of ACE-I. However, as the ARBs selectively block the AT1-receptor, which is responsible for the known cardiovascular actions of Ang II, leave the AT2-receptor unopposed and do not interfere with the breakdown of bradykinin, there is the potential for beneficial effects in hypertensive patients with cardiovascular diseases such as left ventricular hypertrophy. Furthermore, there may be additional benefits when the ARBs are combined with ACE-I in such patients. Animal studies contribute to the elucidation and understanding of the role of AT1- and AT2-receptors in the cardiovascular system, and may help in the design of clinical studies aimed at investigating the effects of ACE-I, ARBs, and their combination, on cardiovascular outcomes in hypertensive patients.

Acute renal haemodynamic and renin-angiotensin system responses to graded renal artery stenosis in the dog.

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Anderson, W P; Johnston, C I; Korner, P I

1979-01-01

1. The acute renal haemodynamic and renin-angiotensin system responses to graded renal artery stenosis were studied in chronically instrumented, unanaesthetized dogs. 2. Stenosis was induced over 30 sec by inflation of a cuff around the renal artery to lower distal pressure to 60, 40 or 20 mmHg, with stenosis maintained for 1 hr. This resulted in an immediate fall in renal vascular resistance, but over the next 5--30 min both resistance and renal artery pressure were restored back towards prestenosis values. Only transient increases in systemic arterial blood pressure and plasma renin and angiotensin levels were seen with the two milder stenoses. Despite restoration of renal artery pressure, renal blood flow remained reduced at all grades of stenosis. 3. Pre-treatment with angiotensin I converting enzyme inhibitor or sarosine1, isoleucone8 angiotensin II greatly attenuated or abolished the restoration of renal artery pressure and renal vascular resistance after stenosis, and plasma renin and angiotensin II levels remained high. Renal dilatation was indefinitely maintained, but the normal restoration of resistance and pressure could be simulated by infusing angiotensin II into the renal artery. 4. The effective resistance to blood flow by the stenosis did not remain constant but varied with changes in the renal vascular resistance. PMID:219182

Estimation of urinary angiotensin II by radioimmunoassay

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Fukuchi, S [Tohoku Univ., Sendai (Japan). School of Medicine

1974-11-01

Urine samples were collected from fasting subjects after maintaining posture for 2 hr in early morning. Urinary angiotensin II was extracted with SE-Sephadex. The extracts, after being dissolved in phosphate buffer, pH 7.5, were measured by radioimmunoassay. Recovery, sensitivity and accuracy were found to be satisfactory. The normal values obtained from 6 subjects were 52-280 pg/2 hr. The values were almost normal in essential hypertension and in chronic glomerulonephritis. They were high in 3 out of 6 cases with renovascular hypertension and subsequently dropped after surgery. In 6 cases with primary aldosteronism, very low levels were found. These increased after the removal of adrenal adenomas. No positive correlation between simultaneous plasma and urinary angiotensin samples was apparent. Also no positive correlation between urinary angiotensin and urine volume was found. In renovascular hypertention, during glucose infusion, lower values in urine volume and angiotensin excretion were observed on the stenotic side as compared to the intact side. Thus, the angiotensin excretion rate does not appear to be regulated by arterial angiotensin concentration, but rather by the angiotensin perfusion rate.

Angiotensin (1-7) ameliorates the structural and biochemical alterations of ovariectomy-induced osteoporosis in rats via activation of ACE-2/Mas receptor axis.

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Abuohashish, Hatem M; Ahmed, Mohammed M; Sabry, Dina; Khattab, Mahmoud M; Al-Rejaie, Salim S

2017-05-23

The local and systemic renin angiotensin system (RAS) influences the skeletal system micro-structure and metabolism. Studies suggested angiotensin 1-7 (Ang(1-7)) as the beneficial RAS molecule via Mas receptor activation. This study examines the function of Ang(1-7) in bone micro-architecture and metabolism in an ovariectomized (OVX) rodent model of osteoporosis. OVX rats showed structural and bone metabolic degeneration in parallel with suppressed expressions of the angiotensin converting enzyme-2 (ACE-2)/Ang(1-7)/Mas components. The infusion of Ang(1-7) markedly alleviated the altered bone metabolism and significantly enhanced both trabecular (metaphyseal) and cortical (metaphyseal-diaphyseal) morphometry. Urinary and bones minerals were also improved in OVX rats by Ang(1-7). The infusion of the heptapeptide enhanced ACE-2/Mas receptor expressions, while down-regulated AngII, ACE, and AngII type-1 receptor (AT1R) in OVX animals. Moreover, Ang(1-7) markedly improved osteoprotegerin (OPG) and lowered receptor activator NF-κB ligand (RANKL) expressions. The defensive properties of Ang(1-7) on bone metabolism, structure and minerals were considerably eradicated after blockage of Mas receptor with A-779. Ang(1-7)-induced up-regulated ACE-2/Ang(1-7)/Mas cascade and OPG expressions were abolished and the expressions of ACE/AngII/AT1R and RANKL were provoked by A-779. These findings shows for the first time the novel valuable therapeutic role of Ang(1-7) on bone health and metabolism through the ACE-2/Mas cascade.

Angiotensin type 1 receptors in the subfornical organ mediate the drinking and hypothalamic-pituitary-adrenal response to systemic isoproterenol.

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Krause, Eric G; Melhorn, Susan J; Davis, Jon F; Scott, Karen A; Ma, Li Y; de Kloet, Annette D; Benoit, Stephen C; Woods, Stephen C; Sakai, Randall R

2008-12-01

Circulating angiotensin II (ANGII) elicits water intake and activates the hypothalamic-pituitary-adrenal (HPA) axis by stimulating angiotensin type 1 receptors (AT1Rs) within circumventricular organs. The subfornical organ (SFO) and the organum vasculosum of the lamina terminalis (OVLT) are circumventricular organs that express AT1Rs that bind blood-borne ANGII and stimulate integrative and effector regions of the brain. The goal of these studies was to determine the contribution of AT1Rs within the SFO and OVLT to the water intake and HPA response to increased circulating ANGII. Antisense oligonucleotides directed against the AT1R [AT1R antisense (AT1R AS)] were administered into the OVLT or SFO. Quantitative receptor autoradiography confirmed that AT1R AS decreased ANGII binding in the SFO and OVLT compared with the scrambled sequence control but did not affect AT1R binding in other nuclei. Subsequently, water intake, ACTH, and corticosterone (CORT) were assessed after administration of isoproterenol, a beta-adrenergic agonist that decreases blood pressure and elevates circulating ANGII. Delivery of AT1R AS into the SFO attenuated water intake, ACTH, and CORT after isoproterenol, whereas similar treatment in the OVLT had no effect. To determine the specificity of this blunted drinking and HPA response, the same parameters were measured after treatment with hypertonic saline, a stimulus that induces drinking independently of ANGII. Delivery of AT1R AS into the SFO or OVLT had no effect on water intake, ACTH, or CORT after hypertonic saline. The results imply that AT1R within the SFO mediate drinking and HPA responses to stimuli that increase circulating ANGII.

AT1 Receptor Gene Polymorphisms in relation to Postprandial Lipemia

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B. Klop

2012-01-01

Full Text Available Background. Recent data suggest that the renin-angiotensin system may be involved in triglyceride (TG metabolism. We explored the effect of the common A1166C and C573T polymorphisms of the angiotensin II type 1 receptor (AT1R gene on postprandial lipemia. Methods. Eighty-two subjects measured daytime capillary TG, and postprandial lipemia was estimated as incremental area under the TG curve. The C573T and A1166C polymorphisms of the AT1R gene were determined. Results. Postprandial lipemia was significantly higher in homozygous carriers of the 1166-C allele (9.39±8.36 mM*h/L compared to homozygous carriers of the 1166-A allele (2.02±6.20 mM*h/L (P<0.05. Postprandial lipemia was similar for the different C573T polymorphisms. Conclusion. The 1166-C allele of the AT1R gene seems to be associated with increased postprandial lipemia. These data confirm the earlier described relationships between the renin-angiotensin axis and triglyceride metabolism.

CO-releasing molecules CORM2 attenuates angiotensin II-induced human aortic smooth muscle cell migration through inhibition of ROS/IL-6 generation and matrix metalloproteinases-9 expression

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Ming-Horng Tsai

2017-08-01

Full Text Available Ang II has been involved in the pathogenesis of cardiovascular diseases, and matrix metalloproteinase-9 (MMP-9 induced migration of human aortic smooth muscle cells (HASMCs is the most common and basic pathological feature. Carbon monoxide (CO, a byproduct of heme breakdown by heme oxygenase, exerts anti-inflammatory effects in various tissues and organ systems. In the present study, we aimed to investigate the effects and underlying mechanisms of carbon monoxide releasing molecule-2 (CORM-2 on Ang II-induced MMP-9 expression and cell migration of HASMCs. Ang II significantly up-regulated MMP-9 expression and cell migration of HASMCs, which was inhibited by transfection with siRNA of p47phox, Nox2, Nox4, p65, angiotensin II type 1 receptor (AT1R and pretreatment with the inhibitors of NADPH oxidase, ROS, and NF-κB. In addition, Ang II also induced NADPH oxidase/ROS generation and p47phox translocation from the cytosol to the membrane. Moreover, Ang II-induced oxidative stress and MMP-9-dependent cell migration were inhibited by pretreatment with CORM-2. Finally, we observed that Ang II induced IL-6 release in HASMCs via AT1R, but not AT2R, which could further caused MMP-9 secretion and cell migration. Pretreatment with CORM-2 reduced Ang II-induced IL-6 release. In conclusion, CORM-2 inhibits Ang II-induced HASMCs migration through inactivation of suppression of NADPH oxidase/ROS generation, NF-κB inactivation and IL-6/MMP-9 expression. Thus, application of CO, especially CORM-2, is a potential countermeasure to reverse the pathological changes of various cardiovascular diseases. Further effects aimed at identifying novel antioxidant and anti-inflammatory substances protective for heart and blood vessels that targeting CO and establishment of well-designed in vivo models properly evaluating the efficacy of these agents are needed. Keywords: Angiotensin II, Carbon monoxide, Human aortic smooth muscle cell, Inflammation, Matrix metallopeptidase

Angiotensin-(1-7 Promotes Resolution of Neutrophilic Inflammation in a Model of Antigen-Induced Arthritis in Mice

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Lívia C. Barroso

2017-11-01

Full Text Available Defective resolution of inflammation may be crucial for the initiation and development of chronic inflammatory diseases, such as arthritis. Therefore, it has been suggested that therapeutic strategies based on molecules that facilitate inflammation resolution present great potential for the treatment of chronic inflammatory diseases. In this study, we investigated the effects and role of angiotensin-(1-7 [Ang-(1-7] in driving resolution of neutrophilic inflammation in a model of arthritis. For this purpose, male C57BL/6 mice were subjected to antigen-induced arthritis and treated with Ang-(1-7 at the peak of the inflammatory process. Analysis of the number of inflammatory cells, apoptosis, and immunofluorescence for NF-κB was performed in the exudate collected from the knee cavity. Neutrophil accumulation in periarticular tissue was measured by assaying myeloperoxidase activity. Apoptosis of human neutrophil after treatment with Ang-(1-7 was evaluated morphologically and by flow cytometry, and NF-κB phosphorylation by immunofluorescence. Efferocytosis was evaluated in vivo. Therapeutic treatment with Ang-(1-7 at the peak of inflammation promoted resolution, an effect associated with caspase-dependent neutrophils apoptosis and NF-κB inhibition. Importantly, Ang-(1-7 was also able to induce apoptosis of human neutrophils, an effect associated with NF-κB inhibition. The pro-resolving effects of Ang-(1-7 were inhibited by the Mas receptor antagonist A779. Finally, we showed that Ang-(1-7 increased the efferocytic ability of murine macrophages. Our results clearly demonstrate that Ang-(1-7 resolves neutrophilic inflammation in vivo acting in two key step of resolution: apoptosis of neutrophils and their removal by efferocytosis. Ang-(1-7 is a novel mediator of resolution of inflammation.

Combined Angiotensin Receptor Antagonism and Neprilysin Inhibition

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Hubers, Scott A.; Brown, Nancy J.

2016-01-01

Heart failure affects approximately 5.7 million people in the United States alone. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and aldosterone antagonists have improved mortality in patients with heart failure and reduced ejection fraction, but mortality remains high. In July 2015, the FDA approved the first of a new class of drugs for the treatment of heart failure; valsartan/sacubitril (formerly known as LCZ696 and currently marketed by Novartis as Entresto) combines the angiotensin receptor blocker valsartan and the neprilysin inhibitor prodrug sacubitril in a 1:1 ratio in a sodium supramolecular complex. Sacubitril is converted by esterases to LBQ657, which inhibits neprilysin, the enzyme responsible for the degradation of the natriuretic peptides and many other vasoactive peptides. Thus, this combined angiotensin receptor antagonist and neprilysin inhibitor addresses two of the pathophysiologic mechanisms of heart failure - activation of the renin-angiotensin-aldosterone system and decreased sensitivity to natriuretic peptides. In the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF) trial, valsartan/sacubitril significantly reduced mortality and hospitalization for heart failure, as well as blood pressure, compared to enalapril in patients with heart failure, reduced ejection fraction, and an elevated circulating level of brain natriuretic peptide or N-terminal pro-brain natriuretic peptide. Ongoing clinical trials are evaluating the role of valsartan/sacubitril in the treatment of heart failure with preserved ejection fraction and hypertension. We review here the mechanisms of action of valsartan/sacubitril, the pharmacologic properties of the drug, and its efficacy and safety in the treatment of heart failure and hypertension. PMID:26976916

Effector peptides of the renin-angiotensin system in the central mechanisms of acquired and innate behavior in thirst in rats.

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Vlasenko, R Ya; Kotov, A V

2007-03-01

We report here a comparative analysis of the involvement of a number of components of the renin-angiotensin system in the performance of simple and complex forms of drinking behavior and thirst-associated non-drinking types of behavior. On central (intracerebroventricular) microinjection, [des-Asp1]-angiotensin I at doses equieffective to those of angiotensins II and III was found to be involved only in the performance of simple (taking water from the bowl) and linked forms of activity (comfort behavior, stress grooming, orientational-investigative, and feeding behavior). Angiotensin II was involved in the central mechanisms of complex acquired drinking behavior, selectively modulating its key stages (initial, final), while angiotensin III was involved only in the mechanisms of reproduction of the complex skill. All three substances induced "innate patterns of behavior" specific for each compound, these occurring at fixed periods of time after intracerebral microinjection. The effects of these substances were selectively suppressed by the AT1 receptor blocker losartan potassium.

Angiotensin-converting enzyme genotype and arterial oxygen saturation at high altitude in Peruvian Quechua.

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Bigham, Abigail W; Kiyamu, Melisa; León-Velarde, Fabiola; Parra, Esteban J; Rivera-Ch, Maria; Shriver, Mark D; Brutsaert, Tom D

2008-01-01

The I-allele of the angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism has been associated with performance benefits at high altitude (HA). In n = 142 young males and females of largely Quechua origins in Peru, we evaluated 3 specific hypotheses with regard to the HA benefits of the I-allele: (1) the I-allele is associated with higher arterial oxygen saturation (Sa(O(2))) at HA, (2) the I-allele effect depends on the acclimatization state of the subjects, and (3) the putative I-allele effect on Sa(O(2)) is mediated by the isocapnic hypoxic ventilatory response (HVR, l/min(1)/% Sa(O(2))(1)). The subject participants comprised two different study groups including BLA subjects (born at low altitude) who were lifelong sea-level residents transiently exposed to hypobaric hypoxia (<24 h) and BHA subjects (born at HA) who were lifelong residents of HA. To control for the possibility of population stratification, Native American ancestry proportion (NAAP) was estimated as a covariate for each individual using a panel of 70 ancestry-informative molecular markers (AIMS). At HA, resting and exercise Sa(O(2)) was strongly associated with the ACE genotype, p = 0.008 with approximately 4% of the total variance in Sa(O(2)) attributed to ACE genotype. Moreover, I/I individuals maintained approximately 2.3 percentage point higher Sa(O(2)) compared to I/D and D/D. This I-allele effect was evident in both BLA and BHA groups, suggesting that acclimatization state has little influence on the phenotypic expression of the ACE gene. Finally, ACE genotype was not associated with the isocapnic HVR, although HVR had a strong independent effect on Sa(O(2)) (p = 0.001). This suggests that the I-allele effect on Sa(O(2)) is not mediated by the peripheral control of breathing, but rather by some other central cardiopulmonary effect of the ACE gene on the renin-angiotensin-aldosterone system (RAAS).

Effects of a novel bradykinin B1 receptor antagonist and angiotensin II receptor blockade on experimental myocardial infarction in rats.

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Dongmei Wu

Full Text Available The aim of the present study was to evaluate the cardiovascular effects of the novel bradykinin B1 receptor antagonist BI-113823 following myocardial infarction (MI and to determine whether B1 receptor blockade alters the cardiovascular effects of an angiotensin II type 1 (AT1 receptor antagonist after MI in rats.Sprague Dawley rats were subjected to permanent occlusion of the left descending coronary artery. Cardiovascular function was determined at 7 days post MI. Treatment with either B1 receptor antagonist (BI-113823 or AT1 receptor antagonist (irbesartan alone or in combination improved post-MI cardiac function as evidenced by attenuation of elevated left ventricular end diastolic pressure (LVEDP; greater first derivative of left ventricular pressure (± dp/dt max, left ventricle ejection fraction, fractional shorting, and better wall motion; as we as reductions in post-MI up-regulation of matrix metalloproteinases 2 (MMP-2 and collagen III. In addition, the cardiac up-regulation of B1 receptor and AT1 receptor mRNA were markedly reduced in animals treated with BI 113823, although bradykinin B2 receptor and angiotensin 1 converting enzyme (ACE1 mRNA expression were not significantly affected by B1 receptor blockade.The present study demonstrates that treatment with the novel B1 receptor antagonist, BI-113823 improves post-MI cardiac function and does not influence the cardiovascular effects of AT1 receptor antagonist following MI.

Angiotensin II (AngII) induces the expression of suppressor of cytokine signaling (SOCS)-3 in rat hypothalamus - a mechanism for desensitization of AngII signaling.

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Torsoni, Márcio A; Carvalheira, José B; Calegari, Vivian C; Bezerra, Rosangela M N; Saad, Mário J A; Gontijo, José A; Velloso, Lício A

2004-04-01

Angiotensin II exerts a potent dypsogenic stimulus on the hypothalamus, which contributes to its centrally mediated participation in the control of water balance and blood pressure. Repetitive intracerebroventricular (i.c.v.) injections of angiotensin II lead to a loss of effect characterized as physiological desensitization to the peptide's action. In the present study, we demonstrate that angiotensin II induces the expression of suppressor of cytokine signaling (SOCS)-3 via angiotensin receptor 1 (AT1) and JAK-2, mostly located at the median preoptic lateral and anterodorsal preoptic nuclei. SOCS-3 produces an inhibitory effect upon the signal transduction pathways of several cytokines and hormones that employ members of the JAK/STAT families as intermediaries. The partial inhibition of SOCS-3 translation by antisense oligonucleotide was sufficient to significantly reduce the refractoriness of repetitive i.c.v. angiotensin II injections, as evaluated by water ingestion. Thus, by acting through AT1 on the hypothalamus, angiotensin II induces the expression of SOCS-3 which, in turn, blocks further activation of the pathway and consequently leads to desensitization to angiotensin II stimuli concerning its dypsogenic effect.

Effect of angiotensin II on proliferation and differentiation of mouse induced pluripotent stem cells into mesodermal progenitor cells

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Ishizuka, Toshiaki, E-mail: tishizu@ndmc.ac.jp [Department of Pharmacology, National Defense Medical College, Tokorozawa, Saitama 359-8513 (Japan); Goshima, Hazuki; Ozawa, Ayako; Watanabe, Yasuhiro [Department of Pharmacology, National Defense Medical College, Tokorozawa, Saitama 359-8513 (Japan)

2012-03-30

Highlights: Black-Right-Pointing-Pointer Treatment with angiotensin II enhanced LIF-induced DNA synthesis of mouse iPS cells. Black-Right-Pointing-Pointer Angiotensin II may enhance the DNA synthesis via induction of superoxide. Black-Right-Pointing-Pointer Treatment with angiotensin II significantly increased JAK/STAT3 phosphorylation. Black-Right-Pointing-Pointer Angiotensin II enhanced differentiation into mesodermal progenitor cells. Black-Right-Pointing-Pointer Angiotensin II may enhance the differentiation via activation of p38 MAPK. -- Abstract: Previous studies suggest that angiotensin receptor stimulation may enhance not only proliferation but also differentiation of undifferentiated stem/progenitor cells. Therefore, in the present study, we determined the involvement of the angiotensin receptor in the proliferation and differentiation of mouse induced pluripotent stem (iPS) cells. Stimulation with angiotensin II (Ang II) significantly increased DNA synthesis in mouse iPS cells cultured in a medium with leukemia inhibitory factor (LIF). Pretreatment of the cells with either candesartan (a selective Ang II type 1 receptor [AT{sub 1}R] antagonist) or Tempol (a cell-permeable superoxide scavenger) significantly inhibited Ang II-induced DNA synthesis. Treatment with Ang II significantly increased JAK/STAT3 phosphorylation. Pretreatment with candesartan significantly inhibited Ang II- induced JAK/STAT3 phosphorylation. In contrast, induction of mouse iPS cell differentiation into Flk-1-positive mesodermal progenitor cells was performed in type IV collagen (Col IV)- coated dishes in a differentiation medium without LIF. When Col IV-exposed iPS cells were treated with Ang II for 5 days, the expression of Flk-1 was significantly increased compared with that in the cells treated with the vehicle alone. Pretreatment of the cells with both candesartan and SB203580 (a p38 MAPK inhibitor) significantly inhibited the Ang II- induced increase in Flk-1 expression

Effect of angiotensin II on proliferation and differentiation of mouse induced pluripotent stem cells into mesodermal progenitor cells

International Nuclear Information System (INIS)

Ishizuka, Toshiaki; Goshima, Hazuki; Ozawa, Ayako; Watanabe, Yasuhiro

2012-01-01

Highlights: ► Treatment with angiotensin II enhanced LIF-induced DNA synthesis of mouse iPS cells. ► Angiotensin II may enhance the DNA synthesis via induction of superoxide. ► Treatment with angiotensin II significantly increased JAK/STAT3 phosphorylation. ► Angiotensin II enhanced differentiation into mesodermal progenitor cells. ► Angiotensin II may enhance the differentiation via activation of p38 MAPK. -- Abstract: Previous studies suggest that angiotensin receptor stimulation may enhance not only proliferation but also differentiation of undifferentiated stem/progenitor cells. Therefore, in the present study, we determined the involvement of the angiotensin receptor in the proliferation and differentiation of mouse induced pluripotent stem (iPS) cells. Stimulation with angiotensin II (Ang II) significantly increased DNA synthesis in mouse iPS cells cultured in a medium with leukemia inhibitory factor (LIF). Pretreatment of the cells with either candesartan (a selective Ang II type 1 receptor [AT 1 R] antagonist) or Tempol (a cell-permeable superoxide scavenger) significantly inhibited Ang II-induced DNA synthesis. Treatment with Ang II significantly increased JAK/STAT3 phosphorylation. Pretreatment with candesartan significantly inhibited Ang II- induced JAK/STAT3 phosphorylation. In contrast, induction of mouse iPS cell differentiation into Flk-1-positive mesodermal progenitor cells was performed in type IV collagen (Col IV)- coated dishes in a differentiation medium without LIF. When Col IV-exposed iPS cells were treated with Ang II for 5 days, the expression of Flk-1 was significantly increased compared with that in the cells treated with the vehicle alone. Pretreatment of the cells with both candesartan and SB203580 (a p38 MAPK inhibitor) significantly inhibited the Ang II- induced increase in Flk-1 expression. Treatment with Ang II enhanced the phosphorylation of p38 MAPK in Col IV- exposed iPS cells. These results suggest that the stimulation

Activation of thiazide-sensitive co-transport by angiotensin II in the cyp1a1-Ren2 hypertensive rat.

