Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.6.3.1 (NADPH oxidase)
11,281 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Studies were performed to test the hypothesis that the angiotensin-converting enzyme (ACE)/epidermal growth factor receptor (EGFR)/extracellular signal-regulated kinases (ERK) pathway, nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase/lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) pathway, and Rho-kinase pathway contribute to the pathogenesis of aldosterone/salt-induced hypertensive rats. Wistar rats were given 1% NaCl to drink and treated with one of the following combinations for 6 weeks: vehicle; aldosterone (0.75 microg/h); aldosterone plus a mineralocorticoid receptor antagonist, spironolactone (20 mg/kg/day); aldosterone plus an ACE inhibitor, imidapril (1 mg/kg/day); aldosterone plus an NAD(P)H oxidase inhibitor, apocynin (0.5 mmol/l); and aldosterone plus an Rho-kinase inhibitor, Y-27632 (3 mg/kg/day). Upregulated expression of ACE and EGFR and p44/p42ERK phosphorylation were suppressed by spironolactone or imidapril. Upregulated NAD(P)H oxidase subunits and LOX-1 expression were inhibited by spironolactone or apocynin. Increased expression of RhoA and Rho-kinase and myosin light chain phosphorylation were decreased by spironolactone or Y-27632. Moreover, these drugs effectively inhibited the vascular lesion formation, as measured by the medial thickness and level of perivascular fibrosis, and suppressed the expression of transforming growth factor-beta1, type I and III collagen, and monocyte chemoattractant protein-1 mRNA. Spironolactone may be useful as a cardioprotective agent to prevent cardiovascular remodeling via the ACE/EGFR/ERK, NAD(P)H oxidase/LOX-1, and Rho-kinase pathways.
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PMID:Cardioprotective mechanisms of spironolactone associated with the angiotensin-converting enzyme/epidermal growth factor receptor/extracellular signal-regulated kinases, NAD(P)H oxidase/lectin-like oxidized low-density lipoprotein receptor-1, and Rho-kinase pathways in aldosterone/salt-induced hypertensive rats. 1655 82

Angiotensin (ANG) II (AngII) and aldosterone contribute to the development of interstitial cardiac fibrosis. We investigated the potential role of a Nox2-containing NADPH oxidase in aldosterone-induced fibrosis and the involvement of this mechanism in AngII-induced effects. Nox2-/- mice were compared with matched wild-type controls (WT). In WT mice, subcutaneous (s.c.) AngII (1.1 mg/kg/day for 2 wk) significantly increased NADPH oxidase activity, interstitial fibrosis (11.5+/-1.0% vs. 7.2+/-0.7%; P<0.05), expression of fibronectin, procollagen I, and connective tissue growth factor mRNA, MMP-2 activity, and NF-kB activation. These effects were all inhibited in Nox2-/- hearts. The mineralocorticoid receptor antagonist spironolactone inhibited AngII-induced increases in NADPH oxidase activity and the increase in interstitial fibrosis. In a model of mineralocorticoid-dependent hypertension involving chronic aldosterone infusion (0.2 mg/kg/day) and a 1% Na Cl diet ("ALDO"), WT animals exhibited increased NADPH oxidase activity, pro-fibrotic gene expression, MMP-2 activity, NF-kB activation, and significant interstitial cardiac fibrosis (12.0+/-1.7% with ALDO vs. 6.3+/-0.3% without; P<0.05). These effects were inhibited in Nox2-/- ALDO mice (e.g., fibrosis 6.8+/-0.8% with ALDO vs. 5.8+/-1.0% without ALDO; P=NS). These results suggest that aldosterone-dependent activation of a Nox2-containing NADPH oxidase contributes to the profibrotic effect of AngII in the heart as well as the fibrosis seen in mineralocorticoid-dependent hypertension.
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PMID:Aldosterone mediates angiotensin II-induced interstitial cardiac fibrosis via a Nox2-containing NADPH oxidase. 1672 Jul 35

