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

Studies were run to determine whether the renal microvascular endothelium influences renin release. Blood-free rat renal cortical slices were incubated in a bicarbonate buffer for 60 min and sampled at 30 and 60 min to determine renin concentration and at 60 min for prostaglandin (PG) E2 and I2 (6-keto-PGF1 alpha) synthesis. Stimulation by 10(-6) M melittin of endogenous PGs simultaneously increased renin release, PGE2, and PGI2 synthesis, and all were inhibited by 1.6 x 10(-6) M meclofenamate. Renin release was stimulated with isoproterenol [26.2 +/- 2.4 ng angiotensin I (ANG I) .h-1.mg-1.30 min-1; P less than 0.001], PGI2 (32.3 +/- 7.4 ng ANG I.h-1.mg-1.mg-1.30 min-1; P less than 0.005), and PGE2 (25.7 +/- 2.8 ng ANG I.h-1.mg-1.30 min-1, P less than 0.001). Acetylcholine did not affect basal renin but potentiated the response to PGE2 by 80% (46.0 +/- 5.8 ng ANG I.h-1.mg-1.30 min-1; P less than 0.001). Atropine (10(-7) M) reversed this potentiation. Deendothelialization of renal microvessels with H2O2 eliminated PGI2, but neither PGE2 nor renin release, and reversed acetylcholine-potentiation of PGE2-stimulated renin release as did meclofenamate. Hemoglobin increased PGE2-stimulated renin similarly to acetylcholine. These studies suggest that stimulating the endothelium with acetylcholine results in selective potentiation of PGE2-stimulated renin release, which may be mediated through some cyclooxygenase product and is independent of endothelium-derived relaxing factor. Thus the renal endothelium may influence or modulate renin release.
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PMID:Possible endothelial modulation of prostaglandin-stimulated renin release. 218 36

Atherogenic lipoproteins accumulate in the arterial wall and may potentially stimulate neighboring cells. In the glomerulus the vascular pole resembles afferent arteries in close vicinity to the juxtaglomerular apparatus. We examined the effects of native and oxidized LDL and lipoprotein(a) [Lp(a)] on renin release of juxtaglomerular cells (JG cells) prepared in primary culture from mouse kidneys. Renin activity of JG cells was measured in culture supernatants and cells between the 20th and 40th hour of culturing. Spontaneous renin release into the cell supernatant was 26 +/- 1% of total activity. Control stimulation of JG cells by melittin or forskolin dose-dependently increased renin release up to 90 +/- 2%. Incubation of JG cells with native LDL (50 and 300 micrograms/ml) or native Lp(a) (30 micrograms/ml) did not alter renin release. Oxidized LDL increased renin release to 34 +/- 1% and 43 +/- 1% at 50 and 300 micrograms/ml, while oxidized Lp(a) stimulated renin release to 33 +/- 1%, 42 +/- 1%, and 71 +/- 2% at 1, 10, and 30 micrograms/ml, respectively. Coincubation with superoxide dismutase and catalase, enzymes removing O2- and H2O2, completely eliminated oxidized LDL and Lp(a)-stimulated renin release. In the absence of lipoproteins, renin release was significantly stimulated by activation of O2- formation by the xanthine/xanthine oxidase reaction. These data indicate that oxidized LDL and Lp(a) stimulate renin release in JG cells by a mechanism involving oxygen-derived radicals. Thus, oxidatively modified atherogenic lipoproteins may contribute to renin-dependent hypertension in renoparenchymatous kidney disease.
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PMID:Oxidized LDL and lipoprotein(a) stimulate renin release of juxtaglomerular cells. 773 Nov 69

We assessed effects of reactive oxygen metabolites on renin release of juxtaglomerular cells (JG-cells) prepared in primary culture from mouse kidneys. Renin activity was measured in culture supernatants and cells. Basal renin release was increased by incubation of JG-cells with xanthine/xanthine oxidase from 26 +/- 1% up to 58 +/- 3% of total activity. This increase was slightly inhibited by superoxide dismutase, and was eliminated by addition of catalase, implicating H2O2 as an intermediate product in the stimulatory cascade. H2O2 applied exogenously dose-dependently stimulated renin release up to 55 +/- 2%; this effect was also prevented by catalase. We propose that reactive oxygen metabolites stimulate renin release in isolated JG-cells. This could have important implications in inflammatory kidney diseases.
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PMID:Oxygen-derived radicals stimulate renin release of isolated juxtaglomerular cells. 808 86

