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:1.6.99.6 (NADPH oxidase)
10,295 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiotensin II (Ang II) and reactive oxidative species (ROS) that are produced by NADPH oxidase have been implicated in the progression of glomerulonephritis (GN). This study examined the effect of simultaneously interrupting Ang II and ROS with an Ang II receptor blocker (ARB), candesartan, and a free radical scavenger, probucol, in a model of progressive mesangioproliferative GN induced by the injection of anti-Thy-1 antibody into uninephrectomized rats. Nephritic rats were divided into four groups and given daily oral doses of the following: Vehicle, 1% probucol diet, 70 mg/L candesartan in drinking water, and probucol plus candesartan. These treatments lasted until day 56. Vehicle-treated nephritic rats developed progressively elevated proteinuria and glomerulosclerosis. Candesartan kept proteinuria significantly lower than vehicle or probucol. The addition of probucol to candesartan normalized urinary protein excretion. Increases in BP in nephritic rats were lowered by these treatments, except with probucol. It is interesting that both glomerular cell number and glomerulosclerosis were significantly decreased by candesartan and normalized by the addition of probucol. Immunohistochemical studies for TGF-beta1, collagen type I, and fibronectin revealed that the combined treatment abolished glomerular fibrotic findings compared with candesartan. In addition, glomerular expression of NADPH oxidase components and superoxide production suggested that the combined treatment completely eliminated NADPH oxidase-associated ROS production. In conclusion, our study provides the first evidence that the antioxidant probucol, when added to an Ang II receptor blockade, fully arrests proteinuria and disease progression in GN. Furthermore, the data suggest that NADPH oxidase-associated ROS production may play a pivotal role in the progression of GN. The combination of probucol and candesartan may represent a novel route of therapy for patients with progressive GN.
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PMID:Addition of the antioxidant probucol to angiotensin II type I receptor antagonist arrests progressive mesangioproliferative glomerulonephritis in the rat. 1646 49

The matrix fibronectin protein plays an important role in vascular remodeling. Notoginsenoside R1 is the main ingredient with cardiovascular activity in Panax notoginseng; however, its molecular mechanisms are poorly understood. We report that notoginsenoside R1 significantly decreased TNF-alpha-induced activation of fibronectin mRNA, protein levels, and secretion in human arterial smooth muscle cells (HASMCs) in a dose-dependent manner. Notoginsenoside R1 scavenged hydrogen peroxide (H2O2) in a dose-dependent manner in the test tube. TNF-alpha significantly increased intracellular ROS generation and then ERK activation, which was blocked by notoginsenoside R1 or DPI and apocynin, inhibitors of NADPH oxidase, or the antioxidant NAC. Our data demonstrated that TNF-alpha-induced upregulation of fibronectin mRNA and protein levels occurs via activation of ROS/ERK, which was prevented by treatment with notoginsenoside R1, DPI, apocynin, NAC, or MAPK/ERK inhibitors PD098059 and U0126. Notoginsenoside R1 significantly inhibited H2O2-induced upregulation of fibronectin mRNA and protein levels and secretion; it also significantly inhibited TNF-alpha and H2O2-induced migration. These results suggest that notoginsenoside R1 inhibits TNF-alpha-induced ERK activation and subsequent fibronectin overexpression and migration in HASMCs by suppressing NADPH oxidase-mediated ROS generation and directly scavenging ROS.
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PMID:Notoginsenoside R1 inhibits TNF-alpha-induced fibronectin production in smooth muscle cells via the ROS/ERK pathway. 1663 26

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

We examined the effects of adrenomedullin on cardiac oxidative stress and collagen accumulation in aldosterone-dependent malignant hypertensive rats. Spontaneously hypertensive rats (SHRs) were treated with one of the following combinations for 4 weeks: tap water and vehicle [0.5% ethanol, subcutaneously (s.c.), n = 5], 1% NaCl in drinking water and vehicle (n = 8), 1% NaCl and aldosterone (0.75 microg/h s.c., n = 8), and 1% NaCl, aldosterone, and adrenomedullin (1.3 microg/kg/h s.c., n = 8). Systolic blood pressure (SBP) and left ventricular (LV) weight were higher in aldosterone-treated SHRs than vehicle- or vehicle/1% NaCl-treated SHRs. Thiobarbituric acid reactive substances (TBARS) levels and NADPH oxidase activity in LV tissues of aldosterone-treated SHRs were also higher than those of vehicle- or vehicle/1% NaCl-treated SHRs, and these changes were associated with increases in LV mRNA levels of p22phox, gp91phox, fibronectin, collagen types I and III, as well as collagen content. Treatment with adrenomedullin did not alter SBP or LV weight but attenuated aldosterone-induced increases in TBARS levels, NADPH oxidase activity, and mRNA levels of p22phox, gp91phox, fibronectin, collagen types I and III, as well as collagen content in LV tissues. These data suggest that NADPH oxidase-mediated reactive oxygen species production is involved in the pathogenesis of cardiac collagen accumulation in aldosterone-dependent malignant hypertensive rats and that the cardioprotective effects of adrenomedullin are mediated through the suppression of this pathway.
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PMID:Effects of adrenomedullin on cardiac oxidative stress and collagen accumulation in aldosterone-dependent malignant hypertensive rats. 1677 97

