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)

We previously reported that angiotensin II type 1 receptor (AT1R) blockade attenuates renal inflammation/fibrogenesis in immune-mediated glomerulonephritis via angiotensin II type 2 receptor (AT2R). In the present study, further in vivo experiments revealed that AT2R was expressed in tubular epithelial cells of nephritic kidneys in mice, and feedback activation of the renin-angiotensin system during AT1R blockade significantly reduced p-ERK, but not intranuclear nuclear factor-kappaB, levels via AT2R. This led to reduction in mRNA levels of the proinflammatory mediator monocyte chemoattractant protein-1 and overall interstitial inflammation and subsequent fibrogenesis. Specific blockade of ERK expression in tubular epithelium by anti-sense oligodeoxynucleotides also attenuated interstitial inflammation, mimicking the anti-inflammatory action of AT2R in nephritic kidneys. Alternatively, we succeeded in confirming such an AT(2)R function by demonstrating that AT1R blockade did not confer renoprotection in nephritic, AT2R gene-deficient mice. Additional in vitro experiments revealed that AT2R activation did not affect nuclear factor-kappaB activation by tumor necrosis factor-alpha in cultured tubular epithelial cells, although it inhibited ERK phosphorylation, which reduced monocyte chemoattractant protein-1 mRNA levels. These results suggest that feedback activation of AT2Rs in tubular epithelium of nephritic kidneys plays an important role in attenuating interstitial inflammation.
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PMID:A possible anti-inflammatory role of angiotensin II type 2 receptor in immune-mediated glomerulonephritis during type 1 receptor blockade. 1707 82

We investigated whether or not p38 mitogen-activated protein kinase inhibition ameliorates angiotensin II-induced target organ damage. We used double transgenic rats harboring both human renin and angiotensinogen genes (dTGRs). dTGR, with or without p38 inhibitor (BIRB796; 30 mg/kg per day in the diet), and nontransgenic Sprague-Dawley rats were studied in 2 protocols. In protocol 1 (week 7), systolic blood pressure of untreated dTGRs was 204+/-4 mm Hg, but partially reduced after BIRB796 treatment (166+/-7 mm Hg), whereas Sprague-Dawley rats were normotensive. The cardiac hypertrophy index was unchanged in untreated and BIRB796-treated dTGRs. The beta-myosin heavy chain expression of BIRB796-treated hearts was significantly lower in BIRB796 compared with dTGRs, indicating a delayed switch to the fetal isoform. BIRB796 treatment significantly reduced cardiac fibrosis, connective tissue growth factor, tumor necrosis factor-alpha, interleukin-6, and macrophage infiltration. Albuminuria was not reduced in BIRB796-treated dTGRs. Tubular and glomerular damage with tumor necrosis factor-alpha expression was unaltered, although serum creatinine and cystatin C were normalized. Renal macrophage infiltration, fibrosis, and vessel damage were reduced. In protocol 2 (week 8), we focused on mortality and arrhythmogenic electrical remodeling. Mortality of untreated dTGRs was 100% but was reduced to 10% in the BIRB796 group. Cardiac magnetic field mapping showed prolongation of depolarization and repolarization in untreated dTGRs compared with Sprague-Dawley rats with a partial reduction by BIRB796. Programmed electrical stimulation elicited ventricular tachycardias in 81% of untreated dTGRs but only in 48% of BIRB796-treated dTGRs. In conclusion, BIRB796 improved survival, target organ damage, and arrhythmogenic potential in angiotensin II-induced target organ damage.
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PMID:p38 mitogen-activated protein kinase inhibition ameliorates angiotensin II-induced target organ damage. 1722 70