Atherogenic lipoproteins accumulate in the arterial wall as well as within the glomerulus and may accelerate vascular and glomerular injury. We therefore assessed whether oxidized low density lipoprotein (LDL) and lipoprotein(a) [Lp(a)] influence three major systems: (i) endothelium-dependent vasodilation, (ii) renin release of juxtaglomerular (JG) cells, and (iii) proliferation and viability of mesangial cells (MC). Lipoproteins were prepared from human plasma. Renal arteries were obtained from rabbits and JG as well as MC cells from mouse, rat and human kidneys. Dilator responses were detected in isolated arterial segments by a photoelectric device. Renin activity of JG cells was measured in culture supernatants and cells and DNA synthesis by 3H-thymidine incorporation in MC. Acetylcholine-induced, endothelium-dependent dilator responses of renal arteries were not significantly attenuated after incubation with native Lp(a). However, exposure to in vitro oxidized Lp(a) suppressed dilator responses in a dose-dependent manner. Using a chemiluminescence assay, we could detect increased O2- production by arteries pretreated with oxidized Lp(a), which suggested that enhanced nitric oxide (NO) inactivation by O2- might be the underlying mechanism of impairment of endothelium-dependent dilations. In general, oxidized Lp(a) was far more potent than oxidized LDL in this effect. In JG cells, both oxidized LDL and Lp(a) dose-dependently stimulated renin release. Coincubation with HDL significantly suppressed oxidized LDL and Lp(a) stimulated renin release and O2- production. In MC native and oxidized Lp(a) were poor ligands for the LDL receptor, but bound more tightly to extracellular matrix than native LDL. Native and oxidized Lp(a) elicited proliferation or toxicity of MC in a dose-dependent fashion. Stimulation of DNA synthesis in MC or renin release in JG cells was partly blunted or eliminated when cells were incubated with oxidized LDL and Lp(a) in the presence of superoxide dismutase and catalase, enzymes removing O2- and H2O2. These dat suggest a common underlying mechanism. Atherogenic lipoproteins induce formation of oxygen radicals not only in arteries, but also in glomeruli and JG cells, causing an inhibition of nitric oxide mediated vasodilation, stimulation of renin release, and modulation of mesangial cell growth and proliferation. The damaging effect of the lipoproteins can be prevented by antioxidative enzymes and HDL.
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PMID:Lipids and progression of renal disease: role of modified low density lipoprotein and lipoprotein(a). 940 34

Monocyte infiltration into the vessel wall, a key initial step in the process of atherosclerosis, is mediated in part by monocyte chemoattractant protein-1 (MCP-1). Hypertension, particularly in the presence of an activated renin-angiotensin system, is a major risk factor for the development of atherosclerosis. To investigate a potential molecular basis for a link between hypertension and atherosclerosis, we studied the effects of angiotensin II (Ang II) on MCP-1 gene expression in rat aortic smooth muscle cells. Rat smooth muscle cells treated with Ang II exhibited a dose-dependent increase in MCP-1 mRNA accumulation that was prevented by the AT1 receptor antagonist losartan. Ang II also activated MCP-1 gene transcription. Inhibition of NADH/NADPH oxidase, which generates superoxide and H2O2, with diphenylene iodonium or apocynin decreased Ang II-induced MCP-1 mRNA accumulation. Induction of MCP-1 gene expression by Ang II was inhibited by catalase, suggesting a second messenger role for H2O2. The tyrosine kinase inhibitor genistein and the mitogen-activated protein kinase kinase inhibitor PD098059 inhibited Ang II-induced MCP-1 gene expression, consistent with a mitogen-activated protein kinase-dependent signaling mechanism. Ang II may thus promote atherogenesis by direct activation of MCP-1 gene expression in vascular smooth muscle cells.
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PMID:Angiotensin II induces monocyte chemoattractant protein-1 gene expression in rat vascular smooth muscle cells. 979 45