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Ali Ashek

Full Text Available Transgenic rats with inducible expression of the mouse Ren2 gene were used to elucidate mechanisms leading to the development of hypertension and renal injury. Ren2 transgene activation was induced by administration of a naturally occurring aryl hydrocarbon, indole-3-carbinol (100 mg/kg/day by gastric gavage. Blood pressure and renal parameters were recorded in both conscious and anesthetized (butabarbital sodium; 120 mg/kg IP rats at selected time-points during the development of hypertension. Hypertension was evident by the second day of treatment, being preceded by reduced renal sodium excretion due to activation of the thiazide-sensitive sodium-chloride co-transporter. Renal injury was evident after the first day of transgene induction, being initially limited to the pre-glomerular vasculature. Mircoalbuminuria and tubuloinsterstitial injury developed once hypertension was established. Chronic treatment with either hydrochlorothiazide or an AT1 receptor antagonist normalized sodium reabsorption, significantly blunted hypertension and prevented renal injury. Urinary aldosterone excretion was increased ≈ 20 fold, but chronic mineralocorticoid receptor antagonism with spironolactone neither restored natriuretic capacity nor prevented hypertension. Spironolactone nevertheless ameliorated vascular damage and prevented albuminuria. This study finds activation of sodium-chloride co-transport to be a key mechanism in angiotensin II-dependent hypertension. Furthermore, renal vascular injury in this setting reflects both barotrauma and pressure-independent pathways associated with direct detrimental effects of angiotensin II and aldosterone.

Skeletal muscle myoblasts possess a stretch-responsive local angiotensin signalling system.

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Johnston, Adam P W; Baker, Jeff; De Lisio, Michael; Parise, Gianni

2011-06-01

A paucity of information exists regarding the presence of local renin-angiotensin systems (RASs) in skeletal muscle and associated muscle stem cells. Skeletal muscle and muscle stem cells were isolated from C57BL/6 mice and examined for the presence of a local RAS using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), immunohistochemistry (IHC), Western blotting and liquid chromatography-mass spectrometry (LC-MS). Furthermore, the effect of mechanical stimulation on RAS member gene expression was analysed. Whole skeletal muscle, primary myoblasts and C2C12 derived myoblasts and myotubes differentially expressed members of the RAS including angiotensinogen, angiotensin-converting enzyme (ACE), angiotensin II (Ang II) type 1 (AT(1)) and type 2 (AT(2)). Renin transcripts were never detected, however, mRNA for the 'renin-like' enzyme cathepsin D was observed and Ang I and Ang II were identified in cell culture supernatants from proliferating myoblasts. AT(1) appeared to co-localise with polymerised actin filaments in proliferating myoblasts and was primarily found in the nucleus of terminally differentiated myotubes. Furthermore, mechanical stretch of proliferating and differentiating C2C12 cells differentially induced mRNA expression of angiotensinogen, AT(1) and AT(2). Proliferating and differentiated muscle stem cells possess a local stress-responsive RAS in vitro. The precise function of a local RAS in myoblasts remains unknown. However, evidence presented here suggests that Ang II may be a regulator of skeletal muscle myoblasts.

Involvement of Renin-Angiotensin System in Retinopathy of Prematurity - A Possible Target for Therapeutic Intervention.

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Madhu Nath

Full Text Available Examining the Retinal Renin Angiotensin System (RRAS in the ROP neonates and analyzing the possibility of modulating the RRAS to prevent the progression in Oxygen Induced Retinopathy (OIR model.Vitreous of ROP patients (n = 44, median age 5.5 months was quantified for RRAS components, VEGF, HIF-1α and compared with age matched control. The involvement of RRAS in ROP was tested in the rat model of OIR and compared with normoxia. Expressions of RAS components, VEGF and HIF-1α in retina were analyzed using qPCR and retinal structure and function was also analyzed. Effect of Angiotensin Converting Enzyme Inhibitor (ACEI and Angiotensin Receptor Blocker (ARB was evaluated and compared with Bevacizumab which served as a positive control. Drug penetration into retina was confirmed by liquid chromatography coupled ESI-tandem mass spectroscopy (LC-MS/MS.Multifold increase in the expression of RAS components in human vitreous and rat retina showed their involvement in ROP. ERG & fundus studies in OIR revealed the altered function of retina and were successfully prevented by ARB (telmisartan, ACEI (lisinopril and bevacizumab. Retinal analysis revealed the presence of ACEI and ARB in their therapeutic levels.This study for the first time demonstrates the upregulated level of RAS components in human ROP vitreous and further that the pharmacological intervention in RRAS can functionally and structurally preserve retina against the progression of ROP in the OIR model.

Trends in co-prescribing of angiotensin converting enzyme inhibitors and angiotensin receptor blockers in Ireland.

LENUS (Irish Health Repository)

Wan Md Adnan, Wan A H

2011-03-01

(i) To examine the trends in co-prescribing of angiotensin converting enzyme inhibitor (ACEI) and angiotensin-II receptor blocker (ARB) therapy and (ii) to examine the influence of major clinical trials (CALM, COOPERATE, VALIANT and ONTARGET) on co-prescribing.

Angiotensin effects on calcium and steroidogenesis in adrenal glomerulosa cells

International Nuclear Information System (INIS)

Elliott, M.E.; Siegel, F.L.; Hadjokas, N.E.; Goodfriend, T.L.

1985-01-01

We investigated the role of cellular calcium pools in angiotensin II-stimulated aldosterone synthesis in bovine adrenal glomerulosa cells. Angiotensin II decreased the size of the exchangeable cell calcium pool by 34%, consistent with previous observations that angiotensin II causes decreased uptake of 45 Ca+2 into cells and increased efflux of 45 Ca+2 from preloaded cells. Atomic absorption spectroscopy showed that angiotension II caused a decrease of 21% in total cellular calcium. Angiotensin II caused efflux of 45 Ca+2 in the presence of EGTA and retarded uptake of 45 Ca+2 when choline was substituted for sodium, suggesting that hormone effects on calcium pools do not involve influx of trigger calcium or sodium. Cells incubated in calcium-free buffer and 0.1 mM or 0.5 mM EGTA synthesized reduced (but still significant) amounts of the steroid in response to hormone. Cells incubated in increasing concentrations of extracellular calcium contained increasing amounts of intracellular calcium and synthesized increasing amounts of aldosterone in response to angiotensin II. These results point to the participation of intracellular calcium pools in angiotensin II-stimulated steroidogenesis and the importance of extracellular calcium in maintaining these pools

Brain Renin-Angiotensin System and Microglial Polarization: Implications for Aging and Neurodegeneration

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Jose L. Labandeira-Garcia

2017-05-01

Full Text Available Microglia can transform into proinflammatory/classically activated (M1 or anti-inflammatory/alternatively activated (M2 phenotypes following environmental signals related to physiological conditions or brain lesions. An adequate transition from the M1 (proinflammatory to M2 (immunoregulatory phenotype is necessary to counteract brain damage. Several factors involved in microglial polarization have already been identified. However, the effects of the brain renin-angiotensin system (RAS on microglial polarization are less known. It is well known that there is a “classical” circulating RAS; however, a second RAS (local or tissue RAS has been observed in many tissues, including brain. The locally formed angiotensin is involved in local pathological changes of these tissues and modulates immune cells, which are equipped with all the components of the RAS. There are also recent data showing that brain RAS plays a major role in microglial polarization. Level of microglial NADPH-oxidase (Nox activation is a major regulator of the shift between M1/proinflammatory and M2/immunoregulatory microglial phenotypes so that Nox activation promotes the proinflammatory and inhibits the immunoregulatory phenotype. Angiotensin II (Ang II, via its type 1 receptor (AT1, is a major activator of the NADPH-oxidase complex, leading to pro-oxidative and pro-inflammatory effects. However, these effects are counteracted by a RAS opposite arm constituted by Angiotensin II/AT2 receptor signaling and Angiotensin 1–7/Mas receptor (MasR signaling. In addition, activation of prorenin-renin receptors may contribute to activation of the proinflammatory phenotype. Aged brains showed upregulation of AT1 and downregulation of AT2 receptor expression, which may contribute to a pro-oxidative pro-inflammatory state and the increase in neuron vulnerability. Several recent studies have shown interactions between the brain RAS and different factors involved in microglial polarization

Angiotensin Converting Enzyme Regulates Cell Proliferation and Migration.

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Erika Costa de Alvarenga

Full Text Available The angiotensin-I converting enzyme (ACE plays a central role in the renin-angiotensin system, acting by converting the hormone angiotensin-I to the active peptide angiotensin-II (Ang-II. More recently, ACE was shown to act as a receptor for Ang-II, and its expression level was demonstrated to be higher in melanoma cells compared to their normal counterparts. However, the function that ACE plays as an Ang-II receptor in melanoma cells has not been defined yet.Therefore, our aim was to examine the role of ACE in tumor cell proliferation and migration.We found that upon binding to ACE, Ang-II internalizes with a faster onset compared to the binding of Ang-II to its classical AT1 receptor. We also found that the complex Ang-II/ACE translocates to the nucleus, through a clathrin-mediated process, triggering a transient nuclear Ca2+ signal. In silico studies revealed a possible interaction site between ACE and phospholipase C (PLC, and experimental results in CHO cells, demonstrated that the β3 isoform of PLC is the one involved in the Ca2+ signals induced by Ang-II/ACE interaction. Further studies in melanoma cells (TM-5 showed that Ang-II induced cell proliferation through ACE activation, an event that could be inhibited either by ACE inhibitor (Lisinopril or by the silencing of ACE. In addition, we found that stimulation of ACE by Ang-II caused the melanoma cells to migrate, at least in part due to decreased vinculin expression, a focal adhesion structural protein.ACE activation regulates melanoma cell proliferation and migration.

Increased angiotensin II type 1 receptor expression in temporal arteries from patients with giant cell arteritis

DEFF Research Database (Denmark)

Dimitrijevic, Ivan; Malmsjö, Malin; Andersson, Christina

2009-01-01

PURPOSE: Currently, giant cell arteritis (GCA) is primarily treated with corticosteroids or immunomodulating agents, but there is interest in identifying other noncorticosteroid alternatives. Similarities exist in the injury pathways between GCA and atherosclerosis. Angiotensin II is a vasoactive......, internal elastic lamina degeneration, and band-shaped infiltrates of inflammatory cells, including lymphocytes, histocytes, and multinucleated giant cells. AT(1) receptor staining was primarily observed in the medial layer of the temporal arteries and was higher in the patients with GCA than in the control...

Increased expression of vascular endothelin type B and angiotensin type 1 receptors in patients with ischemic heart disease

DEFF Research Database (Denmark)

Dimitrijevic, Ivan; Edvinsson, Lars; Chen, Qingwen

2009-01-01

expression in subcutaneous arteries from patients with different degrees of ischemic heart disease. METHODS: Subcutaneous arteries were obtained, by biopsy from the abdomen, from patients undergoing coronary artery bypass graft (CABG) surgery because of ischemic heart disease (n = 15), patients with angina...... pectoris without established myocardial infarction (n = 15) and matched cardiovascular healthy controls (n = 15). Endothelin type A (ETA) and type B (ETB), and angiotensin type 1 (AT1) and type 2 (AT2) receptors expression and function were examined using immunohistochemistry, Western blot and in vitro...

Fetal betamethasone exposure attenuates angiotensin-(1-7)-Mas receptor expression in the dorsal medulla of adult sheep.

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Marshall, Allyson C; Shaltout, Hossam A; Nautiyal, Manisha; Rose, James C; Chappell, Mark C; Diz, Debra I

2013-06-01

Glucocorticoids including betamethasone (BM) are routinely administered to women entering into early preterm labor to facilitate fetal lung development and decrease infant mortality; however, fetal steroid exposure may lead to deleterious long term consequences. In a sheep model of fetal programming, BM-exposed (BMX) offspring exhibit elevated mean arterial pressure (MAP) and decreased baroreflex sensitivity (BRS) for control of heart rate by 0.5-years of age associated with changes in the circulating and renal renin-angiotensin systems (RAS). In the brain solitary tract nucleus, angiotensin (Ang) II actions through the AT1 receptor oppose the beneficial actions of Ang-(1-7) at the Mas receptor for BRS regulation. Therefore, we examined Ang peptides, angiotensinogen (Aogen), and receptor expression in this brain region of exposed and control offspring of 0.5- and 1.8-years of age. Mas protein expression was significantly lower (>40%) in the dorsal medulla of BMX animals at both ages; however, AT1 receptor expression was not changed. BMX offspring exhibited a higher ratio of Ang II to Ang-(1-7) (2.30±0.36 versus 0.99±0.28; p<0.01) and Ang II to Ang I at 0.5-years. Although total Aogen was unchanged, Ang I-intact Aogen was lower in 0.5-year BMX animals (0.78±0.06 vs. 1.94±0.41; p<0.05) suggesting a greater degree of enzymatic processing of the precursor protein in exposed animals. We conclude that in utero BM exposure promotes an imbalance in the central RAS pathways of Ang II and Ang-(1-7) that may contribute to the elevated MAP and lower BRS in this model. Copyright © 2013 Elsevier Inc. All rights reserved.

Hypertrophic response to hemodynamic overload: role of load vs. renin-angiotensin system activation

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Koide, M.; Carabello, B. A.; Conrad, C. C.; Buckley, J. M.; DeFreyte, G.; Barnes, M.; Tomanek, R. J.; Wei, C. C.; Dell'Italia, L. J.; Cooper, G. 4th;

Reduced glomerular angiotensin II receptor density in diabetes mellitus in the rat: time course and mechanism

International Nuclear Information System (INIS)

Wilkes, B.M.

1987-01-01

Glomerular angiotensin II receptors are reduced in number in early diabetes mellitus, which may contribute to hyperfiltration and glomerular injury. The time course and role of the renin-angiotensin-aldosterone system in the pathogenesis of the receptor abnormality were studied in male Sprague-Dawley rats made diabetic with streptozotocin (65 mg, iv). Glomerular angiotensin II receptors were measured by Scatchard analysis; insulin, renin activity, angiotensin II, and aldosterone were measured by RIA. Diabetes mellitus was documented at 24 h by a rise in plasma glucose (vehicle-injected control, 133 +/- 4; diabetic, 482 +/- 22 mg/dl and a fall in plasma insulin (control, 53.1 +/- 5.7; diabetic, 35.6 +/- 4.0 microIU/ml. At 24 h glomerular angiotensin II receptor density was decreased by 26.5% in diabetic rats (control, 75.5 +/- 9.6 X 10(6); diabetic, 55.5 +/- 8.3 X 10(6) receptors/glomerulus. Receptor occupancy could not explain the defect, because there was reduced binding in diabetic glomeruli after pretreatment with 3 M MgCl 2 , a maneuver that caused dissociation of previously bound hormone. There was a progressive return of the receptor density toward normal over the 60 days following induction of diabetes, with diabetic glomeruli measuring 22.7%, 14.8%, and 3.7% fewer receptors than age-matched controls at 11 days, 1 month, and 2 months, respectively

The Second Transmembrane Domain of the Human Type 1 Angiotensin II Receptor Participates in the Formation of the Ligand Binding Pocket and Undergoes Integral Pivoting Movement during the Process of Receptor Activation*

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Domazet, Ivana; Holleran, Brian J.; Martin, Stéphane S.; Lavigne, Pierre; Leduc, Richard; Escher, Emanuel; Guillemette, Gaétan

2009-01-01

The octapeptide hormone angiotensin II (AngII) exerts a wide variety of cardiovascular effects through the activation of the angiotensin II type-1 (AT1) receptor, which belongs to the G protein-coupled receptor superfamily. Like other G protein-coupled receptors, the AT1 receptor possesses seven transmembrane domains that provide structural support for the formation of the ligand-binding pocket. In order to identify those residues in the second transmembrane domain (TMD2) that contribute to the formation of the binding pocket of the AT1 receptor, we used the substituted cysteine accessibility method. All of the residues within the Leu-70 to Trp-94 region were mutated one at a time to a cysteine, and, after expression in COS-7 cells, the mutant receptors were treated with the sulfhydryl-specific alkylating agent methanethiosulfonate-ethylammonium (MTSEA). MTSEA reacts selectively with water-accessible, free sulfhydryl groups of endogenous or introduced point mutation cysteines. If a cysteine is found in the binding pocket, the covalent modification will affect the binding kinetics of the ligand. MTSEA substantially decreased the binding affinity of D74C-AT1, L81C-AT1, A85C-AT1, T88C-AT1, and A89C-AT1 mutant receptors, which suggests that these residues orient themselves within the water-accessible binding pocket of the AT1 receptor. Interestingly, this pattern of acquired MTSEA sensitivity was altered for TMD2 reporter cysteines engineered in a constitutively active N111G-AT1 receptor background. Indeed, mutant D74C-N111G-AT1 became insensitive to MTSEA, whereas mutant L81C-N111G-AT1 lost some sensitivity and mutant V86C-N111G-AT1 became sensitive to MTSEA. Our results suggest that constitutive activation of the AT1 receptor causes TMD2 to pivot, bringing the top of TMD2 closer to the binding pocket and pushing the bottom of TMD2 away from the binding pocket. PMID:19276075

The second transmembrane domain of the human type 1 angiotensin II receptor participates in the formation of the ligand binding pocket and undergoes integral pivoting movement during the process of receptor activation.

Science.gov (United States)

Domazet, Ivana; Holleran, Brian J; Martin, Stéphane S; Lavigne, Pierre; Leduc, Richard; Escher, Emanuel; Guillemette, Gaétan

2009-05-01

The octapeptide hormone angiotensin II (AngII) exerts a wide variety of cardiovascular effects through the activation of the angiotensin II type-1 (AT(1)) receptor, which belongs to the G protein-coupled receptor superfamily. Like other G protein-coupled receptors, the AT(1) receptor possesses seven transmembrane domains that provide structural support for the formation of the ligand-binding pocket. In order to identify those residues in the second transmembrane domain (TMD2) that contribute to the formation of the binding pocket of the AT(1) receptor, we used the substituted cysteine accessibility method. All of the residues within the Leu-70 to Trp-94 region were mutated one at a time to a cysteine, and, after expression in COS-7 cells, the mutant receptors were treated with the sulfhydryl-specific alkylating agent methanethiosulfonate-ethylammonium (MTSEA). MTSEA reacts selectively with water-accessible, free sulfhydryl groups of endogenous or introduced point mutation cysteines. If a cysteine is found in the binding pocket, the covalent modification will affect the binding kinetics of the ligand. MTSEA substantially decreased the binding affinity of D74C-AT(1), L81C-AT(1), A85C-AT(1), T88C-AT(1), and A89C-AT(1) mutant receptors, which suggests that these residues orient themselves within the water-accessible binding pocket of the AT(1) receptor. Interestingly, this pattern of acquired MTSEA sensitivity was altered for TMD2 reporter cysteines engineered in a constitutively active N111G-AT(1) receptor background. Indeed, mutant D74C-N111G-AT(1) became insensitive to MTSEA, whereas mutant L81C-N111G-AT(1) lost some sensitivity and mutant V86C-N111G-AT(1) became sensitive to MTSEA. Our results suggest that constitutive activation of the AT(1) receptor causes TMD2 to pivot, bringing the top of TMD2 closer to the binding pocket and pushing the bottom of TMD2 away from the binding pocket.

Relationship Between Aldosterone and Parathyroid Hormone, and the Effect of Angiotensin and Aldosterone Inhibition on Bone Health

DEFF Research Database (Denmark)

L.S., Bislev; T., Sikjaer; L., Rolighed

2015-01-01

Emerging evidence suggests a stimulating effect of parathyroid hormone (PTH) on the reninnullangiotensinnullaldosterone system (RAAS). In primary hyperparathyroidism, chronic-elevated PTH levels seem to stimulate the RAAS which may explain the increased risk of cardiovascular disease (CVD......). In addition to increased PTH levels, low vitamin D levels may also directly increase risk of CVD, as vitamin D, itself, has been shown to inhibit the RAAS. Angiotensin II, aldosterone and cortisol all negatively impact bone health. Hyperaldosteronism is associated with a reversible secondary...... hyperparathyroidism due to increased renal calcium excretion. Moreover, the angiotensin II receptor is expressed by human parathyroid tissue, and angiotensin may therefore directly stimulates PTH secretion. An increased bone loss is found in patients with hyperaldosteronism. The angiotensin II receptor seems main...

Angiotensin converting enzyme 2 activity and human atrial fibrillation: increased plasma angiotensin converting enzyme 2 activity is associated with atrial fibrillation and more advanced left atrial structural remodelling.