Cigarette smoke (CS) is the most important source of preventable morbidity and mortality in the United States. Recent clinical studies have suggested that, in addition to being a major cardiovascular risk factor, CS promotes the progression of kidney disease. The mechanisms by which CS promotes the progression of chronic kidney disease have not been elucidated. Here we demonstrate for the first time that human mesangial cells (MCs) are endowed with the nicotinic ACh receptors (nAChRs) alpha4, alpha5, alpha7, beta2, beta3, and beta4. Studies performed in other cell types have shown that these nAChRs are ionotropic receptors that function as agonist-regulated Ca(2+) channels. Nicotine induced MC proliferation in a dose-dependent manner. At 10 (-7) M, a concentration found in the plasma of active smokers, nicotine induced MC proliferation [control, 1,328 +/- 50 vs. nicotine, 2,761 +/- 90 counts/minute (cpm); P < 0.05] and increased the synthesis of fibronectin (50%), a critical matrix component involved in the progression of chronic kidney disease. We and others have shown that, in response to PKC activation, MC synthesize reactive oxygen species (ROS) via NADPH oxidase. In the current studies we demonstrate that PKC inhibition as well as diphenyleneiodonium and apocynin, two inhibitors of NADPH oxidase, prevented the effects of nicotine on MC proliferation and fibronectin production, hence establishing ROS as second messengers of the actions of nicotine. Furthermore, nicotine increased the production of ROS as assessed by 2',7'-dichlorofluorescein diacetate fluorescence [control, 184.4 +/- 26 vs. nicotine, 281.5 +/- 26 arbitrary fluorescence units (AFU); n = 5 experiments, P < 0.05]. These studies unveil previously unrecognized mechanisms that indict nicotine, a component of CS, as an agent that may accelerate and promote the progression of kidney disease.
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PMID:Nicotine: the link between cigarette smoking and the progression of renal injury? 1692 Jul 99

Grancalcin is a protein specifically expressed in neutrophils and monocytes/macrophages. The function of grancalcin has not been identified. Grancalcin-deficient neutrophils were previously demonstrated to exert normal recruitment to the inflamed site, NADPH oxidase activation, extracellular release of secondary granules, apoptosis and activation-induced Ca2+ flux. In this study we analyzed granule numbers in resting and activated grancalcin-deficient neutrophils, their phagocytic activity and adherence to extracellular matrix proteins. Results revealed normal phagocytosis and degranulation of grancalcin-deficient neutrophils, while their adhesion to fibronectin was decreased by 60%. Consistently, the processes associated with neutrophil adhesion, such as formation of focal adhesion complexes and spreading, were also impaired in grancalcin-deficient neutrophils by 89 and 38%, respectively. In contrast, adherence to other extracellular matrix proteins: collagen, laminin and vitronectin, was not significantly altered. We thus report for the first time a function of grancalcin.
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PMID:The role of grancalcin in adhesion of neutrophils. 1693 89

The molecular details linking integrin engagement to downstream cortactin (Ctn) tyrosine phosphorylation are largely unknown. In this report, we show for the first time that Fer and Ctn are potently tyrosine phosphorylated in response to hydrogen peroxide (H2O2) in a variety of cell types. Working with catalytically inactive fer and src/yes/fyn-deficient murine embryonic fibroblasts (ferDR/DR and syf MEF, respectively), we observed that H2O2-induced Ctn tyrosine phosphorylation is primarily dependent on Fer but not Src family kinase (SFK) activity. We also demonstrated for the first time that Fer is activated by fibronectin engagement and, in concert with SFKs, mediates Ctn tyrosine phosphorylation in integrin signaling pathways. Reactive oxygen species (ROS) scavengers or the NADPH oxidase inhibitor, diphenylene iodonium, attenuated integrin-induced Fer and Ctn tyrosine phosphorylation. Taken together, these findings provide novel genetic evidence that a ROS-Fer signaling arm contributes to SFK-mediated Ctn tyrosine phosphorylation in integrin signaling. Lastly, a migration defect in ferDR/DR MEF suggests that integrin signaling through the ROS-Fer-Ctn signaling arm may be linked to mechanisms governing cell motility. These data demonstrate for the first time an oxidative link between integrin adhesion and an actin-binding protein involved in actin polymerization.
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PMID:Fer-mediated cortactin phosphorylation is associated with efficient fibroblast migration and is dependent on reactive oxygen species generation during integrin-mediated cell adhesion. 1760 29