Captopril (D-3-mercapto-2-methylpropanoyl-L-proline) is an angiotensin converting enzyme (ACE) inhibitor, used widely in the treatment of hypertension and congestive heart failure. Captopril also inhibits proliferation of a variety of cell types, including several lacking ACE and renin acitvity. We have previously demonstrated that human mammary ductal carcinoma cells are among the cell types whose mitotic activity is inhibited by captopril. In those cells, captopril also reduces estrogen receptor (ER) and increases progesterone receptor (PR) concentrations. The present study evaluated the mechanism of captopril's antiproliferative action in an ER/PR-negative human mammary ductal carcinoma cell line, Hs578T. Cells grown in a 10% serum medium showed negligible changes in the presence of captopril alone. However, in the presence of subphysiologic concentrations of copper salts or copper-loaded ceruloplasmin, captopril caused a dose-dependent reduction in cell number, thymidine incorporation and mitochondrial dehydrogenase activity. In contrast, iron salts and iron-saturated transferrin had no effect on captopril activity. Catalase and horseradish peroxidase nullified the cytotoxic effects of captopril/Cu++, whereas H2O2 mimicked those effects. These data are consistent with the notion of a copper-catalyzed oxidation of captopril, leading to the generation of H2O2 as the cytotoxin to this clinically important cell type.
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PMID:Mechanism of captopril toxicity to a human mammary ductal carcinoma cell line in the presence of copper. 1051 67

Oxygen free radicals, including hydrogen peroxide, may mediate oxidative stress in target organ tissues and contribute to cardiovascular complications in hypertension. To examine heritability of hydrogen peroxide production, we investigated this trait in a family-based cohort consisting of family members (n=236) ascertained through probands (n=57) with essential hypertension. Significant effects on hydrogen peroxide production were found for gender and ethnicity, with men having greater values than women (P<0.001) and white subjects having greater values than black subjects (P=0.025). Hydrogen peroxide production correlated directly with plasma renin activity (P=0.015), suggesting an important interaction between circulating oxygen radicals and the renin-angiotensin system and a potential mechanism for lower hydrogen peroxide values observed in blacks. Heritability estimates from familial correlations revealed that approximately 20% to 35% of the observed variance in hydrogen peroxide production could be attributed to genetic factors, suggesting a substantial heritable component to the overall determination of this trait. Hydrogen peroxide production negatively correlated with cardiac contractility (r=-0.214, P=0.001) and renal function (r=-0.194, P=0.003). In conclusion, these results indicate that hydrogen peroxide production is heritable and is related to target organ function in essential hypertension. Genetic loci influencing hydrogen peroxide production may represent logical candidates to investigate as susceptibility genes for cardiovascular target organ injury.
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PMID:Plasma hydrogen peroxide production in human essential hypertension: role of heredity, gender, and ethnicity. 1108 60

The role of the renin-angiotensin system in oxidative stress-induced apoptosis of endothelial cells (ECs) was investigated using a rat model and cultured ECs. EC apoptosis was induced by 5-minute intra-arterial treatment of a rat carotid artery with 0.01 mmol/L H2O2 and was evaluated at 24 hours by chromatin staining of en face specimens with Hoechst 33342. Although activity of angiotensin-converting enzyme in arterial homogenates was not increased, administration of an angiotensin-converting enzyme inhibitor temocapril for 3 days before H2O2 treatment inhibited EC apoptosis, followed by reduced neointimal formation 2 weeks later. Also, an angiotensin II type 1 (AT1) receptor blocker (olmesartan) inhibited EC apoptosis, whereas angiotensin II administration accelerated apoptosis independently of blood pressure. Next, cultured ECs derived from a bovine carotid artery were treated with H2O2 to induce apoptosis, as evaluated by DNA fragmentation. Combination of angiotensin II and H2O2 dose-dependently increased EC apoptosis and 8-isoprostane formation, a marker of oxidative stress. Conversely, temocapril and olmesartan reduced apoptosis and 8-isoprostane formation induced by H2O2, suggesting that endogenous angiotensin II interacts with H2O2 to elevate oxidative stress levels and EC apoptosis. Neither an AT2 receptor blocker, PD123319, affected H2O2-induced apoptosis, nor a NO synthase inhibitor, NG-nitro-L-arginine methyl ester, influenced the effect of temocapril on apoptosis in cell culture experiments. These results suggest that AT1 receptor signaling augments EC apoptosis in the process of oxidative stress-induced vascular injury.
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PMID:Renin-angiotensin system modulates oxidative stress-induced endothelial cell apoptosis in rats. 1586 41