Science.gov (United States)

Walters, Tomos E; Kalman, Jonathan M; Patel, Sheila K; Mearns, Megan; Velkoska, Elena; Burrell, Louise M

2017-08-01

Angiotensin converting enzyme 2 (ACE2) is an integral membrane protein whose main action is to degrade angiotensin II. Plasma ACE2 activity is increased in various cardiovascular diseases. We aimed to determine the relationship between plasma ACE2 activity and human atrial fibrillation (AF), and in particular its relationship to left atrial (LA) structural remodelling. One hundred and three participants from a tertiary arrhythmia centre, including 58 with paroxysmal AF (PAF), 20 with persistent AF (PersAF), and 25 controls, underwent clinical evaluation, echocardiographic analysis, and measurement of plasma ACE2 activity. A subgroup of 20 participants underwent invasive LA electroanatomic mapping. Plasma ACE2 activity levels were increased in AF [control 13.3 (9.5-22.3) pmol/min/mL; PAF 16.9 (9.7-27.3) pmol/min/mL; PersAF 22.8 (13.7-33.4) pmol/min/mL, P = 0.006]. Elevated plasma ACE2 was associated with older age, male gender, hypertension and vascular disease, elevated left ventricular (LV) mass, impaired LV diastolic function and advanced atrial disease (P < 0.05 for all). Independent predictors of elevated plasma ACE2 activity were AF (P = 0.04) and vascular disease (P < 0.01). There was a significant relationship between elevated ACE2 activity and low mean LA bipolar voltage (adjusted R2 = 0.22, P = 0.03), a high proportion of complex fractionated electrograms (R2 = 0.32, P = 0.009) and a long LA activation time (R2 = 0.20, P = 0.04). Plasma ACE2 activity is elevated in human AF. Both AF and vascular disease predict elevated plasma ACE2 activity, and elevated plasma ACE2 is significantly associated with more advanced LA structural remodelling. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.

Angiotensin antagonists in the dog with chronic pericardial tamponade

International Nuclear Information System (INIS)

Moore, G.J.; Taub, K.J.

1980-01-01

Assessing the role played by angiotensin in the pathogenesis and maintenance of the renal function and perfusion abnormalities dogs with chronic pericardial tamponade were used in the experiment as a stable model of chronic low output heart failure. The heptapeptide and octapeptide antagonist were used. The results of the experiments suggest that there is a role for angiotensin in the pathologenesis of congestive heart failure. The renin-angiotensin system was activated in the model. Plasma renin activity was elevated and increased further in response to angiotensin blockade. Under the experiment condition there was no evidence for a role for angiotensin in the maintenance of arterial blood pressure. But there was angiotensin-mediated renal vasoconstriction and a reduction in renal blood flow. Both analogues of angiotensin were able to antagonize this effect in similar fashion. Failure to achieve a natriuresis in response to angiotensin blockade may reflect the redistribution of blood flow that occured and suggests that additional factors are operative in this model. (APR)

The effect of angiotensin 1-7 on tyrosine kinases activity in rat anterior pituitary

International Nuclear Information System (INIS)

Rebas, Elzbieta; Zabczynska, Joanna; Lachowicz, Agnieszka

2006-01-01

Angiotensin 1-7 (Ang 1-7) is a peptide originated from Ang II. It is known that in vessels Ang 1-7 shows opposite effects to Ang II. Ang 1-7 can modify processes of proliferation. However, Ang 1-7 action in pituitary gland cells was never studied. Moreover, the specific binding sites for Ang 1-7 are still unknown. The aim of this study was to examine the effects of Ang 1-7 on tyrosine kinases (PTKs) activity in the anterior pituitary. The reaction of phosphorylation was carrying out in presence of different concentration of Ang 1-7 and losartan (antagonist of AT1 receptor) and PD123319 (antagonist of AT2). Our results show that Ang 1-7 inhibited activity of PTK to 60% of basic activity. Losartan did not change the Ang 1-7-induced changes in PTKs activity. The presence of PD123319 together with Ang 1-7 caused stronger inhibition PTKs activity than Ang 1-7 alone. These observations suggest that Ang 1-7 binds to the novel, unknown, specific for this peptide receptor

Overexpression of ß-Arrestin1 in the Rostral Ventrolateral Medulla Downregulates Angiotensin Receptor and Lowers Blood Pressure in Hypertension.

Science.gov (United States)

Sun, Jia-Cen; Liu, Bing; Zhang, Ru-Wen; Jiao, Pei-Lei; Tan, Xing; Wang, Yang-Kai; Wang, Wei-Zhong

2018-01-01

Background: Hypertension is characterized by sympathetic overactivity, which is associated with an enhancement in angiotensin receptor type I (AT1R) in the rostral ventrolateral medulla (RVLM). β-arrestin1, a canonical scaffold protein, has been suggested to show a negative effect on G protein-coupled receptors via its internalization and desensitization and/or the biased signaling pathway. The major objectives of the present study were to observe the effect of β-arrestin1 overexpression in the RVLM on cardiovascular regulation in spontaneously hypertensive rats (SHR), and further determine the effect of β-arrestin1 on AT1R expression in the RVLM. Methods: The animal model of β-arrestin1 overexpression was induced by bilateral injection of adeno-associated virus containing Arrb1 gene (AAV-Arrb1) into the RVLM of WKY and SHR. Results: β-arrestin1 was expressed on the pre-sympathetic neurons in the RVLM, and its expression in the RVLM was significantly ( P Overexpression of β-arrestin1 in SHR significantly decreased baseline levels of blood pressure and renal sympathetic nerve activity, and attenuated cardiovascular effects induced by RVLM injection of angiotensin II (100 pmol). Furthermore, β-arrestin1 overexpression in the RVLM significantly reduced the expression of AT1R by 65% and NF-κB p65 phosphorylation by 66% in SHR. It was confirmed that β-arrestin1 overexpression in the RVLM led to an enhancement of interaction between β-arrestin1 and IκB-α. Conclusion: Overexpression of β-arrestin1 in the RVLM reduces BP and sympathetic outflow in hypertension, which may be associated with NFκB-mediated AT1R downregulation.

Renin-angiotensin system: an old player with novel functions in skeletal muscle.

Science.gov (United States)

Cabello-Verrugio, Claudio; Morales, María Gabriela; Rivera, Juan Carlos; Cabrera, Daniel; Simon, Felipe

2015-05-01

Skeletal muscle is a tissue that shows the most plasticity in the body; it can change in response to physiological and pathological stimuli. Among the diseases that affect skeletal muscle are myopathy-associated fibrosis, insulin resistance, and muscle atrophy. A common factor in these pathologies is the participation of the renin-angiotensin system (RAS). This system can be functionally separated into the classical and nonclassical RAS axis. The main components of the classical RAS pathway are angiotensin-converting enzyme (ACE), angiotensin II (Ang-II), and Ang-II receptors (AT receptors), whereas the nonclassical axis is composed of ACE2, angiotensin 1-7 [Ang (1-7)], and the Mas receptor. Hyperactivity of the classical axis in skeletal muscle has been associated with insulin resistance, atrophy, and fibrosis. In contrast, current evidence supports the action of the nonclassical RAS as a counter-regulator axis of the classical RAS pathway in skeletal muscle. In this review, we describe the mechanisms involved in the pathological effects of the classical RAS, advances in the use of pharmacological molecules to inhibit this axis, and the beneficial effects of stimulation of the nonclassical RAS pathway on insulin resistance, atrophy, and fibrosis in skeletal muscle. © 2015 Wiley Periodicals, Inc.

The Renal Renin-Angiotensin System

Science.gov (United States)

Harrison-Bernard, Lisa M.

2009-01-01

The renin-angiotensin system (RAS) is a critical regulator of sodium balance, extracellular fluid volume, vascular resistance, and, ultimately, arterial blood pressure. In the kidney, angiotensin II exerts its effects to conserve salt and water through a combination of the hemodynamic control of renal blood flow and glomerular filtration rate and…

Angiotensin II upregulates the expression of placental growth factor in human vascular endothelial cells and smooth muscle cells

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Guo Yingqiang

2010-05-01

Full Text Available Abstract Background Atherosclerosis is now recognized as a chronic inflammatory disease. Angiotensin II (Ang II is a critical factor in inflammatory responses, which promotes the pathogenesis of atherosclerosis. Placental growth factor (PlGF is a member of the vascular endothelial growth factor (VEGF family cytokines and is associated with inflammatory progress of atherosclerosis. However, the potential link between PlGF and Ang II has not been investigated. In the current study, whether Ang II could regulate PlGF expression, and the effect of PlGF on cell proliferation, was investigated in human vascular endothelial cells (VECs and smooth muscle cells (VSMCs. Results In growth-arrested human VECs and VSMCs, Ang II induced PlGF mRNA expression after 4 hour treatment, and peaked at 24 hours. 10-6 mol/L Ang II increased PlGF protein production after 8 hour treatment, and peaked at 24 hours. Stimulation with Ang II also induced mRNA expression of VEGF receptor-1 and -2(VEGFR-1 and -2 in these cells. The Ang II type I receptor (AT1R antagonist blocked Ang II-induced PlGF gene expression and protein production. Several intracellular signals elicited by Ang II were involved in PlGF synthesis, including activation of protein kinase C, extracellular signal-regulated kinase 1/2 (ERK1/2 and PI3-kinase. A neutralizing antibody against PlGF partially inhibited the Ang II-induced proliferation of VECs and VSMCs. However, this antibody showed little effect on the basal proliferation in these cells, whereas blocking antibody of VEGF could suppress both basal and Ang II-induced proliferation in VECs and VSMCs. Conclusion Our results showed for the first time that Ang II could induce the gene expression and protein production of PlGF in VECs and VSMCs, which might play an important role in the pathogenesis of vascular inflammation and atherosclerosis.

Increased insulin-stimulated expression of arterial angiotensinogen and angiotensin type 1 receptor in patients with type 2 diabetes mellitus and atheroma.

Science.gov (United States)

Hodroj, Wassim; Legedz, Liliana; Foudi, Nabil; Cerutti, Catherine; Bourdillon, Marie-Claude; Feugier, Patrick; Beylot, Michel; Randon, Jacques; Bricca, Giampiero

2007-03-01

Because inhibition of the renin-angiotensin system (RAS) reduces the onset of type 2 diabetes (T2D) and prevents atherosclerosis, we investigated the expression of RAS in the arterial wall of T2D and nondiabetic (CTR) patients. mRNA and protein levels of angiotensinogen (AGT), angiotensin-converting enzyme (ACE) and AT1 receptor (AT1R) were determined in carotid atheroma plaque, nearby macroscopically intact tissue (MIT), and in vascular smooth muscle cells (VSMCs) before and after insulin stimulation from 21 T2D and 22 CTR patients. AGT and ACE mRNA and their protein levels were 2- to 3-fold higher in atheroma and in MIT of T2D patients. VSMCs from T2D patients had respectively 2.5- and 5-fold higher AGT and AT1R mRNA and protein contents. Insulin induced an increase in AGT and AT1R mRNA with similar ED50. These responses were blocked by PD98059, an inhibitor of MAP-kinase in the two groups whereas wortmannin, an inhibitor of PI3-kinase, partially prevented the response in CTR patients. Phosphorylated ERK1-2 was 4-fold higher in MIT from T2D than from CTR patients. The arterial RAS is upregulated in T2D patients, which can be partly explained by an hyperactivation of the ERK1-2 pathway by insulin.

Angiotensin II Protects Primary Rat Hepatocytes against Bile Salt-Induced Apoptosis

NARCIS (Netherlands)

Karimian, Golnar; Buist-Homan, Manon; Mikus, Bojana; Henning, Robert H.; Faber, Klaas Nico; Moshage, Han

2012-01-01

Angiotensin II (AT-II) is a pro-fibrotic compound that acts via membrane-bound receptors (AT-1R/AT-2R) and thereby activates hepatic stellate cells (HSCs). AT-II receptor blockers (ARBs) are thus important candidates in the treatment of liver fibrosis. However, multiple case reports suggest that

Stimulation of the Angiotensin II AT2 Receptor is Anti-inflammatory in Human Lipopolysaccharide-Activated Monocytic Cells

DEFF Research Database (Denmark)

Menk, Mario; Graw, Jan Adriaan; von Haefen, Clarissa

2015-01-01

and the translational level over course of time. Treatment with C21 attenuated the expression of TNFα, IL-6, and IL-10 after LPS challenge in both cell lines in a time- and dose-dependent manner. We conclude that selective AT2 receptor stimulation acts anti-inflammatory in human monocytes. Modulation of cytokine......Recently, AT2 receptors have been discovered on the surface of human immunocompetent cells such as monocytes. Data on regulative properties of this receptor on the cellular immune response are poor. We hypothesized that direct stimulation of the AT2 receptor mediates anti-inflammatory responses...... in these cells. Human monocytic THP-1 and U937 cells were stimulated with lipopolysaccharide (LPS) and the selective AT2 receptor agonist Compound 21 (C21). Expression of pro- and anti-inflammatory cytokines IL-6, IL-10, tumor necrosis factor-α (TNFα), and IL-1β were analyzed on both the transcriptional...

Angiotensin-2-mediated Ca2+ signaling in the retinal pigment epithelium: role of angiotensin-receptor-associated-protein and TRPV2 channel.

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Rene Barro-Soria

Full Text Available Angiotensin II (AngII receptor (ATR is involved in pathologic local events such as neovascularisation and inflammation including in the brain and retina. The retinal pigment epithelium (RPE expresses ATR in its AT1R form, angiotensin-receptor-associated protein (Atrap, and transient-receptor-potential channel-V2 (TRPV2. AT1R and Atrap co-localize to the basolateral membrane of the RPE, as shown by immunostaining. Stimulation of porcine RPE (pRPE cells by AngII results in biphasic increases in intracellular free Ca(2+inhibited by losartan. Xestospongin C (xest C and U-73122, blockers of IP3R and PLC respectively, reduced AngII-evoked Ca(2+response. RPE cells from Atrap(-/- mice showed smaller AngII-evoked Ca(2+peak (by 22% and loss of sustained Ca(2+elevation compared to wild-type. The TRPV channel activator cannabidiol (CBD at 15 µM stimulates intracellular Ca(2+-rise suggesting that porcine RPE cells express TRPV2 channels. Further evidence supporting the functional expression of TRPV2 channels comes from experiments in which 100 µM SKF96365 (a TRPV channel inhibitor reduced the cannabidiol-induced Ca(2+-rise. Application of SKF96365 or reduction of TRPV2 expression by siRNA reduced the sustained phase of AngII-mediated Ca(2+transients by 53%. Thus systemic AngII, an effector of the local renin-angiotensin system stimulates biphasic Ca(2+transients in the RPE by releasing Ca(2+from cytosolic IP3-dependent stores and activating ATR/Atrap and TRPV2 channels to generate a sustained Ca(2+elevation.

Combination inhibition of the renin-angiotensin system: is more better?

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Krause, Michelle W; Fonseca, Vivian A; Shah, Sudhir V

2011-08-01

Angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers are considered the standard of care for treatment of cardiovascular disease and chronic kidney disease. Combination therapy with both angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers effectively inhibits the renin-angiotensin system as well as potentiates the vasodilatory effects of bradykinin. It has been advocated that this dual blockade approach theoretically should result in improved clinical outcomes in both cardiovascular disease and chronic kidney disease. Clinical trial evidence for the use of combination therapy with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in cardiovascular disease has provided conflicting results in hypertension, congestive heart failure, and ischemic heart disease. Clinical trial evidence to support combination therapy with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in chronic kidney disease has largely been based on proteinuria reduction as a surrogate marker for clinically meaningful outcomes. Recent large-scale randomized clinical trials have not been able to validate protection in halting progression in chronic kidney disease with a dual blockade approach. This review serves as an appraisal on the clinical evidence of combination angiotensin-converting enzyme inhibition and angiotensin II receptor blockade in both cardiovascular disease and chronic kidney disease.

The angiotensin type 2 receptor agonist Compound 21 elicits cerebroprotection in endothelin-1 induced ischemic stroke

DEFF Research Database (Denmark)

Joseph, Jason P; Mecca, Adam P; Regenhardt, Robert W

2014-01-01

Evidence indicates that angiotensin II type 2 receptors (AT2R) exert cerebroprotective actions during stroke. A selective non-peptide AT2R agonist, Compound 21 (C21), has been shown to exert beneficial effects in models of cardiac and renal disease, as well as hemorrhagic stroke. Here, we hypothe...

Prognostic impact of carboxylesterase 1 gene variants in patients with congestive heart failure treated with angiotensin-converting enzyme inhibitors

DEFF Research Database (Denmark)

Nelveg-Kristensen, Karl E.; Madsen, Majbritt B.; Torp-Pedersen, Christian

2016-01-01

OBJECTIVE: Most angiotensin-converting enzyme inhibitors (ACEIs) are prodrugs activated by carboxylesterase 1 (CES1). We investigated the prognostic importance of CES1 gene (CES1) copy number variation and the rs3815583 single-nucleotide polymorphism in CES1 among ACEI-treated patients with conge...

Crosstalk between insulin-like growth factor-1 and angiotensin-II in dopaminergic neurons and glial cells: role in neuroinflammation and aging

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Rodriguez-Perez, Ana I.; Borrajo, Ana; Diaz-Ruiz, Carmen; Garrido-Gil, Pablo; Labandeira-Garcia, Jose L.

2016-01-01

The local renin-angiotensin system (RAS) and insulin-like growth factor 1 (IGF-1) have been involved in longevity, neurodegeneration and aging-related dopaminergic degeneration. However, it is not known whether IGF-1 and angiotensin-II (AII) activate each other. In the present study, AII, via type 1 (AT1) receptors, exacerbated neuroinflammation and dopaminergic cell death. AII, via AT1 receptors, also increased the levels of IGF-1 and IGF-1 receptors in microglial cells. IGF-1 inhibited RAS activity in dopaminergic neurons and glial cells, and also inhibited the AII-induced increase in markers of the M1 microglial phenotype. Consistent with this, IGF-1 decreased dopaminergic neuron death induced by the neurotoxin MPP+ both in the presence and in the absence of glia. Intraventricular administration of AII to young rats induced a significant increase in IGF-1 expression in the nigral region. However, aged rats showed decreased levels of IGF-1 relative to young controls, even though RAS activity is known to be enhanced in aged animals. The study findings show that IGF-1 and the local RAS interact to inhibit or activate neuroinflammation (i.e. transition from the M1 to the M2 phenotype), oxidative stress and dopaminergic degeneration. The findings also show that this mechanism is impaired in aged animals. PMID:27167199

High-Dose Estradiol-Replacement Therapy Enhances the Renal Vascular Response to Angiotensin II via an AT2-Receptor Dependent Mechanism

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Tahereh Safari

2015-01-01

Full Text Available Physiological levels of estrogen appear to enhance angiotensin type 2 receptor- (AT2R- mediated vasodilatation. However, the effects of supraphysiological levels of estrogen, analogous to those achieved with high-dose estrogen replacement therapy in postmenopausal women, remain unknown. Therefore, we pretreated ovariectomized rats with a relatively high dose of estrogen (0.5 mg/kg/week for two weeks. Subsequently, renal hemodynamic responses to intravenous angiotensin II (Ang II, 30–300 ng/kg/min were tested under anesthesia, while renal perfusion pressure was held constant. The role of AT2R was examined by pretreating groups of rats with PD123319 or its vehicle. Renal blood flow (RBF decreased in a dose-related manner in response to Ang II. Responses to Ang II were enhanced by pretreatment with estradiol. For example, at 300 ng kg−1 min−1, Ang II reduced RBF by 45.7±1.9% in estradiol-treated rats but only by 27.3±5.1% in vehicle-treated rats. Pretreatment with PD123319 blunted the response of RBF to Ang II in estradiol-treated rats, so that reductions in RBF were similar to those in rats not treated with estradiol. We conclude that supraphysiological levels of estrogen promote AT2R-mediated renal vasoconstriction. This mechanism could potentially contribute to the increased risk of cardiovascular disease associated with hormone replacement therapy using high-dose estrogen.

N- vs. C-Domain Selectivity of Catalytic Inactivation of Human Angiotensin Converting Enzyme by Lisinopril-Coupled Transition Metal Chelates

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Hocharoen, Lalintip; Joyner, Jeff C.; Cowan, J. A.

2014-01-01

The N- and C-terminal domains of human somatic Angiotensin I Converting Enzyme (sACE-1) demonstrate distinct physiological functions, with resulting interest in the development of domain-selective inhibitors for specific therapeutic applications. Herein, the activity of lisinopril-coupled transition metal chelates were tested for both reversible binding and irreversible catalytic inactivation of sACE-1. C/N domain binding selectivity ratios ranged from 1 to 350, while rates of irreversible catalytic inactivation of the N- and C-domains were found to be significantly greater for the N-domain, suggesting a more optimal orientation of the M-chelate-lisinopril complexes within the active site of the N-domain of sACE-1. Finally, the combined effect of binding selectivity and inactivation selectivity was assessed for each catalyst (double-filter selectivity factors), and several catalysts were found to cause domain-selective catalytic inactivation. The results of this study demonstrate the ability to optimize the target selectivity of catalytic metallopeptides through both binding and orientation factors (double-filter effect). PMID:24228790

N- versus C-domain selectivity of catalytic inactivation of human angiotensin converting enzyme by lisinopril-coupled transition metal chelates.

Science.gov (United States)

Hocharoen, Lalintip; Joyner, Jeff C; Cowan, J A

2013-12-27

The N- and C-terminal domains of human somatic angiotensin I converting enzyme (sACE-1) demonstrate distinct physiological functions, with resulting interest in the development of domain-selective inhibitors for specific therapeutic applications. Herein, the activity of lisinopril-coupled transition metal chelates was tested for both reversible binding and irreversible catalytic inactivation of each domain of sACE-1. C/N domain binding selectivity ratios ranged from 1 to 350, while rates of irreversible catalytic inactivation of the N- and C-domains were found to be significantly greater for the N-domain, suggesting a more optimal orientation of M-chelate-lisinopril complexes within the active site of the N-domain of sACE-1. Finally, the combined effect of binding selectivity and inactivation selectivity was assessed for each catalyst (double-filter selectivity factors), and several catalysts were found to cause domain-selective catalytic inactivation. The results of this study demonstrate the ability to optimize the target selectivity of catalytic metallopeptides through both binding and catalytic factors (double-filter effect).

Crystal structure of the N domain of human somatic angiotensin I-converting enzyme provides a structural basis for domain-specific inhibitor design.