The renin-angiotensin-aldosterone system contributes to cardiac remodeling, hypertrophy, and left ventricular dysfunction. Angiotensin II and aldosterone (corticosterone in rodents) together generate reactive oxygen species (ROS) via reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which likely facilitate this hypertrophy and remodeling. This investigation sought to determine whether cardiac oxidative stress and cellular remodeling could be attenuated by in vivo mineralocorticoid receptor (MR) blockade in a rodent model of the chronically elevated tissue renin-angiotensin-aldosterone system, the transgenic TG (mRen2) 27 rat (Ren2). The Ren2 overexpresses the mouse renin transgene with resultant hypertension, insulin resistance, proteinuria, and cardiovascular damage. Young (6- to 7-wk-old) male Ren2 and age-matched Sprague-Dawley rats were treated with spironolactone or placebo for 3 wk. Heart tissue ROS, immunohistochemical analysis of 3-nitrotyrosine, and NADPH oxidase (NOX) subunits (gp91(phox) recently renamed NOX2, p22(phox), Rac1, NOX1, and NOX4) were measured. Structural changes were assessed with cine-magnetic resonance imaging, transmission electron microscopy, and light microscopy. Significant increases in Ren2 septal wall thickness (cine-magnetic resonance imaging) were accompanied by perivascular fibrosis, increased mitochondria, and other ultrastructural changes visible by light microscopy and transmission electron microscopy. Although there was no significant reduction in systolic blood pressure, significant improvements were seen with MR blockade on ROS formation and NOX subunits (each P < 0.05). Collectively, these data suggest that MR blockade, independent of systolic blood pressure reduction, improves cardiac oxidative stress-induced structural and functional changes, which are driven, in part, by angiotensin type 1 receptor-mediated increases in NOX.
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PMID:Mineralocorticoid receptor blockade attenuates chronic overexpression of the renin-angiotensin-aldosterone system stimulation of reduced nicotinamide adenine dinucleotide phosphate oxidase and cardiac remodeling. 1749 96

It has been well appreciated that aldosterone (Aldo) plays a direct profibrotic role in the kidney but the underlying mechanism is unclear. We examined the role of Aldo in epithelial-mesenchymal transition (EMT) both in vitro and in vivo. Exposure of human renal proximal tubular cells to Aldo for 48 h dose dependently induced EMT as evidenced by conversion to the spindle-like morphology, loss of E-cadherin, and de novo expression of alpha-smooth muscle actin (SMA); the effect was noticeable at 50 nM and maximal at 100 nM. The EMT was completely blocked by the selective mineralocorticoid receptor (MR) antagonist eplerenone. Aldo time dependently increased intracellular reactive oxygen species (ROS) production that was detectable at 15 min and peaked (2.3-fold) at 60 min, as assessed by 2',7'-dichlorofluorescin diacetate fluorescence. Aldo-induced oxidative stress and EMT were both abolished by the mitochondrial respiratory chain complex I inhibitor rotenone, but not the NADPH oxidase inhibitor apocynin. Aldo induced phosphorylation of ERK1/2 that was completely blocked by rotenone. Male 129-C57/BL6 mice were treated with deoxycorticosterone acetate (DOCA) salt (subcutaneous implantation of 50 mg of DOCA pellet plus 1% NaCl as drinking fluid) for 3 wk and animals were treated with vehicle or rotenone (600 ppm in diet) for the last week. DOCA salt induced a 2.5-fold increase in alpha-SMA and a 30% reduction of E-cadherin, as assessed by real-time RT-PCR, that were both restricted to renal epithelial cells, as determined by immunohistochemistry. In contrast, DOCA salt-induced changes in alpha-SMA and E-cadherin were completely blocked by treatment with rotenone. These observations suggest that Aldo induces EMT via MR-mediated, mitochondrial-originated, ROS-dependent ERK1/2 activation in renal tubular epithelial cells.
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PMID:Aldosterone induces epithelial-mesenchymal transition via ROS of mitochondrial origin. 1759 22