Heart disease and depression are highly co-morbid. Clinical and experimental research over the past 70 years has led to several neurohumoral hypotheses of causative factors present under the conditions of either heart failure or of psychological depression. Some of these hypothesized factors are common to both disorders and are therefore attractive candidates to account for the high incidence of co-occurrence of depression and heart disease. One experimental approach to study the co-morbidity of heart failure and depression has been to study the behavioral, biochemical and physiological changes in a chronic mild stress model of depression and in heart failure induced by experimental myocardial infarction. Our studies have led us to focus on the pro-inflammatory cytokines, in particular tumor necrosis factor (TNF)-alpha, and the renin-angiotensin-aldosterone system. Both of these families of humoral factors are elevated in human heart failure and in depression and the two experimental models we have studied. The demonstrated validity of each of these models will be of great value in elucidating the nature of the actions and interactions of these humoral agents as they contribute to the co-morbid conditions of heart failure and depression.
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PMID:Sadness and broken hearts: neurohumoral mechanisms and co-morbidity of ischemic heart disease and psychological depression. 1724 36

Cardiac mast cells proliferate in cardiovascular diseases. In myocardial ischemia, mast cell mediators contribute to coronary vasoconstriction, arrhythmias, leukocyte recruitment, and tissue injury and repair. Arrhythmic dysfunction, coronary vasoconstriction, and contractile failure are also characteristic of cardiac anaphylaxis. In coronary atherosclerosis, mast cell mediators facilitate cholesterol accumulation and plaque destabilization. In cardiac failure, mast cell chymase causes myocyte apoptosis and fibroblast proliferation, leading to ventricular dysfunction. Chymase and tryptase also contribute to fibrosis in cardiomyopathies and myocarditis. In addition, mast cell tumor necrosis factor-alpha promotes myocardial remodeling. Cardiac remodeling and hypertrophy in end-stage hypertension are also induced by mast cell mediators and proteases. We recently discovered that cardiac mast cells contain and release renin, which initiates local angiotensin formation. Angiotensin causes coronary vasoconstriction, arrhythmias, fibrosis, apoptosis, and endothelin release, all demonstrated mechanisms of mast-cell-associated cardiac disease. The effects of angiotensin are further amplified by the release of norepinephrine from cardiac sympathetic nerves. Our discovery of renin in cardiac mast cells and its release in pathophysiological conditions uncovers an important new pathway in the development of mast-cell-associated heart diseases. Several steps in this novel pathway may constitute future therapeutic targets.
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PMID:Renin: at the heart of the mast cell. 1749 56

Reduced insulin sensitivity is characteristic of various pathological conditions such as type 2 diabetes mellitus and hypertension. Angiotensin II, acting through its angiotensin type 1 receptor, inhibits the actions of insulin in the vasculature which may lead to deleterious effects such as vascular inflammation, remodeling, endothelial dysfunction, and insulin resistance. In contrast, insulin normally exerts vasodilatory, antiinflammatory, and prosurvival actions. To explore the impact of angiotensin II on insulin signaling, NADPH oxidase-derived reactive oxygen species formation, vascular inflammation, apoptosis, and remodeling, we used transgenic TG(mRen2)27 (Ren2) rats, which harbor the mouse renin transgene and exhibits elevated tissue angiotensin II levels. Compared with Sprague-Dawley controls, Ren2 aortas exhibited greater NADPH oxidase activity, reactive oxygen species levels, C-reactive protein, tumor necrosis factor-alpha expression, apoptosis, and wall thickness, which were significantly attenuated by in vivo treatment with angiotensin type 1 receptor blockade (valsartan) or the superoxide dismutase/catalase mimetic (tempol). There was substantially diminished Akt and endothelial NO synthase activation in Ren2 aortas in response to in vivo insulin stimulation, and this was significantly improved by in vivo treatment with valsartan or tempol. In vivo treatment with valsartan, but not tempol, significantly reduced blood pressure in Ren2 rats. Further, there was reduced insulin induced Akt activation and increased tumor necrosis factor-alpha levels in vascular smooth muscle cells from Ren2 and Sprague-Dawley rats treated with angiotensin II, abnormalities that were abrogated by angiotensin type 1 receptor blockade with valsartan or antioxidant N-acetylcysteine. Collectively, these data suggest that increased angiotensin type 1 receptor/NADPH oxidase activation/reactive oxygen species contribute to vascular insulin resistance, endothelial dysfunction, apoptosis, and inflammation.
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PMID:NADPH oxidase contributes to vascular inflammation, insulin resistance, and remodeling in the transgenic (mRen2) rat. 1753 99

Guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) signaling antagonizes the physiological effects mediated by the renin-angiotensin system (RAS). The objective of this study was to determine whether the targeted-disruption of Npr1 gene (coding for GC-A/NPRA) leads to the activation of cardiac RAS genes involved on the hypertrophic remodeling process. The Npr1 gene-knockout (Npr1(-/-)) mice showed 30-35 mmHg higher systolic blood pressure (SBP) and a 63% greater heart weight-to-body weight (HW/BW) ratio compared with wild-type (Npr1(+/+)) mice. The mRNA levels of both angiotensin-converting enzyme and angiotensin II type 1a receptor were increased by three- and fourfold, respectively, in Npr1(-/-) null mutant mice hearts compared with the wild-type Npr1(+/+) mice hearts. In parallel, the expression levels of interleukin-6 and tumor necrosis factor-alpha were increased by four- to fivefold, in Npr1(-/-) mice hearts compared with control animals. The NF-kappaB binding activity in nuclear extracts of Npr1(-/-) mice hearts was increased by fourfold compared with wild-type Npr1(+/+) mice hearts. Treatments with captopril or hydralazine equally attenuated SBP; however, only captopril significantly decreased the HW/BW ratio and suppressed cytokine gene expression in Npr1(-/-) mice hearts. The ventricular cGMP level was reduced by almost sixfold in Npr1(-/-) mice compared with wild-type control mice. The results of the present study indicate that disruption of NPRA/cGMP signaling leads to the augmented expression of cardiac RAS pathways that promote the development of cardiac hypertrophy and remodeling.
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PMID:Genetic disruption of guanylyl cyclase/natriuretic peptide receptor-A upregulates ACE and AT1 receptor gene expression and signaling: role in cardiac hypertrophy. 1756 78

Current evidence implicates a prothrombotic state in the development of Shiga-toxin (Stx)-mediated hemolytic uremic syndrome (HUS). We recently reported that Stx modulates procoagulant activity by enhancing functional tissue factor (TF) activity on cytokine-activated human glomerular endothelial cells (HGECs). Since angiotensin II (Ang II), the key effector of the renin angiotensin system (RAS), has been shown to increase TF expression in vascular tissue, we examined the possible involvement of Ang II in TF expression in HGECs. HGECs were exposed to tumor necrosis factor (TNF)-alpha +/- Stx-1 +/- Ang II. Exogenous Ang II significantly increased TF activity and TF mRNA in TNF-alpha- +/- Stx-1-activated HGECs. This increase was mediated via Ang II type I receptor (AT(1)R), as losartan, an AT(1)R inhibitor, attenuated Ang-II-induced TF activity. To study the effect of endogenous Ang II in TF expression by TNF-alpha +/- Stx-1, HGECs were incubated with losartan or an AT(2)R inhibitor (PD 123319) or an angiotensin-converting enzyme inhibitor (enalapril). Losartan but not PD 123319 decreased TF activity induced by TNF-alpha +/- Stx-1 (P < 0.05). Enalapril, also, dose dependently, downregulated TF expression in HGECs exposed to TNF-alpha +/- Stx-1 (P < 0.05). AT(1)R mRNA was upregulated in TNF-alpha- +/- Stx-1-activated HGECs (P < 0.05). These data indicate that TF expression in TNF-alpha- and Stx-1-activated HGECs is enhanced by exogenous Ang II and that endogenous Ang II production may be upregulated by TNF-alpha +/- Stx-1. Hence, local RAS activation may be important in the development of the thrombotic microangiopathy observed in HUS.
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PMID:Role of the renin angiotensin system in TNF-alpha and Shiga-toxin-induced tissue factor expression. 1806 Apr 35