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Corradi, Hazel R; Schwager, Sylva L U; Nchinda, Aloysius T; Sturrock, Edward D; Acharya, K Ravi

2006-03-31

Human somatic angiotensin I-converting enzyme (sACE) is a key regulator of blood pressure and an important drug target for combating cardiovascular and renal disease. sACE comprises two homologous metallopeptidase domains, N and C, joined by an inter-domain linker. Both domains are capable of cleaving the two hemoregulatory peptides angiotensin I and bradykinin, but differ in their affinities for a range of other substrates and inhibitors. Previously we determined the structure of testis ACE (C domain); here we present the crystal structure of the N domain of sACE (both in the presence and absence of the antihypertensive drug lisinopril) in order to aid the understanding of how these two domains differ in specificity and function. In addition, the structure of most of the inter-domain linker allows us to propose relative domain positions for sACE that may contribute to the domain cooperativity. The structure now provides a platform for the design of "domain-specific" second-generation ACE inhibitors.

Overexpression of ß-Arrestin1 in the Rostral Ventrolateral Medulla Downregulates Angiotensin Receptor and Lowers Blood Pressure in Hypertension

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Jia-Cen Sun

2018-03-01

Full Text Available Background: Hypertension is characterized by sympathetic overactivity, which is associated with an enhancement in angiotensin receptor type I (AT1R in the rostral ventrolateral medulla (RVLM. β-arrestin1, a canonical scaffold protein, has been suggested to show a negative effect on G protein-coupled receptors via its internalization and desensitization and/or the biased signaling pathway. The major objectives of the present study were to observe the effect of β-arrestin1 overexpression in the RVLM on cardiovascular regulation in spontaneously hypertensive rats (SHR, and further determine the effect of β-arrestin1 on AT1R expression in the RVLM.Methods: The animal model of β-arrestin1 overexpression was induced by bilateral injection of adeno-associated virus containing Arrb1 gene (AAV-Arrb1 into the RVLM of WKY and SHR.Results: β-arrestin1 was expressed on the pre-sympathetic neurons in the RVLM, and its expression in the RVLM was significantly (P < 0.05 downregulated by an average of 64% in SHR than WKY. Overexpression of β-arrestin1 in SHR significantly decreased baseline levels of blood pressure and renal sympathetic nerve activity, and attenuated cardiovascular effects induced by RVLM injection of angiotensin II (100 pmol. Furthermore, β-arrestin1 overexpression in the RVLM significantly reduced the expression of AT1R by 65% and NF-κB p65 phosphorylation by 66% in SHR. It was confirmed that β-arrestin1 overexpression in the RVLM led to an enhancement of interaction between β-arrestin1 and IκB-α.Conclusion: Overexpression of β-arrestin1 in the RVLM reduces BP and sympathetic outflow in hypertension, which may be associated with NFκB-mediated AT1R downregulation.

ELABELA-APJ axis protects from pressure overload heart failure and angiotensin II-induced cardiac damage.

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Sato, Teruki; Sato, Chitose; Kadowaki, Ayumi; Watanabe, Hiroyuki; Ho, Lena; Ishida, Junji; Yamaguchi, Tomokazu; Kimura, Akinori; Fukamizu, Akiyoshi; Penninger, Josef M; Reversade, Bruno; Ito, Hiroshi; Imai, Yumiko; Kuba, Keiji

2017-06-01

Elabela/Toddler/Apela (ELA) has been identified as a novel endogenous peptide ligand for APJ/Apelin receptor/Aplnr. ELA plays a crucial role in early cardiac development of zebrafish as well as in maintenance of self-renewal of human embryonic stem cells. Apelin was the first identified APJ ligand, and exerts positive inotropic heart effects and regulates the renin-angiotensin system. The aim of this study was to investigate the biological effects of ELA in the cardiovascular system. Continuous infusion of ELA peptide significantly suppressed pressure overload-induced cardiac hypertrophy, fibrosis and impaired contractility in mice. ELA treatment reduced mRNA expression levels of genes associated with heart failure and fibrosis. The cardioprotective effects of ELA were diminished in APJ knockout mice, indicating that APJ is the key receptor for ELA in the adult heart. Mechanistically, ELA downregulated angiotensin-converting enzyme (ACE) expression in the stressed hearts, whereas it showed little effects on angiotensin-converting enzyme 2 (ACE2) expression, which are distinct from the effects of Apelin. FoxM1 transcription factor, which induces ACE expression in the stressed hearts, was downregulated by ELA but not by Apelin. ELA antagonized angiotensin II-induced hypertension, cardiac hypertrophy, and fibrosis in mice. The ELA-APJ axis protects from pressure overload-induced heart failure possibly via suppression of ACE expression and pathogenic angiotensin II signalling. The different effects of ELA and Apelin on the expression of ACE and ACE2 implicate fine-tuned mechanisms for a ligand-induced APJ activation and downstream signalling. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions please email: journals.permissions@oup.com.

Angiotensin II, hypertension and angiotensin II receptor antagonism: Roles in the behavioural and brain pathology of a mouse model of Alzheimer's disease

NARCIS (Netherlands)

Wiesmann, M.; Roelofs, M.; Lugt, R. Van Der; Heerschap, A.; Kiliaan, A.J.; Claassen, J.A.H.R.

2017-01-01

Elevated angiotensin II causes hypertension and contributes to Alzheimer's disease by affecting cerebral blood flow. Angiotensin II receptor blockers may provide candidates to reduce (vascular) risk factors for Alzheimer's disease. We studied effects of two months of angiotensin II-induced

The transcription factor ETS-1 regulates angiotensin II-stimulated fibronectin production in mesangial cells.

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Hua, Ping; Feng, Wenguang; Rezonzew, Gabriel; Chumley, Phillip; Jaimes, Edgar A

2012-06-01

Angiotensin II (ANG II) produced as result of activation of the renin-angiotensin system (RAS) plays a critical role in the pathogenesis of chronic kidney disease via its hemodynamic effects on the renal microcirculation as well as by its nonhemodynamic actions including the production of extracellular matrix proteins such as fibronectin, a multifunctional extracellular matrix protein that plays a major role in cell adhesion and migration as well as in the development of glomerulosclerosis. ETS-1 is an important transcription factor essential for normal kidney development and glomerular integrity. We previously showed that ANG II increases ETS-1 expression and is required for fibronectin production in mesangial cells. In these studies, we determined that ANG II induces phosphorylation of ETS-1 via activation of the type 1 ANG II receptor and that Erk1/2 and Akt/PKB phosphorylation are required for these effects. In addition, we characterized the role of ETS-1 on the transcriptional activation of fibronectin production in mesangial cells. We determined that ETS-1 directly activates the fibronectin promoter and by utilizing gel shift assays and chromatin immunoprecipitation assays identified two different ETS-1 binding sites that promote the transcriptional activation of fibronectin in response to ANG II. In addition, we identified the essential role of CREB and its coactivator p300 on the transcriptional activation of fibronectin by ETS-1. These studies unveil novel mechanisms involved in RAS-induced production of the extracellular matrix protein fibronectin in mesangial cells and establish the role of the transcription factor ETS-1 as a direct mediator of these effects.

Overexpression of angiotensin-converting enzyme in myelomonocytic cells enhances the immune response [version 1; referees: 3 approved

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Kenneth E. Bernstein

2016-03-01

Full Text Available Angiotensin-converting enzyme (ACE converts angiotensin I to the vasoconstrictor angiotensin II and thereby plays an important role in blood pressure control. However, ACE is relatively non-specific in its substrate specificity and cleaves many other peptides. Recent analysis of mice overexpressing ACE in monocytes, macrophages, and other myelomonocytic cells shows that these animals have a marked increase in resistance to experimental melanoma and to infection by Listeria monocytogenes or methicillin-resistant Staphylococcus aureus (MRSA. Several other measures of immune responsiveness, including antibody production, are enhanced in these animals. These studies complement a variety of studies indicating an important role of ACE in the immune response.

Effect of Dual Blockade of Renin-Angiotensin Aldosterone System ...

African Journals Online (AJOL)

Purpose: To investigate the dual effect of angiotensin blockade by irbesartan and enalapril on proteinuria in diabetic patients with azotemia. Methods: Patients with diabetes of > 5 years duration, proteinuria at a nephrotic level and serum creatinine > 1.5 mg/dL were enrolled in the study. Forty-five enrolled patients were ...

Angiotensin-(1-7) attenuates hyposmolarity-induced ANP secretion via the Na+-K+ pump.

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Shah, Amin; Oh, Young-Bin; Shan, Gao; Song, Chang Ho; Park, Byung-Hyun; Kim, Suhn Hee

2010-09-01

The alteration in osmolarity challenges cell volume regulation, a vital element for cell survival. Hyposmolarity causes an increase in cell volume. Recently, it has been reported that the renin-angiotensin system (RAS) plays a role in cell volume regulation. We investigated the effect of angiotensin-(1-7) [Ang-(1-7)] on hyposmolarity-induced atrial natriuretic peptide (ANP) secretion in normal and diabetic (DM) rat atria and modulation of the effect of Ang-(1-7) by the Na(+)-K(+) pump. Using isolated control rat atria, we observed that perfusion of hyposmotic solution into the atria increased ANP secretion. When Ang-(1-7) [0.1 microM or 1 microM] was perfused in a hyposmolar solution, it decreased the hyposmolarity-induced ANP secretion in a dose-dependent manner. This effect of Ang-(1-7) could be mediated by the Na(+)-K(+) pump, since ouabain, an Na(+)-K(+) pump inhibitor, significantly decreased the effect of Ang-(1-7) on hyposmolarity-induced ANP secretion. In contrast, N(omega) Nitro-l-arginine methyl ester hydrochloride (l-NAME) did not modify the effect of Ang-(1-7) on the hyposmolarity-induced ANP secretion. Interestingly, the ANP secretion was increased robustly by the perfusion of the hyposmolar solution in the DM atria, as compared to the control atria. However, the inhibitory effect of Ang-(1-7) on the hyposmolarity-induced ANP secretion was not observed in the DM atria. In the DM atria, atrial contractility was significantly increased. Taken together, we concluded that Ang-(1-7) attenuated hyposmolarity-induced ANP secretion via the Na(+)-K(+) pump and a lack of Ang-(1-7) response in DM atria may partly relate to change in Na(+)-K(+) pump activity. Copyright 2010 Elsevier Inc. All rights reserved.

Reporter mouse strain provides a novel look at angiotensin type-2 receptor distribution in the central nervous system.

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de Kloet, Annette D; Wang, Lei; Ludin, Jacob A; Smith, Justin A; Pioquinto, David J; Hiller, Helmut; Steckelings, U Muscha; Scheuer, Deborah A; Sumners, Colin; Krause, Eric G

2016-03-01

Angiotensin-II acts at its type-1 receptor (AT1R) in the brain to regulate body fluid homeostasis, sympathetic outflow and blood pressure. However, the role of the angiotensin type-2 receptor (AT2R) in the neural control of these processes has received far less attention, largely because of limited ability to effectively localize these receptors at a cellular level in the brain. The present studies combine the use of a bacterial artificial chromosome transgenic AT2R-enhanced green fluorescent protein (eGFP) reporter mouse with recent advances in in situ hybridization (ISH) to circumvent this obstacle. Dual immunohistochemistry (IHC)/ISH studies conducted in AT2R-eGFP reporter mice found that eGFP and AT2R mRNA were highly co-localized within the brain. Qualitative analysis of eGFP immunoreactivity in the brain then revealed localization to neurons within nuclei that regulate blood pressure, metabolism, and fluid balance (e.g., NTS and median preoptic nucleus [MnPO]), as well as limbic and cortical areas known to impact stress responding and mood. Subsequently, dual IHC/ISH studies uncovered the phenotype of specific populations of AT2R-eGFP cells. For example, within the NTS, AT2R-eGFP neurons primarily express glutamic acid decarboxylase-1 (80.3 ± 2.8 %), while a smaller subset express vesicular glutamate transporter-2 (18.2 ± 2.9 %) or AT1R (8.7 ± 1.0 %). No co-localization was observed with tyrosine hydroxylase in the NTS. Although AT2R-eGFP neurons were not observed within the paraventricular nucleus (PVN) of the hypothalamus, eGFP immunoreactivity is localized to efferents terminating in the PVN and within GABAergic neurons surrounding this nucleus. These studies demonstrate that central AT2R are positioned to regulate blood pressure, metabolism, and stress responses.

The inhibitory effect of angiotensin II type 1 receptor blocker combined with radiation on the proliferation and invasion ability of human nasopharyngeal carcinoma cells

International Nuclear Information System (INIS)

Wang Qiong; Zhao Wei; Li Guiling; Zhang Sheng; Wu Gang

2008-01-01

Objective: To investigate the effect of valsartan, an angiotensin II type 1 receptor (AT1 R) blocker, on radiosensitivity, invasive potential and proliferation activity of nasopharyngeal carcinoma cells(CNE-2) in vitro. Methods: Radiosensitization of valsartan on CNE-2 cells in vitro was investigated by colony forming assay. Effect of AT1R blocker combined with radiation on invasive potential of CNE-2 cells was evaluated using 24-well Matrigel invasion chambers (Transwell). Apoptosis-inducing effect of valsartan combined with radiation on apoptosis of CNE-2 was identified by flow cytometry (FCM). Results: When valsartan was given at 10 -9 , 10 -8 and 10 -7 mol/L combined with radiation, sensitivity enhancement ratios (SER) were 1.10, 1.20 and 1.36, and the invasive inhibition rates were 8.11%, 16.49% and 16.77%, respectively. The SER of valsartan on CNE-2 distinctly increased when the exposure time was increased. After 24 h exposure to 10 -8 mol/L valsartan combined with radiation, the apoptosis rate was 1.89% ± 0.09%, which was higher than 1.62% ± 0.06% in radiation alone group (t=4.79, P<0.05). Conclusions: AT1R blocker valsartan combined with radiation can significantly inhibit the proliferation activity of nasopharyngeal carcinoma cells in vitro in a dose- and time-dependent manner. Valsartan combined with radiation can potently inhibit the invasive potential of CNE-2, which may be involved in the mechanism of valsartan treatment in vivo. (authors)

The renin-angiotensin system; development and differentiation of the renal medulla

DEFF Research Database (Denmark)

Madsen, Kirsten; Robdrup Tinning, Anne; Marcussen, Niels

2013-01-01

on mechanisms of postnatal development the renal medulla and putting medullary developmental lesions into perspective with regard to the programming effect. Moreover, the renin-angiotensin system is critically involved in mammalian kidney development and signaling disorders give rise to developmental renal...... disturbances reaching into adulthood. A review of current knowledge of the role of the renin-angiotensin system for renal medullary development will be given. Acta Physiologica © 2013 Scandinavian Physiological Society....... lesions that has been associated with hypertension later in life. A consistent finding in both experimental animal models and in human case reports is atrophy of the renal medulla with developmental lesions to both medullary nephron segments and vascular development with concomitant functional...

Disposition and metabolism of [(14)C] Sacubitril/Valsartan (formerly LCZ696) an angiotensin receptor neprilysin inhibitor, in healthy subjects.

Science.gov (United States)

Flarakos, Jimmy; Du, Yancy; Bedman, Timothy; Al-Share, Qusai; Jordaan, Pierre; Chandra, Priya; Albrecht, Diego; Wang, Lai; Gu, Helen; Einolf, Heidi J; Huskey, Su-Er; Mangold, James B

2016-11-01

1. Sacubitril/valsartan (LCZ696) is an angiotensin receptor neprilysin inhibitor (ARNI) providing simultaneous inhibition of neprilysin (neutral endopeptidase 24.11; NEP) and blockade of the angiotensin II type-1 (AT1) receptor. 2. Following oral administration, [(14)C]LCZ696 delivers systemic exposure to valsartan and AHU377 (sacubitril), which is rapidly metabolized to LBQ657 (M1), the biologically active neprilysin inhibitor. Peak sacubitril plasma concentrations were reached within 0.5-1 h. The mean terminal half-lives of sacubitril, LBQ657 and valsartan were ∼1.3, ∼12 and ∼21 h, respectively. 3. Renal excretion was the dominant route of elimination of radioactivity in human. Urine accounted for 51.7-67.8% and feces for 36.9 to 48.3 % of the total radioactivity. The majority of the drug was excreted as the active metabolite LBQ657 in urine and feces, total accounting for ∼85.5% of the total dose. 4. Based upon in vitro studies, the potential for LCZ696 to inhibit or induce cytochrome P450 (CYP) enzymes and cause CYP-mediated drug interactions clinically was found to be low.

Association between polymorphisms in renin-angiotensin system genes and primary ovarian insufficiency in Korean women.

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Jung, Yong Wook; Jeon, Young Joo; Park, Hye Mi; Lee, Bo Eun; Rah, Hyungchul; Lee, Woo Sik; Yoon, Tae Ki; Kim, Nam Keun

2013-05-01

The purpose of this study was to evaluate the relationship between angiotensin-converting enzyme (ACE; insertion/deletion), angiotensinogen (AGT M235T), and angiotensin II type 1 receptor (AT1R 1166A>C) and the prevalence of primary ovarian insufficiency (POI) in Korean women. A total of 133 women with POI and 238 controls were genotyped for polymorphic sites in each gene using polymerase chain reaction-restriction fragment length polymorphism analysis. ACE ID and ID + II variants occurred more frequently in women with POI than in controls (odds ratio [OR], 1.830; 95% CI, 1.040-3.221; P = 0.040; and OR, 1.797; 95% CI, 1.055-3.060; P = 0.031, respectively). The AT1R 1166AC genotype occurred more frequently in participants with POI than in controls (OR, 3.171; 95% CI, 1.562-6.436; P = 0.002). Comparing the combined genotype frequencies of ACE/AT1R revealed that the frequencies of ID/AA, ID/AC, and II/AC were higher in participants than in controls (OR, 1.916; 95% CI, 1.053-3.485; P = 0.043; OR, 3.544; 95% CI, 1.207-10.407; P = 0.036; and OR, 7.875; 95% CI, 2.224-27.881; P = 0.001, respectively). The TT/AC genotype for combined genotyping of AGT/AT1R was more frequently observed in the POI group than in the control group (OR, 3.472; 95% CI, 1.450-8.313; P = 0.006). In multifactor dimensionality reduction-based haplotype analysis, the I-T-C genotype of ACE/AGT/AT1R was a possible predisposing factor for POI (OR, 4.678; 95% CI, 1.721-12.717; P = 0.002). This study demonstrates that polymorphisms in the renin-angiotensin system are related to the prevalence of POI. Thus, these renin-angiotensin system genes may serve as a novel marker for predicting the development of POI.

Angiotensin II up-regulates PAX2 oncogene expression and activity in prostate cancer via the angiotensin II type I receptor.

Science.gov (United States)

Bose, Sudeep K; Gibson, Willietta; Giri, Shailendra; Nath, Narender; Donald, Carlton D

2009-09-01

Paired homeobox 2 gene (PAX2) is a transcriptional regulator, aberrantly expressed in prostate cancer cells and its down-regulation promotes cell death in these cells. The molecular mechanisms of tumor progression by PAX2 over-expression are still unclear. However, it has been reported that angiotensin-II (A-II) induces cell growth in prostate cancer via A-II type 1 receptor (AT1R) and is mediated by the phosphorylation of mitogen activated protein kinase (MAPK) as well as signal transducer and activator of transcription 3 (STAT3). Here we have demonstrated that A-II up-regulates PAX2 expression in prostate epithelial cells and prostate cancer cell lines resulting in increased cell growth. Furthermore, AT1R receptor antagonist losartan was shown to inhibit A-II induced PAX2 expression in prostate cancer. Moreover, analysis using pharmacological inhibitors against MEK1/2, ERK1/2, JAK-II, and phospho-STAT3 demonstrated that AT1R-mediated stimulatory effect of A-II on PAX2 expression was regulated in part by the phosphorylation of ERK1/2, JAK II, and STAT3 pathways. In addition, we have showed that down-regulation of PAX2 by an AT1R antagonist as well as JAK-II and STAT3 inhibitors suppress prostate cancer cell growth. Collectively, these findings show for the first time that the renin-angiotensin system (RAS) may promote prostate tumorigenesis via up-regulation of PAX2 expression. Therefore, PAX2 may be a novel therapeutic target for the treatment of carcinomas such as prostate cancer via the down-regulation of its expression by targeting the AT1R signaling pathways.

Angiotensin II protects primary rat hepatocytes against bile salt-induced apoptosis.

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Golnar Karimian

Full Text Available UNLABELLED: Angiotensin II (AT-II is a pro-fibrotic compound that acts via membrane-bound receptors (AT-1R/AT-2R and thereby activates hepatic stellate cells (HSCs. AT-II receptor blockers (ARBs are thus important candidates in the treatment of liver fibrosis. However, multiple case reports suggest that AT-1R blockers may induce hepatocyte injury. Therefore, we investigated the effect of AT-II and its receptor blockers on cytokine-, oxidative stress- and bile salt-induced cell death in hepatocytes. Primary rat hepatocytes were exposed to TNF-α/Actinomycin D, the ROS-generating agent menadione or the bile salts: glycochenodeoxycholic acid (GCDCA and tauro-lithocholic acid-3 sulfate (TLCS, to induce apoptosis. AT-II (100 nmol/L was added 10 minutes prior to the cell death-inducing agent. AT-1R antagonists (Sartans and the AT-2R antagonist PD123319 were used at 1 µmol/L. Apoptosis (caspase-3 activity, acridine orange staining and necrosis (Sytox green staining were quantified. Expression of CHOP (marker for ER stress and AT-II receptor mRNAs were quantified by Q-PCR. AT-II dose-dependently reduced GCDCA-induced apoptosis of hepatocytes (-50%, p<0.05 without inducing necrosis. In addition, AT-II reduced TLCS-induced apoptosis of hepatocytes (-50%, p<0.05. However, AT-II did not suppress TNF/Act-D and menadione-induced apoptosis. Only the AT-1R antagonists abolished the protective effect of AT-II against GCDCA-induced apoptosis. AT-II increased phosphorylation of ERK and a significant reversal of the protective effect of AT-II was observed when signaling kinases, including ERK, were inhibited. Moreover, AT-II prevented the GCDCA-induced expression of CHOP (the marker of the ER-mediated apoptosis. CONCLUSION: Angiotensin II protects hepatocytes from bile salt-induced apoptosis through a combined activation of PI3-kinase, MAPKs, PKC pathways and inhibition of bile salt-induced ER stress. Our results suggest a mechanism for the observed hepatocyte

Two distinct calmodulin binding sites in the third intracellular loop and carboxyl tail of angiotensin II (AT(1A receptor.

