Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The atherogenic effect of the renin-angiotensin system can be explained, in part, by the influence of its effector, angiotensin II (Ang II), on vascular smooth muscle cell (VSMC) growth. There is evidence that reactive oxygen species (ROS) play a role in the atherogenesis and activation of mitogen-activating protein (MAP) kinases, which are involved in proliferation and differentiation. The study was performed to further characterize the role of ROS in Ang II-mediated MAP kinase activation and the regulation of the transcription factor activator protein-1 (AP-1). Rat VSMCs were stimulated with Ang II. The activities of MAP kinases were assessed by Western blot analysis or by immunocomplex kinase assay. AP-1 binding was determined by using an electrophoretic mobility shift assay. Rat VSMCs were treated with Ang II-activated MAP kinases, extracellular signal-regulated kinase (ERK), c-Jun amino terminal kinase (JNK), p38 MAP kinase (p38 MAPK), and their downstream effector, AP-1. Interestingly, only the activation of ERK1/2, but not JNK or p38 MAPK, was tyrosine kinase, protein kinase C, and MEK1/2 dependent. Ang II also induced the rapid formation of ROS, which could be inhibited by a specific antibody as well as by antisense against the p22phox subunit of the NAD(P)H oxidase. JNK and p38 MAPK, but not ERK, activation was inhibited by an inhibitor of NAD(P)H oxidase. Antisense against p22phox also solely inhibited p38 MAPK but did not affect ERK. The results indicate that in VSMCs, Ang II activates MAP kinases and AP-1 through different pathways; the results further suggest that ROS, generated by p22phox, mediate Ang II-induced JNK and p38 MAPK activation, which may contribute to the pathogenesis of atherosclerosis.
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PMID:Differential activation of mitogen-activated protein kinases in smooth muscle cells by angiotensin II: involvement of p22phox and reactive oxygen species. 1076 57

1. Angiotensin (Ang) II triggers the expression of a pro- oxidant phenotype in the vascular wall, suggesting that activation of the renin-angiotensin system (RAS) causes endothelial dysfunction in various pathological situations, such as hypertension. However, this hypothesis has been mostly tested in a setting of exogenous administration of AngII. 2. We tested the hypothesis of a role for endogenous activation of the RAS leading to oxidant stress and endothelial dysfunction in a high-renin model of hypertension (i.e. two-kidney, one-clip hypertension) in rats. One month after clipping or sham surgery, aorta were isolated from untreated rats or rats treated by the angiotensin AT1 receptor antagonist irbesartan (10 mg/kg per day). Mesenteric artery segments were also isolated from normotensive or hypertensive rats. 3. Hypertension reduced the relaxations to acetylcholine but did not affect the ratio of contractions to phenylephrine in the presence compared with the absence of a nitric oxide (NO) synthase inhibitor, used as an index of basal release of NO. 4. The free radical scavenger tempol reduced the contractions to phenylephrine in the absence, but not in the presence, of an inhibitor of NO synthesis. This index of free radical-mediated degradation of NO was not affected by hypertension. In parallel, hypertension did not affect the expression of p22phox, a component of the free radical generating enzyme reduced nicotinamide adenine dinucleotide phosphate oxidase. 5. Chronic treatment with the AT1 receptor antagonist decreased blood pressure, moderately improved the response to acetylcholine, but did not affect basal NO release in hypertensive rats, although it did increase basal NO release in normotensive rats. 6. Thus, this model of hypertension is characterized by an impaired stimulated NO release but not of basal NO release in isolated arteries. Furthermore, there was no functional evidence of an increased oxidative stress-mediated impairment of NO release. This is not in favour of a direct link between activation of the RAS and development of endothelial dysfunction in experimental hypertension.
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PMID:Lack of impairment of nitric oxide-mediated responses in a rat model of high-renin hypertension. 1190 58