Renal nicotinamide adenine dinucleotide phosphate reduced form (NADPH) oxidase is an important source of oxidative stress and its expression is enhanced in the glomerulus and distal tubules of diabetic nephropathy. High glucose-induced protein kinase C signalling or renal angiotensin II signalling increases the membrane translocation of cytosolic component p47phox. NADPH oxidase-derived reactive oxygen species (ROS) in the podocytes damage the glomerular basement membrane and the slit diaphragm causing proteinuria, and mesangial and glomerular endothelial NADPH oxidase increase TGF-beta and cause collagen and fibronectin accumulation. Tubular NADPH oxidase stimulated by angiotensin II or aldosterone contributes to sodium retention and to tubulointerstitial damage. Thus, inhibition of the renal renin-angiotensin II-aldosterone system with angiotensin-converting enzyme inhibitor, angiotensin II type 1 receptor blocker or selective aldosterone inhibitor indirectly suppresses NADPH oxidase reducing renal ROS, proteinuria and glomerulosclerosis. Statins are also effective in blocking the membrane translocation of Rac, especially in diabetes with hypercholesterolemia where ROS is produced by the intrinsic NADPH oxidase and by the activated macrophages. A medical herb, picrorhiza, inhibits the membrane translocation of p47phox, is a specific inhibitor of NADPH oxidase and, more so than superoxide dismutase mimetics, may be a promising strategy for the treatment of diabetic nephropathy.
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PMID:Suppressing renal NADPH oxidase to treat diabetic nephropathy. 1766 74

The role of glomerular SREBP-1c in diabetic nephropathy was investigated. PEPCK-promoter transgenic mice overexpressing nuclear SREBP-1c exhibited enhancement of proteinuria with mesangial proliferation and matrix accumulation, mimicking diabetic nephropathy, despite the absence of hyperglycemia or hyperlipidemia. Isolated transgenic glomeruli had higher expression of TGFbeta-1, fibronectin, and SPARC in the absence of marked lipid accumulation. Gene expression of P47phox, p67phox, and PU.1 were also activated, accompanying increased 8-OHdG in urine and kidney, demonstrating that glomerular SREBP-1c could directly cause oxidative stress through induced NADPH oxidase. Similar changes were observed in STZ-treated diabetic mice with activation of endogenous SREBP-1c. Finally, diabetic proteinuria and oxidative stress were ameliorated in SREBP-1-null mice. Adenoviral overexpression of active and dominant-negative SREBP-1c caused consistent reciprocal changes in expression of both profibrotic and oxidative stress genes in MES13 mesangial cells. These data suggest that activation of glomerular SREBP-1c could contribute to emergence and/or progression of diabetic nephropathy.
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PMID:Involvement of glomerular SREBP-1c in diabetic nephropathy. 1796 14

The Ras-related GTPases Rap1a and 1b have been implicated in multiple biological events including cell adhesion, free radical production, and cancer. To gain a better understanding of Rap1 function in mammalian physiology, we deleted the Rap1a gene. Although loss of Rap1a expression did not initially affect mouse size or viability, upon backcross into C57BL/6J mice some Rap1a-/- embryos died in utero. T cell, B cell, or myeloid cell development was not disrupted in Rap1a-/- mice. However, macrophages from Rap1a null mice exhibited increased haptotaxis on fibronectin and vitronectin matrices that correlated with decreased adhesion. Chemotaxis of lymphoid and myeloid cells in response to CXCL12 or CCL21 was significantly reduced. In contrast, an increase in FcR-mediated phagocytosis was observed. Because Rap1a was previously copurified with the human neutrophil NADPH oxidase, we addressed whether GTPase loss affected superoxide production. Neutrophils from Rap1a-/- mice had reduced fMLP-stimulated superoxide production as well as a weaker initial response to phorbol ester. These results suggest that, despite 95% amino acid sequence identity, similar intracellular distribution, and broad tissue distribution, Rap1a and 1b are not functionally redundant but rather differentially regulate certain cellular events.
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PMID:Rap1a null mice have altered myeloid cell functions suggesting distinct roles for the closely related Rap1a and 1b proteins. 1805 77


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