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Renwen Zhang

Full Text Available In this study, we present data that support the presence of two distinct calmodulin binding sites within the angiotensin II receptor (AT(1A, at juxtamembrane regions of the N-terminus of the third intracellular loop (i3, amino acids 214-231 and carboxyl tail of the receptor (ct, 302-317. We used bioluminescence resonance energy transfer assays to document interactions of calmodulin with the AT(1A holo-receptor and GST-fusion protein pull-downs to demonstrate that i3 and ct interact with calmodulin in a Ca²⁺-dependent fashion. The former is a 1-12 motif and the latter belongs to 1-5-10 calmodulin binding motif. The apparent Kd of calmodulin for i3 is 177.0±9.1 nM, and for ct is 79.4±7.9 nM as assessed by dansyl-calmodulin fluorescence. Replacement of the tryptophan (W219 for alanine in i3, and phenylalanine (F309 or F313 for alanine in ct reduced their binding affinities for calmodulin, as predicted by computer docking simulations. Exogenously applied calmodulin attenuated interactions between G protein βγ subunits and i3 and ct, somewhat more so for ct than i3. Mutations W219A, F309A, and F313A did not alter Gβγ binding, but reduced the ability of calmodulin to compete with Gβγ, suggesting that calmodulin and Gβγ have overlapping, but not identical, binding requirements for i3 and ct. Calmodulin interference with the Gβγ binding to i3 and ct regions of the AT(1A receptor strongly suggests that calmodulin plays critical roles in regulating Gβγ-dependent signaling of the receptor.

Two Distinct Calmodulin Binding Sites in the Third Intracellular Loop and Carboxyl Tail of Angiotensin II (AT1A) Receptor

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Zhang, Renwen; Liu, Zhijie; Qu, Youxing; Xu, Ying; Yang, Qing

2013-01-01

In this study, we present data that support the presence of two distinct calmodulin binding sites within the angiotensin II receptor (AT1A), at juxtamembrane regions of the N-terminus of the third intracellular loop (i3, amino acids 214–231) and carboxyl tail of the receptor (ct, 302–317). We used bioluminescence resonance energy transfer assays to document interactions of calmodulin with the AT1A holo-receptor and GST-fusion protein pull-downs to demonstrate that i3 and ct interact with calmodulin in a Ca2+-dependent fashion. The former is a 1–12 motif and the latter belongs to 1-5-10 calmodulin binding motif. The apparent Kd of calmodulin for i3 is 177.0±9.1 nM, and for ct is 79.4±7.9 nM as assessed by dansyl-calmodulin fluorescence. Replacement of the tryptophan (W219) for alanine in i3, and phenylalanine (F309 or F313) for alanine in ct reduced their binding affinities for calmodulin, as predicted by computer docking simulations. Exogenously applied calmodulin attenuated interactions between G protein βγ subunits and i3 and ct, somewhat more so for ct than i3. Mutations W219A, F309A, and F313A did not alter Gβγ binding, but reduced the ability of calmodulin to compete with Gβγ, suggesting that calmodulin and Gβγ have overlapping, but not identical, binding requirements for i3 and ct. Calmodulin interference with the Gβγ binding to i3 and ct regions of the AT1A receptor strongly suggests that calmodulin plays critical roles in regulating Gβγ-dependent signaling of the receptor. PMID:23755207

Correlation of Endothelin-1 Concentration and Angiotensin-Converting Enzyme Activity with the Staging of Liver Fibrosis

OpenAIRE

Kardum, Duško; Fabijanić, Damir; Lukić, Anita; Romić, Željko; Petrovečki, Mladen; Bogdanović, Zoran; Jurić, Klara; Urek-Crnčević, Marija; Banić, Marko

2012-01-01

Increased serum angiotensin-converting enzyme (SACE) activity and serum concentration of endothelin-1 (ET-1) were found in liver cirrhosis. We investigated a correlation between the different stages of liver fibrosis and SACE activity and serum ET-1 concentration. Seventy patients with pathohistologically established chronic liver disease were divided in three groups according to Ishak criteria for liver fibrosis: minimal fibrosis (Ishak score 0–1, n=20), medium fibrosis (Ishak sc...

Angiotensin Converting Enzyme Inhibitor Has a Protective Effect on Decompression Sickness in Rats

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Aleksandra Mazur

2018-03-01

Full Text Available Introduction: Commercial divers, high altitude pilots, and astronauts are exposed to some inherent risk of decompression sickness (DCS, though the mechanisms that trigger are still unclear. It has been previously showed that diving may induce increased levels of serum angiotensin converting enzyme. The renin angiotensin aldosterone system (RAAS is one of the most important regulators of blood pressure and fluid volume. The purpose of the present study was to control the influence of angiotensin II on the appearance of DCS.Methods: Sprague Dawley rats have been pre-treated with inhibitor of angiotensin II receptor type 1 (losartan; 10 mg/kg, angiotensin-converting enzyme (ACE inhibitor (enalapril; 10 mg/kg, and calcium-entry blocker (nifedipine; 20 mg/kg. The experimental groups were treated for 4 weeks before exposure to hyperbaric pressure while controls were not treated. Seventy-five rats were subjected to a simulated dive at 1000 kPa absolute pressure for 45 min before starting decompression. Clinical assessment took place over a period of 60 min after surfacing. Blood samples were collected for measurements of TBARS, interleukin 6 (IL-6, angiotensin II (ANG II and ACE.Results: The diving protocol induced 60% DCS in non-treated animals. This ratio was significantly decreased after treatment with enalapril, but not other vasoactive drugs. Enalapril did not change ANG II or ACE concentration, while losartant decreased post dive level of ACE but not ANG II. None of the treatment modified the effect of diving on TBARS and IL-6 values.Conclusion: Results suggests that the rennin angiotensin system is involved in a process of triggering DCS but this has to be further investigated. However, a vasorelaxation mediated process, which potentially could increase the load of inert gas during hyperbaric exposure, and antioxidant properties were excluded by our results.

Effects of cocoa extract and dark chocolate on angiotensin-converting enzyme and nitric oxide in human endothelial cells and healthy volunteers--a nutrigenomics perspective.

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Persson, Ingrid A L; Persson, Karin; Hägg, Staffan; Andersson, Rolf G G

2011-01-01

Evidence suggests that cocoa from the bean of Theobroma cacao L. has beneficial effects on cardiovascular disease. The aim of this study was to investigate if cocoa extract and dark chocolate influence angiotensin-converting enzyme (ACE) and nitric oxide (NO) in human endothelial cells (in vitro) and in healthy volunteers (in vivo). ACE activity was analyzed with a commercial radioenzymatic assay and measured in human endothelial cells from umbilical veins (HUVEC) after 10 minutes of incubation with cocoa extract. NO was measured after 24 hours of incubation. ACE activity and NO were measured at baseline and after 30, 60, and 180 minutes in 16 healthy volunteers after a single intake of 75 g of dark chocolate containing 72% cocoa. Significant inhibition of ACE activity (P cocoa inhibits ACE activity in vitro and in vivo.

Severe hypoglycaemia in type 1 diabetes: impact of the renin-angiotensin system and other risk factors

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Pedersen-Bjergaard, Ulrik

2009-01-01

Hypoglycaemia is an unavoidable side effect to insulin therapy of diabetes. In daily life some hypoglycaemic episodes are recognised by the patients and corrected by ingestion of glucose, but occasionally unrecognised episodes progress into severe hypoglycaemia with cognitive impairment and the n......Hypoglycaemia is an unavoidable side effect to insulin therapy of diabetes. In daily life some hypoglycaemic episodes are recognised by the patients and corrected by ingestion of glucose, but occasionally unrecognised episodes progress into severe hypoglycaemia with cognitive impairment...... both subjects at low and at high risk within a one-year period were identified. Preliminary data suggest that this is explained by impaired capability of subjects with high renin-angiotensin system activity to maintain cognitive function during hypoglycaemia. The clinical implications of this finding...... which, however, must await additional independent confirmation, include prediction and possibly some prevention of severe hypoglycaemia. An evaluation of renin-angiotensin system activity may - together with assessment of other risk factors - contribute to rational individualized setting of glycaemic...

Statin Treatment in Hypercholesterolemic Men Does Not Attenuate Angiotensin II-Induced Venoconstriction

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Schindler, Christoph; Guenther, Kristina; Hermann, Cosima; Ferrario, Carlos M.; Schroeder, Christoph; Haufe, Sven

2014-01-01

Experimental studies suggested that statins attenuate vascular AT1 receptor responsiveness. Moreover, the augmented excessive pressor response to systemic angiotensin II infusions in hypercholesterolemic patients was normalized with statin treatment. In 12 hypercholesterolemic patients, we tested the hypothesis that statin treatment attenuates angiotensin II-mediated vasoconstriction in hand veins assessed by a linear variable differential transducer. Subjects ingested daily doses of either atorvastatin (40 mg) or positive control irbesartan (150 mg) for 30 days in a randomized and cross-over fashion. Ang II–induced venoconstriction at minute 4 averaged 59%±10% before and 28%±9% after irbesartan (mean ± SEM; Pblood pressure buffering reflexes. Trial Registration ClinicalTrials.gov NCT00154024 PMID:25264877

Angiotensin-converting enzyme inhibition in diabetic nephropathy

DEFF Research Database (Denmark)

Parving, H H; Rossing, P; Hommel, E

1995-01-01

The aim of our prospective study was to evaluate putative progression promoters, kidney function, and prognosis during long-term treatment with angiotensin-converting enzyme inhibition in insulin-dependent diabetes mellitus patients suffering from diabetic nephropathy. Eighteen consecutive......, albuminuria (geometric mean +/- antilog SE) 982 +/- 1.2 micrograms/min, and GFR 98 +/- 5 mL/min/1.73 m2. Angiotensin-converting enzyme inhibition induced a significant reduction during the whole treatment period of blood pressure (137/85 +/- 3/1 mm Hg; P ....01), and the rate of decline in GFR was 4.4 +/- 0.7 mL/min/yr, in contrast to previous reports of 10 to 14 mL/min/yr (natural history). Univariate analysis revealed a significant correlation between the rate of decline in GFR and mean arterial blood pressure (r = 0.58, P = 0.01), albuminuria (r = 0.67, P

Angiotensin-converting enzyme insertion/deletion gene ...

Indian Academy of Sciences (India)

Angiotensin-converting enzyme insertion/deletion gene polymorphism in cystic fibrosis patients. Sabrine Oueslati Sondess Hadj Fredj Hajer Siala Amina Bibi Hajer Aloulou Lamia Boughamoura Khadija Boussetta Sihem Barsaoui Taieb Messaoud. Research Note Volume 95 Issue 1 March 2016 pp 193-196 ...

The renin-angiotensin system and its blockers

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Igić Rajko

2014-01-01

Full Text Available Research on the renin-angiotensin system (RAS has contributed significantly to advances in understanding cardiovascular and renal homeostasis and to the treatment of cardiovascular diseases. This review offers a brief history of the RAS with an overview of its major components and their functions, as well as blockers of the RAS, their clinical usage and current research that targets various components of the RAS. Because angiotensin-converting enzyme (ACE metabolizes two biologically active peptides, one in the kallikrein-kinin system (KKS and one in the RAS, it is the essential connection between the two systems. ACE releases very powerful hypertensive agent, angiotensin II and also inactivates strong hypotensive peptide, bradykinin. Inhibition of ACE thus has a dual effect, resulting in decreased angiotensin II and increased bradykinin. We described the KKS as well.

Increased Angiotensin II Sensitivity Contributes to Microvascular Dysfunction in Women Who Have Had Preeclampsia.

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Stanhewicz, Anna E; Jandu, Sandeep; Santhanam, Lakshmi; Alexander, Lacy M

2017-08-01

Women who have had preeclampsia have increased cardiovascular disease risk; however, the mechanism(s) responsible for this association remain unclear. Microvascular damage sustained during a preeclamptic pregnancy may persist postpartum. The putative mechanisms mediating this dysfunction include a reduction in NO-dependent dilation and an increased sensitivity to angiotensin II. In this study, we evaluated endothelium-dependent dilation, angiotensin II sensitivity, and the therapeutic effect of angiotensin II receptor blockade (losartan) on endothelium-dependent dilation in vivo in the microvasculature of women with a history of preeclampsia (n=12) and control women who had a healthy pregnancy (n=12). We hypothesized that preeclampsia would have (1) reduced endothelium-dependent dilation, (2) reduced NO-mediated dilation, and (3) increased sensitivity to angiotensin II. We further hypothesized that localized losartan would increase endothelium-dependent vasodilation in preeclampsia. We assessed microvascular endothelium-dependent vasodilator function by measurement of cutaneous vascular conductance responses to graded infusion of acetylcholine (acetylcholine; 10 -7 -102 mmol/L) and a standardized local heating protocol in control sites and sites treated with 15 mmol/L L-NAME ( N G -nitro-l-arginine methyl ester; NO-synthase inhibitor) or 43 µmol/L losartan. Further, we assessed microvascular vasoconstrictor sensitivity to angiotensin II (10 -20 -10 -4 mol/L). Preeclampsia had significantly reduced endothelium-dependent dilation (-0.3±0.5 versus -1.0±0.4 log EC50 ; P Preeclampsia also had augmented vasoconstrictor sensitivity to angiotensin II (-10.2±1.3 versus -8.3±0.5; P =0.006). Angiotensin II type I receptor inhibition augmented endothelium-dependent vasodilation and NO-dependent dilation in preeclampsia but had no effect in healthy pregnancy. These data suggest that women who have had preeclampsia have persistent microvascular dysfunction postpartum

Angiotensin Converting Enzyme Gene Insertion/Deletion Polymorphism in Migraine Patients

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Belgin Alaşehirli

2009-12-01

Full Text Available OBJECTIVE: The beneficial effects of angiotensin converting enzyme inhibitor drugs on migraine attack frequency have been shown. We aimed to study the relationship between the angiotensin converting enzyme gene and migraine pathophysiology. METHODS: In the present study, to assess whether the angiotensin converting enzyme insertion/deletion (I/D gene polymorphisms have an effect on migraine attacks, we studied the angiotensin converting enzyme genotypes of 102 migraine patients (35 cases of migraine with aura and 67 of migraine without aura and 75 age-and sex-matched normal volunteers. Frequency and age of onset of migraine attacks were also assessed according to angiotensin converting enzyme genotypes. RESULTS: Patients with migraine with and without aura were comparable with each other and the control group with respect to angiotensin converting enzyme genotypes (respectively; p= 0.88 and p= 0.76, p= 0.624. We could not determine a relationship between angiotensin converting enzyme genotypes and attack frequency (p= 0.125, but cases with angiotensin converting enzyme-II genotype showed a significantly younger age for onset of migraine attacks in comparison with the I/D genotype patients (p= 0.021. CONCLUSION: We believe that further angiotensin converting enzyme gene studies are warranted in younger age groups of patients with migraine and also in different populations

A comparative study of the prevalence of hyperkalemia with the use of angiotensin-converting enzyme inhibitors versus angiotensin receptor blockers

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Seyed Ali Sadjadi

2009-07-01

Full Text Available Seyed Ali Sadjadi1, James I McMillan1, Navin Jaipaul1, Patricia Blakely1, Su Su Hline21Section of Nephrology (111N, Jerry L Pettis Memorial Veterans Medical Center, Loma Linda, CA, USA; 2Divison of Nephrology, Loma Linda University Medical Center, Loma Linda, CA, USABackground and objectives: Angiotensin-converting enzyme inhibitors (ACEI and angiotensin receptor blockers (ARB are increasingly used in a variety of settings including heart failure, renal failure, arterial hypertension, and diabetic nephropathy. The objective of this study was to investigate the prevalence of hyperkalemia with ACEI and ARB use, in a population of the United States veterans.Design, settings, material, and measurements: Retrospective observational cohort study of 1163 patients on ACEIs and 1168 patients on ARBs in a single Veterans Affairs Medical Center. Electronic medical records were reviewed over a 12-month period with data collected on various demographic, laboratory, comorbidity, and medication related variables. Results: Hyperkalemia (>5 mEq/L was observed in 20.4% of patients on ACEIs and 31.0% on ARBs. Severe hyperkalemia (6 mEq/L or higher, was observed in 0.8% of ACEI and 2.8% of ARB users. In univariate logistic regression analyses, diabetes mellitus; serum glucose, total carbon dioxide content, creatinine, and estimated glomerular filtration rate (GFR were significantly associated with hyperkalemia. ARB use, when compared to ACEI, was associated with a 42% increase in odds of hyperkalemia (odds ratio [OR] = 1.42; p = 0.001 in a model including adjustment for GFR and a 56% increase in odds of hyperkalemia (OR = 1.56; p < 0.001 in a model including adjustment for serum creatinine.Conclusions: Hyperkalemia, associated with the use of ACEIs and ARBs, is usually mild and severe hyperkalemia is rare. Hyperkalemia is more common with ARBs than ACEIs. ARB use, when compared to ACEI use, may significantly and independently be associated with increased odds of

Data supporting the angiotensin II activates MEL18 to deSUMOylate HSF2 for hypertension-related heart failure

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Chih-Yang Huang

2018-02-01

Full Text Available In association with the published article “Inhibition of HSF2 SUMOylation via MEL18 upregulates IGF-IIR and leads to hypertension-induced cardiac hypertrophy” (Huang et al., 2017 [1], this data article contains information about deSUMOylation of HSF2 on lysine 82 on angiotensin II (ANG II -induced cardiac hypertrophy, which is mediated by MEL18. Isolated adult human whole heart tissue showed MEL18-mediated HSF2-IGF-IIR pathway is upregulated in hypertension human heart, compared to health human heart.

THE MECHANISM AND DIAGNOSTIC-VALUE OF ANGIOTENSIN-I CONVERTING ENZYME-INHIBITION RENOGRAPHY

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DEZEEUW, D; JONKER, GJ; HOVINGA, TKK; BEEKHUIS, H; PIERS, DA; HUISMAN, RM; DEJONG, PE

1991-01-01

The effect of angiotensin converting enzyme (ACE) inhibition on the sensitivity of radionuclide renography in the diagnosis of a unilateral renal artery stenosis was tested both in a conscious dog model and in the human situation. ACE inhibition (10 mg enalaprilic acid, intravenously) markedly

Angiotensin II type 1 receptor (A1166C gene polymorphism and essential hypertension in Egyptian population

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Marium M. Shamaa

2016-09-01

Full Text Available The pathogenesis of essential hypertension (EH is affected by genetic and environmental factors. Mutations in hypertension-related genes can affect blood pressure (BP via alteration of salt and water reabsorption by the nephron. The genes of the renin-angiotensin system (RAS have been extensively studied because of the well documented role of this system in the control of BP. It has been previously shown that Angiotensin II type 1 receptor (ATR1 gene polymorphism could be associated with increased risk of EH. So, in the current study, we evaluated the frequency of ATR1 (A1166C polymorphism in relation to EH in a group of Egyptian population. The study population included 83 hypertensive patients and 60 age and sex matched healthy control subjects. Restriction fragment length polymorphism – Polymerase chain reaction (RFLP – PCR was used for the analysis of A1166C polymorphism of ATR1 genes in peripheral blood samples of all patients and controls. The results revealed that there was a positive risk of developing EH when having the T allele whether in homozygous or heterozygous state. From this work, it was concluded that there was an association between ATR1 (A1166C gene polymorphism and the risk of developing EH.

Severe hepatic encephalopathy in a patient with liver cirrhosis after administration of angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker combination therapy: a case report

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Podda Mauro

2010-05-01

Full Text Available Abstract Introduction A combination therapy of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers has been used to control proteinuria, following initial demonstration of its efficacy. However, recently concerns about the safety of this therapy have emerged, prompting several authors to urge for caution in its use. In the following case report, we describe the occurrence of a serious and unexpected adverse drug reaction after administration of a combination of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers to a patient with nephrotic syndrome and liver cirrhosis with severe portal hypertension. Case presentation We administered this combination therapy to a 40-year-old Caucasian man with liver cirrhosis in our Hepatology Clinic, given the concomitant presence of glomerulopathy associated with severe proteinuria. While the administration of one single drug appeared to be well-tolerated, our patient developed severe acute encephalopathy after the addition of the second one. Discontinuation of the therapy led to the disappearance of the side-effect. A tentative rechallenge with the same drug combination led to a second episode of acute severe encephalopathy. Conclusion We speculate that this adverse reaction may be directly related to the effect of angiotensin II on the excretion of blood ammonia. Therefore, we suggest that patients with liver cirrhosis and portal hypertension are at risk of developing clinically relevant encephalopathy when angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker combination therapy is administered, thus indicating the need for a careful clinical follow-up. In addition, the incidence of this serious side-effect should be rigorously evaluated in all patients with liver cirrhosis administered with this common treatment combination.

Changes in distribution of hepatic blood flow induced by intra-arterial infusion of angiotensin II in human hepatic cancer

International Nuclear Information System (INIS)

Sasaki, Y.; Imaoka, S.; Hasegawa, Y.

1985-01-01

Changes in the distribution of the hepatic blood flow induced by intra-arterial infusion of angiotensin II (AT-II) were studied in human hepatic cancers using extremely short-lived radioisotope (RI) (krypton 81 m [/sup 81m/Kr]; half-life, 13 seconds). After the start of continuous infusion of AT-II, the radioactivity of the tumor showed about a two-fold increase, whereas that of the nontumor region decreased to about one half as much as the level before the infusion. Consequently, the mean ratio of the arterial blood flow in the tumor region to that in the nontumor region (T/N ratio) increased to 3.30 (P less than 0.001). The T/N ratio showed a peak before the peripheral blood pressure reached the maximum, and thereafter tended to decrease. Intra-arterial infusion of AT-II raised the T/N ratio more obviously than did intravenous infusion of the drug, with less rise in the peripheral blood pressure. It is believed that intra-arterial infusion chemotherapy with local use of AT-II enables better accessibility of chemotherapeutic drugs to tumors

Expression of the Components of the Renin-Angiotensin System in Venous Malformation

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Sam eSiljee

2016-05-01

Full Text Available Background Venous malformation (VM is the most common form of vascular malformation, consisting of a network of thin-walled ectatic venous channels with deficient or absent media. This study investigated the expression of the components of the renin-angiotensin system (RAS, namely (prorenin receptor (PRR, angiotensin converting enzyme (ACE, angiotensin II receptor 1 (ATIIR1 and angiotensin II receptor 2 (AIITR2 in subcutaneous (SC and intramuscular (IM VM. Materials and Methods SC (n=7 and IM (n=7 VM were analyzed for the expression of PRR, ACE, ATIIR1, and ATIIR2 using 3,3-diaminobenzidine (DAB and immunofluorescent (IF immunohistochemical (IHC staining and NanoString gene expression analysis. Results IHC staining showed expression of PRR, ACE, ATIIR1 and faint expression of ATIIR2 in the endothelium of SC and IM VM. Furthermore, ATIIR2 was expressed by cells away from the endothelium in both SC and IM VM lesions examined. NanoString analysis demonstrated the presence of PRR, ACE and ATIIR1 but not ATIIR2.Conclusions The presence of PRR, ACE, ATIIR1 and potentially ATIIR2, in both SC and IM VM suggests a role for the RAS in the biology of VM. This novel finding may lead to a mechanism-based therapy for VM.