Angiotensin (Ang) II promotes renal infiltration by immunocompetent cells in double-transgenic rats (dTGRs) harboring both human renin and angiotensinogen genes. To elucidate disease mechanisms, we investigated whether or not dexamethasone (DEXA) immunosuppression ameliorates renal damage. Untreated dTGRs developed hypertension, renal damage, and 50% mortality at 7 weeks. DEXA reduced albuminuria, renal fibrosis, vascular reactive oxygen stress, and prevented mortality, independent of blood pressure. In dTGR kidneys, p22phox immunostaining co-localized with macrophages and partially with T cells. dTGR dendritic cells expressed major histocompatibility complex II and CD86, indicating maturation. DEXA suppressed major histocompatibility complex II+, CD86+, dendritic, and T-cell infiltration. In additional experiments, we treated dTGRs with mycophenolate mofetil to inhibit T- and B-cell proliferation. Reno-protective actions of mycophenolate mofetil and its effect on dendritic and T cells were similar to those obtained with DEXA. We next investigated whether or not Ang II directly promotes dendritic cell maturation in vitro. Ang II did not alter CD80, CD83, and MHC II expression, but increased CCR7 expression and cell migration. To explore the role of tumor necrosis factor (TNF)-alpha on dendritic cell maturation in vivo, we treated dTGRs with the soluble TNF-alpha receptor etanercept. This treatment had no effect on blood pressure, but decreased albuminuria, nuclear factor-kappaB activation, and infiltration of all immunocompetent cells. These data suggest that immunosuppression prevents dendritic cell maturation and T-cell infiltration in a nonimmune model of Ang II-induced renal damage. Ang II induces dendritic migration directly, whereas in vivo TNF-alpha is involved in dendritic cell infiltration and maturation. Thus, Ang II may initiate events leading to innate and acquired immune response.
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PMID:Immunosuppressive treatment protects against angiotensin II-induced renal damage. 1241 15

Until recently elevated blood pressure was considered as a hemodynamic entity representing an increase in workload for the heart and the arterial tree. Control of hypertension meant hemodynamic unloading, through inhibition of vasoconstrictor pathways, principally renin-angiotensin system and sympathetic system. In recent years however a new pharmacological approach has evolved as a result of (i) the dissociation of endothelial dysfunction and vascular pathology from increased blood pressure; (ii) the recognition that endothelial dysfunction regards not only the vascular reactivity, but also promotes atherosclerosis and thrombosis; and (iii) an improved understanding of the complexity of local-tissue renin angiotensin system and of the vasodilatory and cytoprotective role of natriuretic peptides. This has led to a reconsideration of existing medicines in terms of specification on endothelial function, more rationalized application of drugs and search for new compounds targeting both vasodilatory and anti-proliferative pathways. Examples include beta1-adrenergic antagonists, such as Nebivolol and Carvedilol, and vasopeptidase inhibitors, such as Omapatrilat, that inhibit simultaneously the angiotensin converting enzyme and neutral endopeptidase. Furthermore the identification of genetic polymorphisms in the effectors involved in the pathophysiology of hypertension or in the response to anti-hypertensive drugs, such as the p22phox subunit of NADPH oxidase, alpha-adducin or adrenergic receptors, has promoted the prospective of both better understanding of hypertension and individualized strategies for its treatment.
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PMID:The shift in the "paradigm" of the pharmacology of hypertension. 1496 15

Angiotensin II (Ang II), the dominant effector of the renin-angiotensin system, regulates numerous inflammatory-proliferative responses in vascular wall cells and is thus involved in atherosclerosis. We have previously shown that pigment epithelium-derived factor (PEDF) inhibits advanced glycation end-product-induced pericyte apoptosis, thereby exerting beneficial effects on diabetic retinopathy. However, a role for PEDF in vascular inflammation and atherosclerosis remains to be elucidated. In this study, we have examined whether PEDF inhibits the Ang-II-induced endothelial cell (EC) activation in vitro and the way that it might achieve this effect. Ang II significantly induced redox-sensitive transcriptional factor NF-kappaB activation and subsequent monocyte chemoattractant protein-1 expression in human umbilical vein ECs (HUVEC), both of which were completely inhibited by PEDF or the anti-oxidant N-acetylcysteine. PEDF or diphenylene iodonium, an inhibitor of NADPH oxidase, inhibited Ang-II-induced intracellular reactive oxygen species (ROS) generation in HUVEC. Furthermore, PEDF inhibited Ang-II-induced up-regulation of mRNA levels of p22phox, Nox4, and gp91phox/Nox2, which are membrane components of NADPH oxidase, and its enzymatic activity in HUVEC. Antisense, but not sense, DNAs against p22phox, Nox4, or gp91phox/Nox2 were found significantly to inhibit Ang-II-induced ROS generation in HUVEC. These results demonstrate that PEDF inhibits Ang-II-induced EC activation by suppressing NADPH-oxidase-mediated ROS generation and that PEDF may play a protective role in the development and progression of atherosclerosis.
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PMID:Pigment epithelium-derived factor (PEDF) blocks angiotensin II signaling in endothelial cells via suppression of NADPH oxidase: a novel anti-oxidative mechanism of PEDF. 1584 9