Maternal spiral artery remodeling is the consequence of controlled trophoblast invasive interaction with the maternal cellular environment and is fundamentally important for successful placentation. In preeclampsia, trophoblast invasion is shallow, remodeling is incomplete, and vessels develop an inflammatory appearance, termed "acute atherosis." We noted that, in our preeclampsia, human renin-human angiotensinogen transgenic rat model, complement component 3 (C3), and tumor necrosis factor-alpha were upregulated and heavily expressed in atherotic uteroplacental vessels. We next used coculture involving human trophoblasts, rat vascular smooth muscle cells (VSMCs), and human VSMCs to observe VSMC-trophoblast regulatory interactions. Tumor necrosis factor-alpha induced complement C3 and interleukin-6 expression in VSMCs. We found that trophoblasts were able to reduce VSMC C3 and interleukin-6 expression after the VSMCs were stimulated with tumor necrosis factor-alpha. However, a direct VSMC-trophoblast cell-cell contact was necessary for this anti-inflammatory response. We also studied double-transgenic VSMCs that express inflammatory components and exhibit accelerated proliferation ("synthetic" phenotype). Trophoblasts could not downregulate C3 in these cells. We then examined uteroplacental tissues from preeclamptic and control patients. In control deciduas, only traces of C3 staining were observed, and vessels were thin walled without thrombus formation. In preeclampsia, the decidual vessels showed atherosis, thrombus formation, and C3 expression. Our data suggest that fetally derived trophoblasts require direct cell-cell contact with maternally derived VSMCs to downregulate VSMC C3 and interleukin-6 expression and to avoid atherosis. The findings also implicate C3 in the placental vasculopathy observed in preeclampsia.
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PMID:Trophoblasts reduce the vascular smooth muscle cell proatherogenic response. 1819 63

Reduced uterine perfusion pressure during pregnancy is an important initiating event in preeclampsia. Inflammatory cytokines are thought to link placental ischemia with cardiovascular and renal dysfunction. Supporting a role for cytokines are findings of elevated tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 plasma levels in preeclamptic women. Blood pressure regulatory systems (eg, renin-angiotensin system [RAS] and sympathetic nervous system) interact with proinflammatory cytokines, which affect angiogenic and endothelium-derived factors regulating endothelial function. Chronic reductions in placental perfusion in pregnant rats are associated with enhanced TNF-alpha and IL-6 production. Chronic infusion of TNF-alpha or 11-6 into normal pregnant rats significantly increases arterial pressure and impairs renal hemodynamics. TNF-alpha activates the endothelin system in placental, renal, and vascular tissues, and IL-6 stimulates the RAS. These findings suggest that inflammatory cytokines elevate blood pressure during pregnancy by activating multiple neurohumoral and endothelial factors.
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PMID:Inflammatory cytokines in the pathophysiology of hypertension during preeclampsia. 1836 11

Pepsin-digested soy protein hydrolysate has been reported to be responsible for many of the physiological benefits associated with soy protein consumption. In the present study, we investigated the effects of soy protein hydrolysate with angiotensin-converting enzyme (ACE) inhibitory potential on the blood pressure and cardiovascular remodeling in rats with N(omega)-nitro-L-arginine methyl ester hydrochloride (L-NAME)-induced hypertension. Rats were fed a diet containing L-NAME (50 mg/kg body weight) with or without soy protein hydrolysate (1%, 3% or 5%) for 6 weeks. We found that ingestion of soy protein hydrolysate retarded the development of hypertension during the 6-week experimental period without affecting the amount of food intake. Although there was no difference in plasma ACE activity or tissue nitric oxide levels, ACE activity in the heart of rats consuming soy protein hydrolysate was significantly lower than that of the control group. Moreover, cardiac malonaldehyde and tumor necrosis factor-alpha concentrations were also lower in the soy protein hydrolysate group. No difference in plasminogen activator inhibitor-1 level was found in plasma or cardiovascular tissue. In the histopathological analysis, we also found that soy protein hydrolysate ameliorated inflammation and left ventricle hypertrophy in the heart. These findings suggest that soy protein hydrolysate might not only improve the balance between circulating nitric oxide and renin-angiotensin system but also show beneficial effects on cardiovascular tissue through its ACE inhibitory activity.
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PMID:Soy protein hydrolysate ameliorates cardiovascular remodeling in rats with L-NAME-induced hypertension. 1847 99


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