Expression of Angiotensin II and Aldosterone in Radiation-induced Lung Injury.

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Cao, Shuo; Wu, Rong

2012-12-01

Radiation-induced lung injury (RILI) is the most common, dose-limiting complication in thoracic malignancy radiotherapy. Considering its negative impact on patients and restrictions to efficacy, the mechanism of RILI was studied. Wistar rats were locally irradiated with a single dose of 0, 16, and 20 Gy to the right half of the lung to establish a lung injury model. Two and six months after irradiation, the right half of the rat lung tissue was removed, and the concentrations of TGF-β1, angiotensin II, and aldosterone were determined via enzyme-linked immunosorbent assay. Statistical differences were observed in the expression levels of angiotensin II and aldosterone between the non-irradiation and irradiation groups. Moreover, the expression level of the angiotensin II-aldosterone system increased with increasing doses, and the difference was still observed as time progressed. Angiotensin II-aldosterone system has an important pathophysiological function in the progression of RILI.

Expression of Angiotensin II and Aldosterone in Radiation-induced Lung Injury

International Nuclear Information System (INIS)

Cao, Shuo; Wu, Rong

2012-01-01

Radiation-induced lung injury (RILI) is the most common, dose-limiting complication in thoracic malignancy radiotherapy. Considering its negative impact on patients and restrictions to efficacy, the mechanism of RILI was studied. Wistar rats were locally irradiated with a single dose of 0, 16, and 20 Gy to the right half of the lung to establish a lung injury model. Two and six months after irradiation, the right half of the rat lung tissue was removed, and the concentrations of TGF-β1, angiotensin II, and aldosterone were determined via enzyme-linked immunosorbent assay. Statistical differences were observed in the expression levels of angiotensin II and aldosterone between the non-irradiation and irradiation groups. Moreover, the expression level of the angiotensin II-aldosterone system increased with increasing doses, and the difference was still observed as time progressed. Angiotensin II-aldosterone system has an important pathophysiological function in the progression of RILI

Targeting the renin-angiotensin system as novel therapeutic strategy for pulmonary diseases.

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Tan, Wan Shun Daniel; Liao, Wupeng; Zhou, Shuo; Mei, Dan; Wong, Wai-Shiu Fred

2017-12-27

The renin-angiotensin system (RAS) plays a major role in regulating electrolyte balance and blood pressure. RAS has also been implicated in the regulation of inflammation, proliferation and fibrosis in pulmonary diseases such as asthma, acute lung injury (ALI), chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF) and pulmonary arterial hypertension (PAH). Current therapeutics suffer from some drawbacks like steroid resistance, limited efficacies and side effects. Novel intervention is definitely needed to offer optimal therapeutic strategy and clinical outcome. This review compiles and analyses recent investigations targeting RAS for the treatment of inflammatory lung diseases. Inhibition of the upstream angiotensin (Ang) I/Ang II/angiotensin receptor type 1 (AT 1 R) pathway and activation of the downstream angiotensin-converting enzyme 2 (ACE2)/Ang (1-7)/Mas receptor pathway are two feasible strategies demonstrating efficacies in various pulmonary disease models. More recent studies favor the development of targeting the downstream ACE2/Ang (1-7)/Mas receptor pathway, in which diminazene aceturate, an ACE2 activator, GSK2586881, a recombinant ACE2, and AV0991, a Mas receptor agonist, showed much potential for further development. As the pathogenesis of pulmonary diseases is so complex that RAS modulation may be used alone or in combination with existing drugs like corticosteroids, pirfenidone/nintedanib or endothelin receptor antagonists for different pulmonary diseases. Personalized medicine through genetic screening and phenotyping for angiotensinogen or ACE would aid treatment especially for non-responsive patients. This review serves to provide an update on the latest development in the field of RAS targeting for pulmonary diseases, and offer some insights into future direction. Copyright © 2017 Elsevier Ltd. All rights reserved.

Pericardial Parietal Mesothelial Cells: Source of the Angiotensin-Converting-Enzyme of the Bovine Pericardial Fluid

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Ilsione Ribeiro de Sousa Filho

Full Text Available Abstract Background: Angiotensin II (Ang II, the primary effector hormone of the renin-angiotensin system (RAS, acts systemically or locally, being produced by the action of angiotensin-converting-enzyme (ACE on angiotensin I. Although several tissue RASs, such as cardiac RAS, have been described, little is known about the presence of an RAS in the pericardial fluid and its possible sources. Locally produced Ang II has paracrine and autocrine effects, inducing left ventricular hypertrophy, fibrosis, heart failure and cardiac dysfunction. Because of the difficulties inherent in human pericardial fluid collection, appropriate experimental models are useful to obtain data regarding the characteristics of the pericardial fluid and surrounding tissues. Objectives: To evidence the presence of constituents of the Ang II production paths in bovine pericardial fluid and parietal pericardium. Methods: Albumin-free crude extracts of bovine pericardial fluid, immunoprecipitated with anti-ACE antibody, were submitted to electrophoresis (SDS-PAGE and gels stained with coomassie blue. Duplicates of gels were probed with anti-ACE antibody. In the pericardial membranes, ACE was detected by use of immunofluorescence. Results: Immunodetection on nitrocellulose membranes showed a 146-KDa ACE isoform in the bovine pericardial fluid. On the pericardial membrane sections, ACE was immunolocalized in the mesothelial layer. Conclusions: The ACE isoform in the bovine pericardial fluid and parietal pericardium should account at least partially for the production of Ang II in the pericardial space, and should be considered when assessing the cardiac RAS.

Local renin–angiotensin system contributes to hyperthyroidism-induced cardiac hypertrophy

OpenAIRE

Kobori, H; Ichihara, A; Miyashita, Y; Hayashi, M; Saruta, T

1999-01-01

We have reported previously that thyroid hormone activates the circulating and tissue renin–angiotensin systems without involving the sympathetic nervous system, which contributes to cardiac hypertrophy in hyperthyroidism. This study examined whether the circulating or tissue renin–angiotensin system plays the principal role in hyperthyroidism-induced cardiac hypertrophy. The circulating renin–angiotensin system in Sprague–Dawley rats was fixed by chronic angiotensin II infusion (40 ng/ min, ...

Evidence for modulation of pericryptal sheath myofibroblasts in rat descending colon by Transforming Growth Factor β and Angiotensin II.

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Pedley Kevin C

2002-02-01

Full Text Available Abstract Background Absorption of water and Na+ in descending colonic crypts is dependent on the barrier function of the surrounding myofibroblastic pericryptal sheath. Here the effects of high and low Na+ diets and exposure to whole body ionising radiation on the growth and activation of the descending colonic pericryptal myofibroblasts are evaluated. In addition the effect of a post-irradiation treatment with the angiotensin converting enzyme inhibitor Captopril was investigated. Methods The levels of Angiotensin II type 1 receptor (AT1, ACE, collagen type IV, transforming growth factor-β type 1 receptor (TGF-βR1, OB cadherin and α-smooth muscle actin in both descending colon and caecum were evaluated, using immunocytochemistry and confocal microscopy, in rats fed on high and low Na+ diets (LS. These parameters were also determined during 3 months post-irradiation with 8Gy from a 60Co source in the presence and absence of the angiotensin converting enzyme inhibitor, Captopril. Results Increases in AT1 receptor (135.6% ± 18.3, P Conclusions These results demonstrate an activation of descending colonic myofibroblasts to trophic stimuli, or irradiation, which can be attenuated by Captopril, indicative of local trophic control by angiotensin II and TGF-β release.

Cardiac remodeling during and after renin-angiotensin system stimulation in Cyp1a1-Ren2 transgenic rats

DEFF Research Database (Denmark)

Heijnen, Bart Fj; Pelkmans, Leonie Pj; Danser, Ah Jan

2013-01-01

This study investigated renin-angiotensin system (RAS)-induced cardiac remodeling and its reversibility in the presence and absence of high blood pressure (BP) in Cyp1a1-Ren2 transgenic inducible hypertensive rats (IHR). In IHR (pro)renin levels and BP can be dose-dependently titrated by oral...... administration of indole-3-carbinol (I3C). Young (four-weeks old) and adult (30-weeks old) IHR were fed I3C for four weeks (leading to systolic BP >200 mmHg). RAS-stimulation was stopped and animals were followed-up for a consecutive period. Cardiac function and geometry was determined echocardiographically...

Resveratrol promotes regression of renal carcinoma cells via a renin-angiotensin system suppression-dependent mechanism.

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Li, Jianchang; Qiu, Mingning; Chen, Lieqian; Liu, Lei; Tan, Guobin; Liu, Jianjun

2017-02-01

The aim of the present study was to investigate the effect of resveratrol on renal carcinoma cells and explore possible renin-angiotensin system-associated mechanisms. Subsequent to resveratrol treatment, the cell viability, apoptosis rate, cytotoxicity levels, caspase 3/7 activity and the levels of angiotensin II (AngII), AngII type 1 receptor (AT1R), vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2) were evaluated in renal carcinoma cells. The effects of AngII, AT1R, VEGF and COX-2 on resveratrol-induced cell growth inhibition and apoptosis were also examined. The results indicated that resveratrol treatment may suppress growth, induce apoptosis, and decrease AngII, AT1R, VEGF and COX-2 levels in renal carcinoma ACHN and A498 cells. In addition, resveratrol-induced cell growth suppression and apoptosis were reversed when co-culturing with AT1R or VEGF. Thus, resveratrol may suppress renal carcinoma cell proliferation and induce apoptosis via an AT1R/VEGF pathway.

Sympatho-inhibitory properties of various AT1 receptor antagonists

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Balt, Jippe C.; Mathy, Marie-Jeanne; Pfaffendorf, Martin; van Zwieten, Peter A.

2002-01-01

It is well known that angiotensin II (Ang II) can facilitate the effects of sympathetic neurotransmission. In the present study, using various experimental models, we investigated the inhibitory effects of several Ang II subtype 1 receptor (AT1) antagonists on this Ang II-induced facilitation. We

Emerging drugs which target the renin-angiotensin-aldosterone system.

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Steckelings, Ulrike Muscha; Paulis, Ludovit; Unger, Thomas; Bader, Michael

2011-12-01

The renin-angiotensin-aldosterone system (RAAS) is already the most important target for drugs in the cardiovascular system. However, still new developments are underway to interfere with the system on different levels. The novel strategies to interfere with RAAS aim to reduce the synthesis of the two major RAAS effector hormones, angiotensin (Ang) II and aldosterone, or interfere with their receptors, AT1 and mineralocorticoid receptor, respectively. Moreover, novel targets have been identified in RAAS, such as the (pro)renin receptor, and molecules, which counteract the classical actions of Ang II and are therefore beneficial in cardiovascular diseases. These include the AT2 receptor and the ACE2/Ang-(1-7)/Mas axis. The search for drugs activating these tissue-protective arms of RAAS is therefore the most innovative field in RAAS pharmacology. Most of the novel pharmacological strategies to inhibit the classical RAAS need to prove their superiority above the existing treatment in clinical trials and then have to compete against these now quite cheap drugs in a competitive market. The newly discovered targets have functions beyond the cardiovascular system opening up novel therapeutic areas for drugs interfering with RAAS components.

Acute Urinary Bladder Distension Triggers ICAM-1-mediated Renal Oxidative Injury via the Norepinephrine–renin–angiotensin II System in Rats

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Show-Shing Chen

2009-08-01

Conclusion: Acute urinary retention enhances renal sympathetic activity, which causes renal vasoconstriction and increases oxidative stress, adhesion-molecule expression and leukocyte infiltration in the rat kidney via the angiotensin II type 1 receptor pathway.

Recent Advances in the Gastric Mucosal Protection Against Stress-induced Gastric Lesions. Importance of Renin-angiotensin Vasoactive Metabolites, Gaseous Mediators and Appetite Peptides.

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Brzozowski, Tomasz; Magierowska, Katarzyna; Magierowski, Marcin; Ptak-Belowska, Agata; Pajdo, Robert; Kwiecien, Slawomir; Olszanecki, Rafal; Korbut, Ryszard

2017-01-01

Stress is known to cause severe adverse effects in the human gastrointestinal tract including mucosal microbleedings and erosions or even gastric ulceration but the mechanism of these complications has not been fully elucidated. The pathogenesis of stress-induced gastric damage involves the fall in Gastric Blood Flow (GBF), an increase in gastric acid secretion and gastric motility, enhanced adrenergic and cholinergic nerve activity and the rise in gastric mucosal generation of reactive oxygen species. The gastric mucosal defense mechanisms against the deleterious effect of stress include the activation of the hypothalamic-pituitary-adrenal axis which has been linked with glucocorticoids release capable of counteracting of stress-induced gastric lesions. Here we summarize the novel gastroprotective mechanisms against stress damage exhibited by angiotensin-(1-7), the newly discovered metabolite of Renin-Angiotensin System (RAS), the gaseous mediators such as nitric oxide (NO), hydrogen sulfide (H2S) or Carbon Monoxide (CO), and the food intake controlling peptides ghrelin, nesfatin- 1 and apelin possibly acting via brain-gut axis. These bioactive molecules such as RAS vasoactive metabolite angiotensin-(1-7) and appetite peptides have been shown to afford gastroprotective effect against stressinduced gastric lesions mainly mediated by an increase in gastric microcirculation. Gaseous mediators protect the gastric mucosa against stress lesions by mechanism involving the activation of PG/COX and CO/HO-1 biosynthetic pathways, and their anti-inflammatory and anti-oxidizing properties. Thus, these new components add new mechanistic aspects to the common cooperation of NO/NO-synthase, PG/COX systems and vasoactive sensory neuropeptides including CGRP but their gastroprotective efficacy against experimental stress ulcerogenesis requires the confirmation in human clinical trials. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Angiotensin II induces apoptosis in intestinal epithelial cells through the AT2 receptor, GATA-6 and the Bax pathway

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Sun, Lihua; Wang, Wensheng; Xiao, Weidong; Liang, Hongyin; Yang, Yang; Yang, Hua

2012-01-01

Highlights: ► Ang II-induced apoptosis in intestinal epithelial cell through AT2 receptor. ► The apoptosis process involves in the Bax/Bcl-2 intrinsic pathway. ► GATA-6 short hairpin RNA reduced Bax expression, but not Bcl-2. ► GATA-6 may play a critical role in apoptosis in response to the Ang II challenge. -- Abstract: Angiotensin II (Ang II) has been shown to play an important role in cell apoptosis. However, the mechanisms of Ang-II-induced apoptosis in intestinal epithelial cells are not fully understood. GATA-6 is a zinc finger transcription factor expressed in the colorectal epithelium, which directs cell proliferation, differentiation and apoptosis. In the present study we investigated the underlying mechanism of which GATA-6 affects Ang-II induced apoptosis in intestinal epithelial cells. The in vitro intestinal epithelial cell apoptosis model was established by co-culturing Caco-2 cells with Ang II. Pretreatment with Angiotensin type 2 (AT2) receptor antagonist, PD123319, significantly reduced the expression of Bax and prevented the Caco-2 cells apoptosis induced by Ang II. In addition, Ang II up-regulated the expression of GATA-6. Interestingly, GATA-6 short hairpin RNA prevented Ang II-induced intestinal epithelial cells apoptosis and reduced the expression of Bax, but not Bcl-2. Taken together, the present study suggests that Angiotensin II promotes apoptosis in intestinal epithelial cells through GATA-6 and the Bax pathway in an AT2 receptor-dependent manner.

Spectrum of mutations in the renin-angiotensin system genes in autosomal recessive renal tubular dysgenesis

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Gribouval, Olivier; Morinière, Vincent; Pawtowski, Audrey

2012-01-01

, pulmonary hypoplasia, and refractory arterial hypotension. The disease is linked to mutations in the genes encoding several components of the renin-angiotensin system (RAS): AGT (angiotensinogen), REN (renin), ACE (angiotensin-converting enzyme), and AGTR1 (angiotensin II receptor type 1). Here, we review...... the series of 54 distinct mutations identified in 48 unrelated families. Most of them are novel and ACE mutations are the most frequent, observed in two-thirds of families (64.6%). The severity of the clinical course was similar whatever the mutated gene, which underlines the importance of a functional RAS...

Valsartan regulates the interaction of angiotensin II type 1 receptor and endothelial nitric oxide synthase via Src/PI3K/Akt signalling.

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Su, Kuo-Hui; Tsai, Jin-Yi; Kou, Yu Ru; Chiang, An-Na; Hsiao, Sheng-Huang; Wu, Yuh-Lin; Hou, Hsin-Han; Pan, Ching-Chian; Shyue, Song-Kun; Lee, Tzong-Shyuan

2009-06-01

Valsartan, a selective angiotensin II type 1 receptor (AT1R) blocker, has beneficial effects in the cardiovascular system in part by its increase of nitric oxide (NO) bioavailability, yet the mechanisms are unclear. We investigated the molecular mechanisms underlying this effect in endothelial cells (ECs). NO production was examined by Griess reagent assay, DAF-2 DA fluorescence staining and cGMP ELISA kits. Protein interaction was determined by western blotting and immunoprecipitation. Treating bovine or human aortic ECs with valsartan increased NO production, as evidenced by elevated level of stable NO metabolites and intracellular cGMP. Valsartan increased the phosphorylation but not the protein level of endothelial NO synthase (eNOS). Inhibition of phosphoinositide-3 kinase (PI3K)/Akt and Src pathways by specific inhibitors suppressed valsartan-induced NO release. In addition, valsartan increased the tyrosine residue phosphorylation of AT1R, which was attenuated by inhibition of Src but not PI3K activities. Valsartan also suppressed the interaction of eNOS and AT1R, which was blocked by Src or PI3K inhibition. Valsartan-induced NO production in ECs is mediated through Src/PI3K/Akt-dependent phosphorylation of eNOS. Valsartan-induced AT1R phosphorylation depends on Src but not PI3K, whereas valsartan-induced suppression of AT1R-eNOS interaction depends on Src/PI3K/Akt signalling. These results indicate a novel vasoprotective mechanism of valsartan in upregulating NO production in ECs.

The role of local renin-angiotensin system in arterial chemoreceptors in sleep-breathing disorders

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Man Lung eFung

2014-09-01

Full Text Available The renin-angiotensin system (RAS plays pivotal roles in the regulation of cardiovascular and renal functions to maintain the fluid and electrolyte homeostasis. Experimental studies have demonstrated a locally expressed RAS in the carotid body, which is functional significant in the effect of angiotensin peptides on the regulation of the activity of peripheral chemoreceptors and the chemoreflex. The physiological and pathophysiological implications of the RAS in the carotid body have been proposed upon recent studies showing a significant upregulation of the RAS expression under hypoxic conditions relevant to altitude acclimation and sleep apnea and also in animal model of heart failure. Specifically, the increased expression of angiotensinogen, angiotensin-converting enzyme and angiotensin AT1 receptors plays significant roles in the augmented carotid chemoreceptor activity and inflammation of the carotid body. This review aims to summarize these results with highlights on the pathophysiological function of the RAS under hypoxic conditions. It is concluded that the maladaptive changes of the RAS in the carotid body plays a pathogenic role in sleep apnea and heart failure, which could potentially be a therapeutic target for the treatment of the pathophysiological consequence of sleep apnea.

Treatment with salvianolic acid B restores endothelial function in angiotensin II-induced hypertensive mice.

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Ling, Wei Chih; Liu, Jian; Lau, Chi Wai; Murugan, Dharmani Devi; Mustafa, Mohd Rais; Huang, Yu

2017-07-15

Salvianolic acid B (Sal B) is one of the most abundant phenolic acids derived from the root of Danshen with potent anti-oxidative properties. The present study examined the vasoprotective effect of Sal B in hypertensive mice induced by angiotensin II (Ang II). Sal B (25mg/kg/day) was administered via oral gavage for 11days to Ang II (1.2mg/kg/day)-infused C57BL/6J mice (8-10weeks old). The vascular reactivity (both endothelium-dependent relaxations and contractions) in mouse arteries was examined by wire myography. The production of reactive oxygen species (ROS), protein level and localization of angiotensin AT 1 receptors and the proteins involved in ROS formation were evaluated using dihydroethidium (DHE) fluorescence, lucigenin-enhanced chemiluminescence, immunohistochemistry and Western blotting, respectively. The changes of ROS generating proteins were also assessed in vitro in human umbilical vein endothelial cells (HUVECs) exposed to Ang II with and without co-treatment with Sal B (0.1-10nM). Oral administration of Sal B reversed the Ang II-induced elevation of arterial systolic blood pressure in mice, augmented the impaired endothelium-dependent relaxations and attenuated the exaggerated endothelium-dependent contractions in both aortas and renal arteries of Ang II-infused mice. In addition, Sal B treatment normalized the elevated levels of AT 1 receptors, NADPH oxidase subunits (NOx-2 and NOx-4) and nitrotyrosine in arteries of Ang II-infused mice or in Ang II-treated HUVECs. In summary, the present study provided additional evidence demonstrating that Sal B treatment for 11days reverses the impaired endothelial function and with a marked inhibition of AT 1 receptor-dependent vascular oxidative stress. This vasoprotective and anti-oxidative action of Sal B most likely contributes to the anti-hypertensive action of the plant-derived compound. Copyright © 2017 Elsevier Inc. All rights reserved.

[Angiotensin converting enzyme: the antigenic properties of the domain, role in Alzheimer's disease and tumor progression].