Treatment of Wistar rats for 7 days with 1,3-dipropyl-8-sulfophenylxanthine (DPSPX), an antagonist of adenosine receptors, induces long-lasting hypertension associated with marked changes in vascular structure and reactivity and renin-angiotensin system activation. This study aimed at evaluating the role of oxidative stress in the development of DPSPX-induced hypertension and also at identifying the relative contribution of superoxide radical (O2.-) vs hydrogen peroxide (H2O2). Vascular and systemic prooxidant/antioxidant status was evaluated in sham (saline, i.p., 7 days) and DPSPX (90 microg/kg/h, i.p., 7 days)-treated rats. Systolic blood pressure was determined by invasive and non-invasive methods. The activity of vascular NADPH oxidase, superoxide dismutase (SOD), catalase and glutathione peroxidase was assayed by fluorometric/spectrophotometric methods. H2O2 levels were measured using an Amplex Red Hydrogen Peroxide kit. Plasma thiobarbituric acid reactive substances and plasma antioxidant capacity were also measured. In addition we tested the effects of antioxidants or inhibitors of reactive oxygen species generation on blood pressure, vascular hyperplasia and oxidative stress parameters. DPSPX-hypertensive rats showed increased activity of vascular NADPH oxidase, SOD, catalase and glutathione peroxidase, as well as increased H2O2 generation. DPSPX-hypertensive rats also had increased plasma lipid peroxidation and decreased plasma antioxidant capacity. Treatment with apocynin (1.5 mmol/l, per os, 14 days), or with polyethylene glycol (PEG)-catalase (10,000 U/kg/day, i.p., 8 days), prevented the DPSPX-induced effects on blood pressure, vascular structure and H2O2 levels. Tempol (3 mmol/l, per os, 14 days) failed to inhibit these changes, unless PEG-catalase was co-administered. It is concluded that O2.- generation with subsequent formation of H2O2 plays a major role in the development of DPSPX-induced hypertension.
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PMID:Role of superoxide and hydrogen peroxide in hypertension induced by an antagonist of adenosine receptors. 1851 34

Intrarenal renin-angiotensin system (RAS) activation plays a critical role in the development and progression of renal injury. In the kidney, all of the RAS components are present and intrarenal angiotensin II (Ang II) is formed by multiple independent mechanisms. Angiotensinogen (AGT) is the only known substrate for renin that is a rate-limiting enzyme of the RAS. Recently, enhanced intrarenal AGT levels have been shown to reflect the intrarenal RAS status in hypertension, chronic glomerular disease and diabetic nephropathy. In this review, we focus on AGT expression of the diseased glomeruli in the progression of glomerular disease. An anti-glomerular basement membrane nephritis rat model developed progressive proteinuria and glomerular crescent formation, accompanied by increased macrophage infiltration and glomerular expression of AGT and Ang II. The addition of Ang II type 1 receptor blocker to CC-chemokine recaptor 2 antagonist markedly attenuated the induction of macrophage infiltration, AGT and Ang II, and reduced glomerular crescent formation. Next, the levels of glomerular AGT expression and marker of reactive oxygen species in Zucker diabetic fatty (ZDF) obese rats were higher than those in ZDF lean rats. Hydrogen peroxide (H(2)O(2)) induced an increase in the AGT expression in primary rat mesangial cells. Furthermore, the H(2)O(2)-induced upregulation of AGT was inhibited by a mitogen-activated protein kinase kinase and a c-Jun N-terminal kinase inhibitor. These data suggest the potential contribution of enhanced AGT expression in glomeruli to the intrarenal RAS activation for the development of glomerular disease.
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PMID:Angiotensinogen Expression Is Enhanced in the Progression of Glomerular Disease. 2224 11


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