Aldosterone is involved in many cardiovascular diseases with increased oxidative stress. Aldosterone-induced cardiac fibrosis is abolished by blockade of angiotensin II Type-1 (AT1) receptor. Recently, non-genomic vasoconstrictor effects of aldosterone were reported in various vascular beds. We tested the hypothesis that aldosterone stimulates angiotensin AT1 receptor, and causes vasoconstriction by increasing oxidative stress in coronary microcirculation. Coronary arterioles (60-120 microm) were isolated from spontaneously hypertensive rats (SHR) and control Wistar Kyoto (WKY) rats, aged 23-26 weeks. They were cannulated, and pressurized at 60 cm H2O. Effect of aldosterone (10(-15) to 10(-6) M) on coronary arteriolar diameter was examined. Aldosterone rapidly and dose-dependently decreased coronary arteriolar diameter in WKY rats and SHR (diameter changes, 8.4+/-0.7% vs 13.9+/-0.8%, P<0.05). Aldosterone-induced vasoconstriction was enhanced by 1.6-folds in SHR compared to WKY rats (P<0.05). Mineralocorticoid receptor antagonist spironolactone (10(-6) M) did not influence aldosterone-induced vasoconstriction. Selective angiotensin AT1 receptor blocker valsartan (10(-4) M) or candesartan (10(-7) M) abolished aldosterone-induced vasoconstriction. Similarly, superoxide dismutase (SOD, 300 U/ml), and NADPH oxidase inhibitor apocynin (10(-4) M) abolished it. Moreover, the vasoconstrictor effect of aldosterone disappeared in denuded vessels. Real-time quantitative RT-PCR revealed that angiotensin AT1 receptor mRNA level in coronary arterioles of SHR was upregulated by 1.5-folds compared to that in WKY rats (P<0.05). Aldosterone causes vasoconstriction in coronary arterioles, and this vasoconstrictor effect is enhanced by genetically defined hypertension. Aldosterone-induced vasoconstriction is mediated by angiotensin AT1 receptor presumably via oxidative stress.
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PMID:Aldosterone causes vasoconstriction in coronary arterioles of rats via angiotensin II type-1 receptor: influence of hypertension. 1764 87

Recent clinical studies have indicated the utility of mineralocorticoid receptor (MR) antagonists in cardiovascular and renal injuries. Chronic treatment with aldosterone/salt resulted in severe cardiac and renal injuries in rats. Further studies showed that the aldosterone-induced organ injuries were associated with increases in expression of NADPH oxidase components and reactive oxygen species (ROS) levels. Treatment with a selective MR antagonist, eplerenone, prevented the elevation of ROS levels and ameliorated organ injuries. In vitro studies also showed that MR is highly expressed in cultured vascular smooth muscle cells, glomerular mesangial cells and renal fibroblasts. In these cells, aldosterone-induced cell injuries were associated with increases in NADPH oxidase activity and superoxide generation. Further, the aldosterone-dependent cell injuries were markedly attenuated by treatment with eplerenone. These accumulating data support the notion that the aldosterone/MR is involved in the pathogenesis of cardiovascular and renal injuries through NADPH oxidase-dependent ROS production.
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PMID:[Role of aldosterone in oxidative stress and renal injury]. 1782 15

Although the pro-inflammatory and pro-fibrotic actions of aldosterone on the vasculature have been reported, the effects and molecular mechanisms of aldosterone on endothelial function are yet to be determined. We investigated how aldosterone regulates endothelial nitric oxide synthase (eNOS) function in human umbilical vein endothelial cells (HUVECs). HUVECs were incubated for 16 hrs with 10(-7) mol/l of aldosterone. The concentration of reactive oxygen species (ROS) was estimated by measuring DCF chemiluminescence. Signal transduction was estimated by Western immunoblots. Realtime RT-PCR was performed to measure expression of transcripts of endogenous GTP cyclohydrolase-1 (GCH1) and components of NAD(P)H oxidase. In order to eliminate the possible effect of the glucocorticoid receptor (GR), and to emphasize the role of mineralocorticoid receptor (MR), we used GR siRNA and knocked down GR expression in several experiments. NO output was estimated by intracellular cGMP concentration. ROS production increased significantly in aldosterone-treated HUVEC, but was abolished by pre-treatment with eplerenone. Transcripts of p47(phox) were increased by aldosterone treatment. Vascular endothelial growth factor (VEGF)-induced eNOS Ser 1177 but not Akt Ser 473 phosphorylation levels were reduced significantly by pretreatment with aldosterone. Pretreatment with either eplerenone or okadaic acid restored phosphorylation levels of eNOS Ser 1177 in aldosterone-treated cells, suggesting that protein phosphatase (PP) 2A was upregulated by aldosterone via MR. The decrease in NO output caused by aldosterone pretreatment was reversed significantly by either 5,6,7,8-tetrahydrobiopterin (BH(4)), GCH1 overexpression, or p47(phox) knockdown. These results suggest that aldosterone inhibits eNOS function through bimodal mechanisms of BH(4) deficiency and PP2A activation.
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PMID:[Molecular mechanism of cardiovascular damage induced by aldosterone]. 1782 16