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Kugaevskaya, E V; Timoshenko, O S; Solovyeva, N I

2015-01-01

Angiotensin converting enzyme (ACE, EC 3.4.15.1) was discovered and characterized in the Laboratory of biochemistry and chemical pathology of proteins under the direction of academician V.N. Orekhovich, where its physiological function, associated with a key role in the regulation of the renin-angiotensin (RAS) and the kallikrein-kinin systems that control blood flow in the body and homeostasis was first deciphered. We carried out a search for structural differences between the two highly homologous domains (N- and C-domains) of somatic ACE (sACE); it was based on a comparative analysis of antigenic determinants (or B-epitopes) of both domains. The revealed epitopes were classified with variable and conserved regions and functionally important sites of the molecule ACE. Essential difference was demonstrated between locations of the epitopes in the N- and C-domains. These data indicate the existence of structural differences between the domains of sACE. We studied the role of the domains of ACE in the metabolism of human amyloid beta peptide (Ab) - the main component of senile plaques, found in the brains of patients with Alzheimer's disease (AD). Our results demonstrated that only N-domain ACE cleaved the Ab between residues R5-H6, while, the C-domain of ACE failed to hydrolyze this region. In addition, the effect of post-translational modifications of Ab on its hydrolysis by the ACE was investigated. We show that isomerization of residue D7, a common non-enzymatic age-related modification found in AD-associated species, does not reduce the affinity of the peptide to the N-domain of ACE, and conversely, it increases. According to our data, the role of ACE in the metabolism of Ab becomes more significant in the development of AD. RAS is involved in malignant transformation and tumor progression. RAS components, including ACE and angiotensin II receptors type 1 (AT1R) are expressed in various human tumors. We found a significant increase in the level of ACE activity

Effect of deletion polymorphism of angiotensin converting enzyme gene on progression of diabetic nephropathy during inhibition of angiotensin converting enzyme

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Parving, H H; Jacobsen, P; Tarnow, L

1996-01-01

OBJECTIVE: To evaluate the concept that an insertion/deletion polymorphism of the angiotensin converting enzyme gene predicts the therapeutic efficacy of inhibition of angiotensin converting enzyme on progression of diabetic nephropathy. DESIGN: Observational follow up study of patients with insu...

Recombinant erythropoietin acutely decreases renal perfusion and decouples the renin-angiotensin-aldosterone system

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Aachmann-Andersen, Niels J.; Christensen, Soren J.; Lisbjerg, Kristian

2018-01-01

The effect of recombinant erythropoietin (rhEPO) on renal and systemic hemodynamics was evaluated in a randomized double-blinded, cross-over study. Sixteen healthy subjects were tested with placebo, or low-dose rhEPO for 2 weeks, or high-dose rhEPO for 3 days. Subjects refrained from excessive salt...... that seems to decouple the activity of the renin-angiotensin-aldosterone system from changes in renal hemodynamics. This may serve as a negative feed-back mechanism on endogenous synthesis of EPO when circulating levels of EPO are high. These results demonstrates for the first time in humans a direct effect...... of rhEPO on renal hemodynamics and a decoupling of the renin-angiotensin-aldosterone system....

Increased methylglyoxal formation with upregulation of renin angiotensin system in fructose fed Sprague Dawley rats.

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Indu Dhar

Full Text Available The current epidemic of obesity and type 2 diabetes is attributed to a high carbohydrate diet, containing mainly high fructose corn syrup and sucrose. More than two thirds of diabetic patients have hypertension. Methylglyoxal is a highly reactive dicarbonyl generated during glucose and fructose metabolism, and a major precursor of advanced glycation end products (AGEs. Plasma methylglyoxal levels are increased in hypertensive rats and diabetic patients. Our aim was to examine the levels of methylglyoxal, mediators of the renin angiotensin system and blood pressure in male Sprague-Dawley rats treated with a high fructose diet (60% of total calories for 4 months. The thoracic aorta and kidney were used for molecular studies, along with cultured vascular smooth muscle cells (VSMCs. HPLC, Western blotting and Q-PCR were used to measure methylglyoxal and reduced glutathione (GSH, proteins and mRNA, respectively. Fructose treated rats developed a significant increase in blood pressure. Methylglyoxal level and protein and mRNA for angiotensin II, AT1 receptor, adrenergic α1D receptor and renin were significantly increased, whereas GSH levels were decreased, in the aorta and/or kidney of fructose fed rats. The protein expression of the receptor for AGEs (RAGE and NF-κB were also significantly increased in the aorta of fructose fed rats. MG treated VSMCs showed increased protein for angiotensin II, AT1 receptor, and α1D receptor. The effects of methylglyoxal were attenuated by metformin, a methylglyoxal scavenger and AGEs inhibitor. In conclusion, we report a strong association between elevated levels of methylglyoxal, RAGE, NF-κB, mediators of the renin angiotensin system and blood pressure in high fructose diet fed rats.

Increased methylglyoxal formation with upregulation of renin angiotensin system in fructose fed Sprague Dawley rats.

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Dhar, Indu; Dhar, Arti; Wu, Lingyun; Desai, Kaushik M

2013-01-01

The current epidemic of obesity and type 2 diabetes is attributed to a high carbohydrate diet, containing mainly high fructose corn syrup and sucrose. More than two thirds of diabetic patients have hypertension. Methylglyoxal is a highly reactive dicarbonyl generated during glucose and fructose metabolism, and a major precursor of advanced glycation end products (AGEs). Plasma methylglyoxal levels are increased in hypertensive rats and diabetic patients. Our aim was to examine the levels of methylglyoxal, mediators of the renin angiotensin system and blood pressure in male Sprague-Dawley rats treated with a high fructose diet (60% of total calories) for 4 months. The thoracic aorta and kidney were used for molecular studies, along with cultured vascular smooth muscle cells (VSMCs). HPLC, Western blotting and Q-PCR were used to measure methylglyoxal and reduced glutathione (GSH), proteins and mRNA, respectively. Fructose treated rats developed a significant increase in blood pressure. Methylglyoxal level and protein and mRNA for angiotensin II, AT1 receptor, adrenergic α1D receptor and renin were significantly increased, whereas GSH levels were decreased, in the aorta and/or kidney of fructose fed rats. The protein expression of the receptor for AGEs (RAGE) and NF-κB were also significantly increased in the aorta of fructose fed rats. MG treated VSMCs showed increased protein for angiotensin II, AT1 receptor, and α1D receptor. The effects of methylglyoxal were attenuated by metformin, a methylglyoxal scavenger and AGEs inhibitor. In conclusion, we report a strong association between elevated levels of methylglyoxal, RAGE, NF-κB, mediators of the renin angiotensin system and blood pressure in high fructose diet fed rats.

Brain penetration of telmisartan, a unique centrally acting angiotensin II type 1 receptor blocker, studied by PET in conscious rhesus macaques

International Nuclear Information System (INIS)

Noda, Akihiro; Fushiki, Hiroshi; Murakami, Yoshihiro; Sasaki, Hiroshi; Miyoshi, Sosuke; Kakuta, Hirotoshi; Nishimura, Shintaro

2012-01-01

Introduction: Telmisartan is a widely used, long-acting antihypertensive agent. Known to be a selective angiotensin II type 1 (AT 1 ) receptor (AT 1 R) blocker (ARB), telmisartan acts as a partial agonist of peroxisome proliferator-activated receptor-gamma (PPAR-γ) and inhibits centrally mediated effects of angiotensin II in rats following peripheral administration, although the brain penetration of telmisartan remains unclear. We investigated the brain concentration and localization of telmisartan using 11 C-labeled telmisartan and positron emission tomography (PET) in conscious rhesus macaques. Methods: Three male rhesus macaques were bolus intravenously administered [ 11 C]telmisartan either alone or as a mixture with unlabeled telmisartan (1 mg/kg). Dynamic PET images were acquired for 95 min following administration. Blood samples were collected for the analysis of plasma concentration and metabolites, and brain and plasma concentrations were calculated from detected radioactivity using the specific activity of the administered drug preparation, in which whole blood radioactivity was used for the correction of intravascular blood radioactivity in brain. Results: Telmisartan penetrated into the brain little but enough to block AT 1 R and showed a consistently increasing brain/plasma ratio within the PET scanning period, suggesting slow clearance of the compound from the brain compared to the plasma clearance. Brain/plasma ratios at 30, 60, and 90 min were 0.06, 0.13, and 0.18, respectively. No marked localization according to the AT 1 R distribution was noted over the entire brain, even on tracer alone dosing. Conclusions: Telmisartan penetrated into the brain enough to block AT 1 R and showed a slow clearance from the brain in conscious rhesus macaques, supporting the long-acting and central responses of telmisartan as a unique property among ARBs.

Changes in the renin angiotensin system during the development of colorectal cancer liver metastases

International Nuclear Information System (INIS)

Neo, Jaclyn H; Ager, Eleanor I; Angus, Peter W; Zhu, Jin; Herath, Chandana B; Christophi, Christopher

2010-01-01

Blockade of the renin angiotensin system (RAS) via angiotensin I converting enzyme (ACE) inhibition reduces growth of colorectal cancer (CRC) liver metastases in a mouse model. In this work we defined the expression of the various components of the RAS in both tumor and liver during the progression of this disease. Immunohistochemistry and quantitative RT-PCR was used to examine RAS expression in a mouse CRC liver metastases model. CRC metastases and liver tissue was assessed separately at key stages of CRC liver metastases development in untreated (control) mice and in mice treated with the ACE inhibitor captopril (750 mg/kg/day). Non-tumor induced (sham) mice indicated the effect of tumors on normal liver RAS. The statistical significance of multiple comparisons was determined using one-way analysis of variance followed by Bonferroni adjustment with SAS/STAT software. Reduced volume of CRC liver metastases with captopril treatment was evident. Local RAS of CRC metastases differed from the surrounding liver, with lower angiotensin II type 1 receptor (AT1R) expression but increased ANG-(1-7) receptor (MasR) compared to the liver. The AT1R localised to cancer and stromal infiltrating cells, while other RAS receptors were detected in cancer cells only. Tumor induction led to an initial increase in AT1R and ACE expression while captopril treatment significantly increased ACE expression in the final stages of tumor growth. Conversely, captopril treatment decreased expression of AT1R and angiotensinogen. These results demonstrate significant changes in RAS expression in the tumor-bearing captopril treated liver and in CRC metastases. The data suggests the existence of a tumor-specific RAS that can be independently targeted by RAS blockade

A Novel Splice-Site Mutation in Angiotensin I-Converting Enzyme (ACE) Gene, c.3691+1G>A (IVS25+1G>A), Causes a Dramatic Increase in Circulating ACE through Deletion of the Transmembrane Anchor

Science.gov (United States)

Persu, Alexandre; Lambert, Michel; Deinum, Jaap; Cossu, Marta; de Visscher, Nathalie; Irenge, Leonid; Ambroise, Jerôme; Minon, Jean-Marc; Nesterovitch, Andrew B.; Churbanov, Alexander; Popova, Isolda A.; Danilov, Sergei M.; Danser, A. H. Jan; Gala, Jean-Luc

2013-01-01

Background Angiotensin-converting enzyme (ACE) (EC 4.15.1) metabolizes many biologically active peptides and plays a key role in blood pressure regulation and vascular remodeling. Elevated ACE levels are associated with different cardiovascular and respiratory diseases. Methods and Results Two Belgian families with a 8-16-fold increase in blood ACE level were incidentally identified. A novel heterozygous splice site mutation of intron 25 - IVS25+1G>A (c.3691+1G>A) - cosegregating with elevated plasma ACE was identified in both pedigrees. Messenger RNA analysis revealed that the mutation led to the retention of intron 25 and Premature Termination Codon generation. Subjects harboring the mutation were mostly normotensive, had no left ventricular hypertrophy or cardiovascular disease. The levels of renin-angiotensin-aldosterone system components in the mutated cases and wild-type controls were similar, both at baseline and after 50 mg captopril. Compared with non-affected members, quantification of ACE surface expression and shedding using flow cytometry assay of dendritic cells derived from peripheral blood monocytes of affected members, demonstrated a 50% decrease and 3-fold increase, respectively. Together with a dramatic increase in circulating ACE levels, these findings argue in favor of deletion of transmembrane anchor, leading to direct secretion of ACE out of cells. Conclusions We describe a novel mutation of the ACE gene associated with a major familial elevation of circulating ACE, without evidence of activation of the renin-angiotensin system, target organ damage or cardiovascular complications. These data are consistent with the hypothesis that membrane-bound ACE, rather than circulating ACE, is responsible for Angiotensin II generation and its cardiovascular consequences. PMID:23560051

The role of the renin-angiotensin-aldosterone system in heart failure

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Thomas Unger

2004-03-01

Full Text Available Activity of the renin-angiotensin-aldosterone system (RAAS is increased in patients with heart failure, and its maladaptive mechanisms may lead to adverse effects such as cardiac remodelling and sympathetic activation. Elevated renin activity has been demonstrated in patients with dilated cardiomyopathy. (Third-generation synthetic non-peptide renin inhibitors, with more favourable properties than earlier renin inhibitors, lower ambulatory blood pressure and may have a role to play in other cardiovascular disease. Chymase, a protease inhibitor stored in mast cells that generates angiotensin II (Ang II (in addition to angiotensin-converting enzyme [ACE], has been linked to extracellular matrix remodelling in heart failure. Again, chymase inhibitors have been developed to investigate its functions in vitro and in vivo. Bradykinin is thought to contribute to the cardioprotective effect of ACE inhibition through modification of nitric oxide release, calcium handling and collagen accumulation. Ang II is believed to influence a number of molecular and structural changes in the heart, mostly mediated through the AT1-receptor. The importance of the RAAS in heart failure is shown by the survival benefit conferred by treatment with ACE inhibitors.

The renin-angiotensin system in kidney development

DEFF Research Database (Denmark)

Jensen, B L; Stubbe, J; Madsen, K

2004-01-01

Recent data from studies in rodents with targeted gene disruption and pharmacological antagonists have shown that the renin-angiotensin-aldosterone system (RAAS) and cyclooxygenase type-2 (COX-2) are necessary for late stages of kidney development. The present review summarizes data on the develo......Recent data from studies in rodents with targeted gene disruption and pharmacological antagonists have shown that the renin-angiotensin-aldosterone system (RAAS) and cyclooxygenase type-2 (COX-2) are necessary for late stages of kidney development. The present review summarizes data...... on the developmental changes of RAAS and COX-2 and the pathways by which they are activated; their possible interplay and the mechanisms by which they affect kidney development. Intrarenal and circulating renin and angiotensin II (ANG II) are stimulated at birth in most mammals. In rats, renin and ANG II stay...... glucocorticoid concentration and by a low NaCl intake. Studies with selective inhibitors of COX-2 and COX-2 null mice show that COX-2 activity stimulates renin secretion from JG-cells during postnatal kidney development and that lack of COX-2 activity leads to pathological change in cortical architecture...

Cognitive enhancing effect of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on learning and memory

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Nade, V. S.; Kawale, L. A.; Valte, K. D.; Shendye, N. V.

2015-01-01

Objective: The present study was designed to investigate cognitive enhancing property of angiotensin-converting enzymes inhibitors (ACEI) and angiotensin receptor blockers (ARBs) in rats. Materials and Methods: The elevated plus maze (EPM), passive avoidance test (PAT), and water maze test (WMT) were used to assess cognitive enhancing activity in young and aged rats. Ramipril (10 mg/kg, p.o.), perindopril (10 mg/kg, i.p), losartan (20 mg/kg, i.p), and valsartan (20 mg/kg, p.o) were administered to assess their effect on learning and memory. Scopolamine (1 mg/kg, i.p) was used to impair cognitive function. Piracetam (200 mg/kg, i.p) was used as reference drug. Results: All the treatments significantly attenuated amnesia induced by aging and scopolamine. In EPM, aged and scopolamine-treated rats showed an increase in transfer latency (TL) whereas, ACEI and ARBs showed a significant decrease in TL. Treatment with ACEI and ARBs significantly increased step down latencies and decreased latency to reach the platform in target quadrant in young, aged and scopolamine-treated animals in PAT and WMT, respectively. The treatments inhibited acetylcholinesterase (AChE) enzyme in the brain. Similarly, all the treatments attenuated scopolamine-induced lipid peroxidation and normalize antioxidant enzymes. Conclusion: The results suggest that the cognitive enhancing effect of ACEI and ARBs may be due to inhibition of AChE or by regulation of antioxidant system or increase in formation of angiotensin IV. PMID:26069362

Proton transfer and complex formation of angiotensin I ions with gaseous molecules at various temperature

International Nuclear Information System (INIS)

Nonose, Shinji; Yamashita, Kazuki; Sudo, Ayako; Kawashima, Minami

2013-01-01

Highlights: • Proton transfer from angiotensin I ions (z = 2, 3) to gaseous molecules was studied. • Temperature dependence of absolute reaction rate constants was measured. • Remarkable changes were obtained for distribution of product ions and reaction rate constants. • Proton transfer reaction was enhanced and reduced by complex formation. • Conformation changes are induced by complex formation and or by thermal collision with He. - Abstract: Proton transfer reactions of angiotensin I ions for +2 charge state, [M + 2H] 2+ , to primary, secondary and aromatic amines were examined in the gas phase. Absolute reaction rate constants for proton transfer were determined from intensities of parent and product ions in the mass spectra. Temperature dependence of the reaction rate constants was measured. Remarkable change was observed for distribution of product ions and reaction rate constants. Proton transfer reaction was enhanced or reduced by complex formation of [M + 2H] 2+ with gaseous molecules. The results relate to conformation changes of [M + 2H] 2+ with change of temperature, which are induced by complex formation and or by thermal collision with He. Proton transfer reactions of angiotensin I ions for +3 charge state, [M + 3H] 3+ , were also studied. The reaction rates did not depend on temperature so definitely

The water channel AQP1 is expressed in human atherosclerotic vascular lesions and AQP1 deficiency augments angiotensin II-induced atherosclerosis in mice

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Wintmo, P.; Johansen, S. H.; Hansen, P. B. L.

2017-01-01

Aim: The water channel aquaporin 1 (AQP1) promotes endothelial cell migration. It was hypothesized that AQP1 promotes neovascularization and growth of atherosclerotic plaques. Methods: AQP1 immunoreactivity and protein abundance was examined in human and murine atherosclerotic lesions and aortic...... minipumps for 4 weeks. Results: In human atherosclerotic lesions and AAA, AQP1 immunoreactive protein was associated with intralesional small vessels. In ApoE-/- mouse aorta, APQ1 mRNA levels were increased with time on WD (n = 7-9, P ... increased with time on WD but was not different between ApoE-/- and AQP1-/-ApoE-/- mice at either 8 or 16 weeks (n = 13-15). Baseline blood pressure and ANGII-induced hypertension were not different between genotypes. Conclusion: AQP1 is expressed in atherosclerotic lesion neovasculature in human and mouse...

Insight into the structural requirement of substituted quinazolinone biphenyl acylsulfonamides derivatives as Angiotensin II AT1 receptor antagonist: 2D and 3D QSAR approach

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Mukesh C. Sharma

2014-01-01

Full Text Available A series of 19 molecules substituted quinazolinone biphenyl acylsulfonamides derivatives displaying variable inhibition of Angiotensin II receptor AT1 activity were selected to develop models for establishing 2D and 3D QSAR. The compounds in the selected series were characterized by spatial, molecular and electro topological descriptors using QSAR module of Molecular Design Suite (VLife MDS™ 3.5. The best 2D QSAR model was selected, having correlation coefficient r2 (0.8056 and cross validated squared correlation coefficient q2 (0.6742 with external predictive ability of pred_r2 0.7583 coefficient of correlation of predicted data set (pred_r2se 0.2165. The results obtained from QSAR studies could be used in designing better Ang II activity among the congeners in future. The optimum QSAR model showed that the parameters SsssCHE index, SddCE-index, T_2_Cl_4, and SssNHE-index contributed in the model. 3D QSAR analysis by kNN-molecular field analysis approach developed based on principles of the k-nearest neighbor method combined with Genetic algorithms, stepwise forward variable selection approach; a leave-one-out cross-validated correlation coefficient (q2 of 0.6516 and a non-cross-validated correlation coefficient (r2 of 0.8316 and pred_r2 0.6954 were obtained. Contour maps using this approach showed that steric, electrostatic, and hydrophobic field effects dominantly determine binding affinities. The information rendered by 3D QSAR models may lead to a better understanding of structural requirements of Angiotensin II receptor and can help in the design of novel potent antihypertensive molecules.