Alcohol abuse increases the incidence of acute respiratory distress syndrome and causes oxidative stress and cellular dysfunction in the lung. The mechanisms of ethanol (EtOH)-induced oxidative stress in the lung remain to be defined. Chronic alcohol ingestion has been associated with increased renin-angiotensin system (RAS) activity. Therefore, the current study investigated the ability of lisinopril, an angiotensin-converting enzyme (ACE) inhibitor, to modulate oxidative stress in the lung after chronic EtOH ingestion in a well-established rat model. Male Sprague-Dawley rats were fed liquid diets containing EtOH (36% of calories) or maltose-dextrin as an isocaloric substitution for EtOH (Control) for 6 wk. Selected animals were also treated with lisinopril (3 mg/liter) for 6 wk. Chronic EtOH ingestion increased bronchoalveolar lavage fluid glutathione disulfide levels and superoxide formation in lung parenchyma. These effects of EtOH were attenuated by lisinopril treatment. Chronic EtOH ingestion failed to increase ACE expression or angiotensin II levels in lung homogenates, but increased angiotensinogen, angiotensin II type 1 and type 2 receptor levels, and ACE activity. Chronic EtOH ingestion also increased the levels of the NADPH oxidase subunit, gp91phox, an effect that was attenuated by lisinopril, but had no effect on lung p22phox or p47phox levels. These findings suggest that EtOH-mediated RAS activation plays an important role in pulmonary oxidative stress and provide new insights into mechanisms by which EtOH causes oxidative stress in the lung and potential strategies of lung protection through ACE inhibition.
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PMID:Chronic ethanol ingestion increases superoxide production and NADPH oxidase expression in the lung. 1628 59

Recently, aldosterone has been shown to activate local renin-angiotensin system in vitro. To elucidate the potential role of local renin-angiotensin system in aldosterone-induced cardiovascular injury, we investigated the effects of selective mineralocorticoid receptor (MR) antagonist eplerenone (EPL), angiotensin (Ang) II type 1 receptor antagonist candesartan (ARB), and superoxide dismutase mimetic tempol (TEM) on the development of hypertension, vascular injury, oxidative stress, and inflammatory-related gene expression in aldosterone-treated hypertensive rats. The increased systolic blood pressure and vascular inflammatory changes were attenuated by cotreatment either with EPL, ARB, or TEM. Aldosterone increased angiotensin-converting enzyme expression in the aortic tissue; its effects were blocked by EPL but not by ARB or TEM. Aldosterone also increased Ang II contents in the aortic tissue in the presence of low circulating Ang II concentrations. Aldosterone induced expression of various inflammatory-related genes, whose effects were abolished by EPL, whereas the inhibitory effects of ARB and TEM varied depending on the gene. Aldosterone caused greater accumulation of the oxidant stress marker 4-hydroxy-2-neonenal in the endothelium; its effect was abolished by EPL, ARB, or TEM. Aldosterone increased mRNA levels of reduced nicotinamide adenine dinucleotide phosphate oxidase components; their effect was abolished by EPL, whereas ARB and TEM decreased only the p47phox mRNA level but not that of p22phox or gp91phox. The present findings suggest that the Ang II-dependent pathway resulting from vascular angiotensin-converting enzyme up-regulation and Ang II-independent pathway are both involved in the underlying mechanisms resulting in the development of hypertension, vascular inflammation, and oxidative stress induced by aldosterone.
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PMID:Angiotensin II receptor type 1-mediated vascular oxidative stress and proinflammatory gene expression in aldosterone-induced hypertension: the possible role of local renin-angiotensin system. 1721 15