Mineralocorticoid receptor blockade improves mortality early after myocardial infarction (MI). This study investigated the vascular effects of mineralocorticoid receptor blockade in the early phase postinfarction in rats. Starting immediately after coronary ligation, male Wistar rats were treated with placebo or eplerenone (100 mg/kg/d). After 7 days, hemodynamic assessment was performed and endothelial function was determined. Maximum acetylcholine-induced relaxation was significantly attenuated in aortic rings from rats with heart failure after MI, and ameliorated by eplerenone treatment. Endothelium-independent relaxation by DEA-NONOate was similar among the groups. Endothelial NO synthase phosphorylation was reduced in the aorta of MI rats and restored by eplerenone therapy. Angiotensin I-induced vasoconstriction as well as angiotensin-converting enzyme protein levels were enhanced in aortas from MI placebo rats, and reduced by mineralocorticoid receptor inhibition. Aortic reactive oxygen species formation as well as the expression of the NAD(P)H oxidase subunit p22(phox) were increased after MI and normalized in eplerenone treated rats. In conclusion, mineralocorticoid receptor antagonism improved endothelial dysfunction in the early phase post-MI. Underlying mechanisms involve inhibition of vascular angiotensin-converting enzyme upregulation and improvement of endothelial NO synthase-derived NO bioavailability.
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PMID:Mineralocorticoid receptor blockade improves vasomotor dysfunction and vascular oxidative stress early after myocardial infarction. 1787 16

This study evaluated the effects of aldosterone upon Na+/H+ exchange (NHE) activity in immortalized proximal tubular epithelial (PTE) cells from the spontaneously hypertensive rat (SHR) and the normotensive controls (Wistar Kyoto rat; WKY). Increases in NHE activity after exposure to aldosterone occurred in time- and concentration-dependent manner in SHR PTE cells, but not in WKY PTE cells. The aldosterone-induced increases in NHE activity were prevented by spironolactone, but not by the glucocorticoid receptor antagonist Ru 38486. The presence of the mineralocorticoid receptor transcript was confirmed by PCR and NHE1, NHE2, and NHE3 proteins were detected by immunoblot analysis. Cariporide and EIPA, but not S3226, inhibited the aldosterone-induced increase in NHE activity, indicating that NHE1 is the most likely involved NHE isoform. Pretreatment of SHR PTE cells with actinomycin D attenuated the aldosterone-induced increases in NHE activity. The SHR PTE cells had an increased rate of H2O2 production when compared with WKY PTE cells. Treatment of cells with apocynin, a NADPH oxidase inhibitor, markedly reduced the rate of H2O2 production. The aldosterone-induced increase in NHE activity SHR PTE cells was completely prevented by apocynin. In conclusion, the aldosterone-induced stimulation of NHE1 activity is a genomic event unique in SHR PTE cells, which involves the activation of the mineralocorticoid receptor, but ultimately requires the availability of H2O2 in excess.
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PMID:Oxidative stress and the genomic regulation of aldosterone-stimulated NHE1 activity in SHR renal proximal tubular cells. 1809 44

Aldosterone is traditionally viewed as a hormone regulating electrolyte and blood pressure homeostasis by acting on the distal nephron. Accumulating evidence suggests that aldosterone also plays pathogenetic roles in cardiovascular and renal injury. For example, aldosterone is a potent inducer of proteinuria. We demonstrated that podocyte injury underlies the pathogenesis of proteinuria in aldosterone-infused rats on a high salt diet. Mineralocorticoid receptor was detected in the podocytes in vivo and in vitro, and aldosterone caused induction of its effector kinase Sgk1, activation of NADPH oxidase and generation of reactive oxygen species. Selective aldosterone blocker eplerenone, as well as antioxidant tempol, ameliorated aldosterone-induced podocyte injury and proteinuria. Aldosterone was also involved in the podocyte damage and proteinuria of metabolic syndrome model SHR/NDmcr-cp. Adipocyte-derived aldosterone releasing factors were suggested to contribute to the aldosterone excess of this model. Furthermore, high salt diet markedly worsened the renal injury of SHR/NDmcr-cp. Although salt lowered serum aldosterone levels, it caused MR activation in the kidney. Accordingly, eplerenone dramatically improved the salt-evoked nephropathy. Taken together, aldosterone blockers can be an excellent therapeutic strategy for the treatment of podocyte injury, proteinuria, and cardiovascular and renal complications, not only in high aldosterone states but also in patients with activated MR signaling in the target tissue, whose circulating aldosterone level is not necessarily high. Addition of aldosterone blockers in patients treated with ACEIs or ARBs are also promising, because of "aldosterone breakthrough" phenomenon. Careful monitoring of hyperkalemia is necessary, especially in patients with impaired renal function.
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PMID:Aldosterone and glomerular podocyte injury. 1831 76


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