A cleavable signal peptide enhances cell surface delivery and heterodimerization of Cerulean-tagged angiotensin II AT1 and bradykinin B2 receptor

International Nuclear Information System (INIS)

Quitterer, Ursula; Pohl, Armin; Langer, Andreas; Koller, Samuel; AbdAlla, Said

2011-01-01

Highlights: → A new FRET-based method detects AT1/B2 receptor heterodimerization. → First time application of AT1-Cerulean as a FRET donor. → Method relies on signal peptide-enhanced cell surface delivery of AT1-Cerulean. → A high FRET efficiency revealed efficient heterodimerization of AT1/B2R proteins. → AT1/B2R heterodimers were functionally coupled to desensitization mechanisms. -- Abstract: Heterodimerization of the angiotensin II AT1 receptor with the receptor for the vasodepressor bradykinin, B2R, is known to sensitize the AT1-stimulated response of hypertensive individuals in vivo. To analyze features of that prototypic receptor heterodimer in vitro, we established a new method that uses fluorescence resonance energy transfer (FRET) and applies for the first time AT1-Cerulean as a FRET donor. The Cerulean variant of the green fluorescent protein as donor fluorophore was fused to the C-terminus of AT1, and the enhanced yellow fluorescent protein (EYFP) as acceptor fluorophore was fused to B2R. In contrast to AT1-EGFP, the AT1-Cerulean fusion protein was retained intracellularly. To facilitate cell surface delivery of AT1-Cerulean, a cleavable signal sequence was fused to the receptor's amino terminus. The plasma membrane-localized AT1-Cerulean resembled the native AT1 receptor regarding ligand binding and receptor activation. A high FRET efficiency of 24.7% between membrane-localized AT1-Cerulean and B2R-EYFP was observed with intact, non-stimulated cells. Confocal FRET microscopy further revealed that the AT1/B2 receptor heterodimer was functionally coupled to receptor desensitization mechanisms because activation of the AT1-Cerulean/B2R-EYFP heterodimer with a single agonist triggered the co-internalization of AT1/B2R. Receptor co-internalization was sensitive to inhibition of G protein-coupled receptor kinases, GRKs, as evidenced by a GRK-specific peptide inhibitor. In agreement with efficient AT1/B2R heterodimerization, confocal FRET imaging of

A cleavable signal peptide enhances cell surface delivery and heterodimerization of Cerulean-tagged angiotensin II AT1 and bradykinin B2 receptor

Energy Technology Data Exchange (ETDEWEB)

Quitterer, Ursula, E-mail: ursula.quitterer@pharma.ethz.ch [Molecular Pharmacology Unit, Swiss Federal Institute of Technology and University of Zurich, Zurich (Switzerland); Pohl, Armin; Langer, Andreas; Koller, Samuel; AbdAlla, Said [Molecular Pharmacology Unit, Swiss Federal Institute of Technology and University of Zurich, Zurich (Switzerland)

2011-06-10

Highlights: {yields} A new FRET-based method detects AT1/B2 receptor heterodimerization. {yields} First time application of AT1-Cerulean as a FRET donor. {yields} Method relies on signal peptide-enhanced cell surface delivery of AT1-Cerulean. {yields} A high FRET efficiency revealed efficient heterodimerization of AT1/B2R proteins. {yields} AT1/B2R heterodimers were functionally coupled to desensitization mechanisms. -- Abstract: Heterodimerization of the angiotensin II AT1 receptor with the receptor for the vasodepressor bradykinin, B2R, is known to sensitize the AT1-stimulated response of hypertensive individuals in vivo. To analyze features of that prototypic receptor heterodimer in vitro, we established a new method that uses fluorescence resonance energy transfer (FRET) and applies for the first time AT1-Cerulean as a FRET donor. The Cerulean variant of the green fluorescent protein as donor fluorophore was fused to the C-terminus of AT1, and the enhanced yellow fluorescent protein (EYFP) as acceptor fluorophore was fused to B2R. In contrast to AT1-EGFP, the AT1-Cerulean fusion protein was retained intracellularly. To facilitate cell surface delivery of AT1-Cerulean, a cleavable signal sequence was fused to the receptor's amino terminus. The plasma membrane-localized AT1-Cerulean resembled the native AT1 receptor regarding ligand binding and receptor activation. A high FRET efficiency of 24.7% between membrane-localized AT1-Cerulean and B2R-EYFP was observed with intact, non-stimulated cells. Confocal FRET microscopy further revealed that the AT1/B2 receptor heterodimer was functionally coupled to receptor desensitization mechanisms because activation of the AT1-Cerulean/B2R-EYFP heterodimer with a single agonist triggered the co-internalization of AT1/B2R. Receptor co-internalization was sensitive to inhibition of G protein-coupled receptor kinases, GRKs, as evidenced by a GRK-specific peptide inhibitor. In agreement with efficient AT1/B2R

Brain renin-angiotensin system: fetal epigenetic programming by maternal protein restriction during pregnancy.

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Goyal, Ravi; Goyal, Dipali; Leitzke, Arthur; Gheorghe, Ciprian P; Longo, Lawrence D

2010-03-01

Maternal protein malnutrition during pregnancy can lead to significant alterations in the systemic renin-angiotensin system (RAS) in the fetus. All components of the RAS are present in brain and may be altered in many disease states. Importantly, these disorders are reported to be of higher incidence in prenatally malnourished individuals. In the current study, we tested the hypothesis that antenatal maternal low protein diet (MLPD) leads to epigenetic changes and alterations in gene expression of brain RAS of the mouse fetus. Mice dams were given control and 50% MLPD during second half of the gestation. We analyzed messenger RNA (mRNA), microRNA (miRNA), promoter DNA methylation, and protein expression of various RAS genes in the fetal offspring. As a consequence of 50% MLPD, fetal brains showed increased mRNA expression of angiotensinogen and angiotensin converting enzyme-1 (ACE-1), with a decrease in mRNA levels of angiotensin II type-2 (AT2) receptors. In contrast, while angiotensinogen protein expression was unaltered, the protein levels of ACE-1 and AT2 receptor genes were significantly reduced in the fetal brain from the MLPD dams. Our results also demonstrated hypomethylation of the CpG islands in the promoter regions of ACE-1 gene, and upregulation of the miRNAs, mmu-mir-27a and 27b, which regulate ACE-1 mRNA translation. Furthermore, our study showed reduced expression of the miRNA mmu-mir-330, which putatively regulates AT2 translation. For the developing fetal brain RAS, MLPD leads to significant alterations in the mRNA and protein expression, with changes in DNA methylation and miRNA, key regulators of hypertension in adults.

Organisation and functional role of the brain angiotensin system

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Catherine Llorens-Cortes

2002-03-01

Full Text Available The discovery that all components of the renin-angiotensin system (RAS are present in the brain led investigators to postulate the existence of a local brain RAS. Supporting this, angiotensin immunoreactive neurones have been visualised in the brain. Two major pathways were described: a forebrain pathway which connects circumventricular organs to the median preoptic nucleus, paraventricular and supraoptic nuclei, and a second pathway connecting the hypothalamus to the medulla oblongata. Blood-brain-barrier deficient circumventricular organs are rich in angiotensin II (Ang II receptors. By activating these receptors, circulating Ang II may act on central cardiovascular centres via angiotensinergic neurones, providing a link between peripheral and central Ang II systems. Among the effector peptides of the brain RAS, Ang II and angiotensin III (Ang III have the same affinity for type 1 and type 2 Ang II receptors. When injected into the brain, both peptides increase blood pressure (BP, water intake and pituitary hormone release and may modify learning and memory. Since Ang II is converted in vivo to Ang III, the nature of the true effector is unknown. This review summarises new insights into the predominant role of brain Ang III in the control of BP and underlines the fact that brain aminopeptidase A, the enzyme forming central Ang III, could constitute a putative central therapeutic target for the treatment of hypertension.

21 CFR 862.1090 - Angiotensin converting enzyme (A.C.E.) test system.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Angiotensin converting enzyme (A.C.E.) test system... Test Systems § 862.1090 Angiotensin converting enzyme (A.C.E.) test system. (a) Identification. An angiotensin converting enzyme (A.C.E.) test system is a device intended to measure the activity of angiotensin...

Electroacupuncture improves cerebral blood flow and attenuates moderate ischemic injury via Angiotensin II its receptors-mediated mechanism in rats.

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Li, Jing; He, Jiaojun; Du, Yuanhao; Cui, Jingjun; Ma, Ying; Zhang, Xuezhu

2014-11-11

To investigate the effects and potential mechanism of electroacupuncture intervention on expressions of Angiotensin II and its receptors-mediated signaling pathway in experimentally induced cerebral ischemia. Totally 126 male Wistar rats were randomly divided into control group, model group and EA group. The latter two were further divided into ten subgroups (n = 6) following Middle Cerebral Artery Occlusion (MCAO). Changes in regional cerebral blood flow (rCBF) and expressions of Angiotensin II and its receptors (AT1R, AT2R), as well as effector proteins in phosphatidyl inositol signal pathway were monitored before and at different times after MCAO. MCAO-induced decline of ipsilateral rCBF was partially suppressed by electroacupuncture, and contralateral blood flow was also superior to that of model group. Angiotensin II level was remarkably elevated immediately after MCAO, while electroacupuncture group exhibited significantly lower levels at 1 to 3 h and the value was significantly increased thereafter. The enhanced expression of AT1R was partially inhibited by electroacupuncture, while increased AT2R level was further induced. Electroacupuncture stimulation attenuated and postponed the upregulated-expressions of Gq and CaM these upregulations. ELISA results showed sharply increased expressions of DAG and IP3, which were remarkably neutralized by electroacupuncture. MCAO induced significant increases in expression of Angiotensin II and its receptor-mediated signal pathway. These enhanced expressions were significantly attenuated by electroacupuncture intervention, followed by reduced vasoconstriction and improved blood supply in ischemic region, and ultimately conferred beneficial effects on cerebral ischemia.

Effects of angiotensin converting enzyme inhibitor and angiotensin II antagonist receptor on neointima hyperplasia after vascular balloon injury

International Nuclear Information System (INIS)

Wang Yeling; Zhao Lihua

2004-01-01

Objective: To study the effects of angiotensin converting enzyme inhibitor (captopril) and angiotensin II antagonist receptor (valsartan) on neointima hyperplasia after vascular balloon injury. Methods: Thirty-six rabbit models were randomly divided into three groups: injuried group, captopril group and valsartan group. Captopril (2 mg·kg -1 ·d -1 po) and valsartan (10 mg·kg -1 ·d -1 po) were given to twelve rabbits respectively from 1 day before the right carotidarteries were injuried by 2.0 mm ballon cathether to 14 days after injury in captopil group and valsartan group. The medicine was not administered in the injuried group. The tissue plasminogen activator (tPA), plaminogen activor inhibitor-1 (PAI-1) antigen level and plasma endothelin (ET) levels were measured before injury, and 7, 14 days after vascular injury. The pathomorphoiogical examination were carried out 14 days after angioplasty. Results: The levels of plasma PAI-1 and ET in captopril group and valsartan group were significantly lower than those in the injuried group (P<0.05). The intimal thickness and extent of lumen stenosis in captopril and valsartan groups were significantly lower than those in the injuried group (P<0.05). Conclusion: Captopril and valsartan can inhibit neointima hyperplasia after vascular ballon injury. (authors)

Renin-angiotensin system antagonists, glomerular filtration rate and blood pressure

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D.D. Ivanov

2018-02-01

Full Text Available The article deals with the mModern data on the influence of renin-angiotensin system blockers on the glomerular filtration rate, the level of arterial pressure and the outcome of chronic kidney disease. The strategy of  rennin-angiotensine blockade is offered to be changed depending on the criteria va­lues of glomerular filtration rate: a combination of inhibitors of angiotensin-converting enzyme + angiotensin receptors blo­ckers, monotherapy and drug withdrawal in glomerular filtration rate under 15–30 ml/min/m2. The formula BRIMONEL for treatment of chronic kidney disease is given.

Molecular and Thermodynamic Mechanisms of the Chloride-dependent Human Angiotensin-I-converting Enzyme (ACE)*

Science.gov (United States)

Yates, Christopher J.; Masuyer, Geoffrey; Schwager, Sylva L. U.; Akif, Mohd; Sturrock, Edward D.; Acharya, K. Ravi

2014-01-01

Somatic angiotensin-converting enzyme (sACE), a key regulator of blood pressure and electrolyte fluid homeostasis, cleaves the vasoactive angiotensin-I, bradykinin, and a number of other physiologically relevant peptides. sACE consists of two homologous and catalytically active N- and C-domains, which display marked differences in substrate specificities and chloride activation. A series of single substitution mutants were generated and evaluated under varying chloride concentrations using isothermal titration calorimetry. The x-ray crystal structures of the mutants provided details on the chloride-dependent interactions with ACE. Chloride binding in the chloride 1 pocket of C-domain ACE was found to affect positioning of residues from the active site. Analysis of the chloride 2 pocket R522Q and R522K mutations revealed the key interactions with the catalytic site that are stabilized via chloride coordination of Arg522. Substrate interactions in the S2 subsite were shown to affect chloride affinity in the chloride 2 pocket. The Glu403-Lys118 salt bridge in C-domain ACE was shown to stabilize the hinge-bending region and reduce chloride affinity by constraining the chloride 2 pocket. This work demonstrated that substrate composition to the C-terminal side of the scissile bond as well as interactions of larger substrates in the S2 subsite moderate chloride affinity in the chloride 2 pocket of the ACE C-domain, providing a rationale for the substrate-selective nature of chloride dependence in ACE and how this varies between the N- and C-domains. PMID:24297181

Gene expression profiling following maternal deprivation: Involvement of the brain renin-angiotensin system

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Claudia Liebl

2009-05-01

Full Text Available The postnatal development of the mouse is characterized by a stress hyporesponsive period (SHRP, where basal corticosterone levels are low and responsiveness to mild stressors is reduced. Maternal separation is able to disrupt the SHRP and is widely used to model early trauma. In this study we aimed at identifying of brain systems involved in acute and possible long-term effects of maternal separation. We conducted a microarray-based gene expression analysis in the hypothalamic paraventricular nucleus after maternal separation, which revealed 52 differentially regulated genes compared to undisturbed controls, among them are 37 up-regulated and 15 down-regulated genes. One of the prominently up-regulated genes, angiotensinogen, was validated using in-situ hybridization. Angiotensinogen is the precursor of angiotensin II, the main effector of the brain renin-angiotensin system (RAS, which is known to be involved in stress system modulation in adult animals. Using the selective angiotensin type I receptor (AT(1 antagonist candesartan we found strong effects on CRH and GR mRNA expression in the brain a nd ACTH release following maternal separation. AT(1 receptor blockade appears to enhance central effects of maternal separation in the neonate, suggesting a suppressing function of brain RAS during the SHRP. Taken together, our results illustrate the molecular adaptations that occur in the paraventricular nucleus following maternal separation and contribute to identifying signaling cascades that control stress system activity in the neonate.

Increased Sensitivity to Angiotensin II is Present Postpartum in Women with History of Hypertensive Pregnancy

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Saxena, Aditi R.; Karumanchi, S. Ananth; Brown, Nancy J.; Royle, Caroline M.; McElrath, Thomas F.; Seely, Ellen W.

2010-01-01

Pregnancies complicated by new onset hypertension are associated with increased sensitivity to angiotensin II, but it is unclear if this sensitivity persists postpartum. We studied pressor response to infused angiotensin II in 25 normotensive postpartum women in both high and low sodium balance. Ten women had history of hypertensive pregnancy (five with preeclampsia; five with transient hypertension of pregnancy) and 15 women had history of uncomplicated, normotensive pregnancy. Systolic and diastolic blood pressures, aldosterone and soluble fms-like tyrosine kinase 1 (sFlt-1) levels were measured before and after angiotensin II infusion in both dietary phases. In high sodium balance, women with history of hypertensive pregnancy were normotensive but had significantly higher systolic and diastolic blood pressures than controls (115 vs. 104 mmHg and 73 vs. 65 mmHg, respectively, ppregnancy had pressor response to salt loading, demonstrated by increase in systolic blood pressure on high salt diet. They also had greater systolic pressor response (10 vs. 2 mmHg, p=0.03), greater increase in aldosterone (56.8 vs. 30.8 ng/dL, p=0.03) and increase in sFlt-1 levels (11.0 vs. -18.9 pg/mL, p=0.02) after infusion of angiotensin II in low sodium balance, compared with controls. Thus, women with history of hypertensive pregnancy demonstrated salt sensitivity of blood pressure and had increased pressor, adrenal and sFlt-1 responses to infused angiotensin II in low sodium balance. Increased sensitivity to angiotensin II observed during pregnancy in women with hypertensive pregnancy is present postpartum; this feature may contribute to future cardiovascular risk in these women. PMID:20308605

Human fetal malformations associated with the use of an angiotensin II receptor antagonist: Case Report

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Henri Augusto Korkes

2014-09-01

Full Text Available Introduction: The potential risks related to drug exposure during pregnancy represent a vast chapter in modern obstetrics and data regarding the safety of antihypertensive drugs during pregnancy are relatively scarce. Case report: A 37-year-old patient discovered her fifth pregnancy at our hospital after 26 weeks and 4 days of gestation. She reported a history of hypertension and was currently being treated with Losartan. Hospitalization was recommended for the patient and further evaluation of fetal vitality was performed. On the fourth day an ultrasound was performed, resulting in a severe oligohydramnios, fetal centralization and abnormal ductus venosus. After 36 hours, the newborn died. Pathologic evaluation: At autopsy, the skullcap had large fontanels and deficient ossification. The kidneys were slightly enlarged. A microscopic examination detected underdevelopment of the tubules and the presence of some dilated lumens. Immunohistochemical detection of epithelial membrane antigen was positive. Immunoreactivity of CD 15 was also assayed to characterize the proximal tubules, and lumen collapse was observed in some regions. Discussion: Angiotensin-converting enzyme inhibitors (ACEIs and angiotensin receptor antagonists (ARAs are among the most widely prescribed drugs for hypertension. They are often used by hypertensive women who are considering become pregnant. While their fetal toxicity in the second or third trimesters has been documented, their teratogenic effect during the first trimester has only recently been demonstrated. Conclusion: Constant awareness by physicians and patients should be encouraged, particularly in regard to the prescription of antihypertensive drugs in women of childbearing age who are or intend to become pregnant.

An Angiotensin II Type 1 Receptor Blocker Prevents Renal Injury via Inhibition of the Notch Pathway in Ins2 Akita Diabetic Mice

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Masaya Koshizaka

2012-01-01

Full Text Available Recently, it has been reported that the Notch pathway is involved in the pathogenesis of diabetic nephropathy. In this study, we investigated the activation of the Notch pathway in Ins2 Akita diabetic mouse (Akita mouse and the effects of telmisartan, an angiotensin II type1 receptor blocker, on the Notch pathway. The intracellular domain of Notch1 (ICN1 is proteolytically cleaved from the cell plasma membrane in the course of Notch activation. The expression of ICN1 and its ligand, Jagged1, were increased in the glomeruli of Akita mice, especially in the podocytes. Administration of telmisartan significantly ameliorated the expression of ICN1 and Jagged1. Telmisartan inhibited the angiotensin II-induced increased expression of transforming growth factor β and vascular endothelial growth factor A which could directly activate the Notch signaling pathway in cultured podocytes. Our results indicate that the telmisartan prevents diabetic nephropathy through the inhibition of the Notch pathway.

Activation of intracellular angiotensin AT2 receptors induces rapid cell death in human uterine leiomyosarcoma cells

DEFF Research Database (Denmark)

Zhao, Yi; Lützen, Ulf; Fritsch, Jürgen

2015-01-01

The presence of AT2 receptors in mitochondria and their role in NO generation and cell aging were recently demonstrated in various human and mouse non-tumour cells. We investigated the intracellular distribution of AT2 receptors including their presence in mitochondria and the role in the induction...... agonist, Compound 21 (C21) penetrates the cell membrane of quiescent SK-UT-1 cells, activates intracellular AT2 receptors and induces rapid cell death; approximately 70% of cells died within 24 h. The cells, which escaped from the cell death, displayed activation of the mitochondrial apoptotic pathway, i...

The protective arm of the renin-angiotensin system may counteract the intense inflammatory process in fetuses with posterior urethral valves.

Science.gov (United States)

Rocha, Natalia P; Bastos, Fernando M; Vieira, Érica L M; Prestes, Thiago R R; Silveira, Katia D da; Teixeira, Mauro M; Simões E Silva, Ana Cristina

2018-03-11

Posterior urethral valve is the most common lower urinary tract obstruction in male children. A high percentage of patients with posterior urethral valve evolve to end-stage renal disease. Previous studies showed that cytokines, chemokines, and components of the renin-angiotensin system contribute to the renal damage in obstructive uropathies. The authors recently found that urine samples from fetuses with posterior urethral valve have increased levels of inflammatory molecules. The aim of this study was to measure renin-angiotensin system molecules and to investigate their correlation with previously detected inflammatory markers in the same urine samples of fetuses with posterior urethral valve. Urine samples from 24 fetuses with posterior urethral valve were collected and compared to those from 22 healthy male newborns at the same gestational age (controls). Renin-angiotensin system components levels were measured by enzyme-linked immunosorbent assay. Fetuses with posterior urethral valve presented increased urinary levels of angiotensin (Ang) I, Ang-(1-7) and angiotensin-converting enzyme 2 in comparison with controls. ACE levels were significantly reduced and Ang II levels were similar in fetuses with posterior urethral valve in comparison with controls. Increased urinary levels of angiotensin-converting enzyme 2 and of Ang-(1-7) in fetuses with posterior urethral valve could represent a regulatory response to the intense inflammatory process triggered by posterior urethral valve. Copyright © 2018 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

Exogenous and endogenous angiotensin-II decrease renal cortical oxygen tension in conscious rats by limiting renal blood flow.

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Emans, Tonja W; Janssen, Ben J; Pinkham, Maximilian I; Ow, Connie P C; Evans, Roger G; Joles, Jaap A; Malpas, Simon C; Krediet, C T Paul; Koeners, Maarten P

2016-11-01

phenylephrine did not significantly reduce RBF or renal oxygen delivery. Activation of the endogenous renin-angiotensin system in Cyp1a1Ren2 transgenic rats reduced cortical tissue PO2. This could be reversed within minutes by pharmacological angiotensin-II receptor type 1 (AT 1 R) blockade. Thus AngII is an important modulator of renal cortical oxygenation via AT 1 receptors. AngII had a greater influence on cortical oxygenation than did phenylephrine. This phenomenon appears to be attributable to the profound impact of AngII on renal oxygen delivery. We conclude that the ability of AngII to promote renal cortical hypoxia may contribute to its influence on initiation and progression of chronic kidney disease. © 2016 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.

Valsartan ameliorates ageing-induced aorta degeneration via angiotensin II type 1 receptor-mediated ERK activity

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Shan, HaiYan; Zhang, Siyang; Li, Xuelian; yu, Kai; Zhao, Xin; Chen, Xinyue; Jin, Bo; Bai, XiaoJuan

2014-01-01

Angiotensin II (Ang II) plays important roles in ageing-related disorders through its type 1 receptor (AT1R). However, the role and underlying mechanisms of AT1R in ageing-related vascular degeneration are not well understood. In this study, 40 ageing rats were randomly divided into two groups: ageing group which received no treatment (ageing control), and valsartan group which took valsartan (selective AT1R blocker) daily for 6 months. 20 young rats were used as adult control. The aorta structure were analysed by histological staining and electron microscopy. Bcl-2/Bax expression in aorta was analysed by immunohistochemical staining, RT-PCR and Western blotting. The expressions of AT1R, AT2R and mitogen-activated protein kinases (MAPKs) were detected. Significant structural degeneration of aorta in the ageing rats was observed, and the degeneration was remarkably ameliorated by long-term administration of valsartan. With ageing, the expression of AT1R was elevated, the ratio of Bcl-2/Bax was decreased and meanwhile, an important subgroup of MAPKs, extracellular signal-regulated kinase (ERK) activity was elevated. However, these changes in ageing rats could be reversed to some extent by valsartan. In vitro experiments observed consistent results as in vivo study. Furthermore, ERK inhibitor could also acquire partial effects as valsartan without affecting AT1R expression. The results indicated that AT1R involved in the ageing-related degeneration of aorta and AT1R-mediated ERK activity was an important mechanism underlying the process. PMID:24548645