The transgenic (mRen2)27 (Ren2) rat overexpresses mouse renin in extrarenal tissues, causing increased local synthesis of ANG II, oxidative stress, and hypertension. However, little is known about the role of oxidative stress induced by the tissue renin-angiotensin system (RAS) as a contributing factor in pulmonary hypertension (PH). Using male Ren2 rats, we test the hypothesis that lung tissue RAS overexpression and resultant oxidative stress contribute to PH and pulmonary vascular remodeling. Mean arterial pressure (MAP), right ventricular systolic pressure (RVSP), and wall thickness of small pulmonary arteries (PA), as well as intrapulmonary NADPH oxidase activity and subunit protein expression and reactive oxygen species (ROS), were compared in age-matched Ren2 and Sprague-Dawley (SD) rats pretreated with the SOD/catalase mimetic tempol for 21 days. In placebo-treated Ren2 rats, MAP and RVSP, as well as intrapulmonary NADPH oxidase activity and subunits (Nox2, p22phox, and Rac-1) and ROS, were elevated compared with placebo-treated SD rats (P < 0.05). Tempol decreased RVSP (P < 0.05), but not MAP, in Ren2 rats. Tempol also reduced intrapulmonary NADPH oxidase activity, Nox2, p22phox, and Rac-1 protein expression, and ROS in Ren2 rats (P < 0.05). Compared with SD rats, the cross-sectional surface area of small PA was 38% greater (P < 0.001) and luminal surface area was 54% less (P < 0.001) in Ren2 rats. Wall surface area was reduced and luminal area was increased in tempol-treated SD and Ren2 rats compared with untreated controls (P < 0.05). Collectively, the results of this investigation support a seminal role for enhanced tissue RAS/oxidative stress as factors in development of PH and pulmonary vascular remodeling.
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PMID:Oxidative stress contributes to pulmonary hypertension in the transgenic (mRen2)27 rat. 1842 32

Diurnal variations in plasminogen activator inhibitor-1 mRNA expression are different between the spontaneously hypertensive rats (SHRs) and the Wistar-Kyoto (WKY) rats, and between the aorta and the heart. To elucidate the mechanisms, we examined diurnal changes in the circulating renin-angiotensin system in the SHR and WKY rats. Diurnal variations in plasma renin activity (PRA), plasma angiotensin I, and aldosterone concentrations were similar between the SHR and WKY rats. On the other hand, plasma angiotensin II (Ang II) concentration in the SHR was lower than that in the WKY rats at most time points, but increased to the level of the WKY rats in the late light phase. Treatment with AT1 receptor antagonist candesartan increased plasma Ang II concentration except at ZT 8 and lessened its diurnal variation in the SHR. At the peak in plasma Ang II in the SHR, Ang II regulated genes such as transforming growth factor-beta1 and p22phox were upregulated in the aorta. On the other hand, these genes were upregulated throughout the day in the heart of SHR. Candesartan treatment increased AT1a receptor mRNA expression in the heart but not in the aorta of SHR. These findings suggest that an AT1 receptor-mediated mechanism might cause a surge in plasma Ang II concentration at the late light phase in the SHR. Homologous down-regulation of AT1a receptor by Ang II may dampen the effect of a surge in plasma Ang II concentration in the heart of SHR.
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PMID:The mechanism of distinct diurnal variations of renin-angiotensin system in aorta and heart of spontaneously hypertensive rats. 2000 55

Diabetes Mellitus is associated with severe cardiovascular disorders involving the renin-angiotensin system, mainly through activation of the angiotensin II type 1 receptor (AT1R). Although the type 2 receptor (AT2R) opposes the effects of AT1R, with vasodilator and anti-trophic properties, its role in diabetes is debatable. Thus we investigated AT2R-mediated dilatation in a model of type 1 diabetes induced by streptozotocin in 5-month-old male mice lacking AT2R (AT2R-/y). Glucose tolerance was reduced and markers of inflammation and oxidative stress (cyclooxygenase-2, gp91phox p22phox and p67phox) were increased in AT2R-/y mice compared to wild-type (WT) animals. Streptozotocin-induced hyperglycaemia was higher in AT2R-/y than in WT mice. Arterial gp91phox and MnSOD expression levels in addition to blood 8-isoprostane and creatinine were further increased in diabetic AT2R-/y mice compared to diabetic WT mice. AT2R-dependent dilatation in both isolated mesenteric resistance arteries and perfused kidneys was greater in diabetic mice than in non-diabetic animals. Thus, in type 1 diabetes, AT2R may reduce glycaemia and display anti-oxidant and/or anti-inflammatory properties in association with greater vasodilatation in mesenteric arteries and in the renal vasculature, a major target of diabetes. Therefore AT2R might represent a new therapeutic target in diabetes.
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PMID:Microvascular vasodilator properties of the angiotensin II type 2 receptor in a mouse model of type 1 diabetes. 2836 92


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