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)

We examined the role of epidermal growth factor (EGF) receptor in the pathogenesis of leptin-induced hypertension in the rat. Leptin, administered in increasing doses (0.1-0.5 mg/kg/day) for 10 days, increased phosphorylation levels of non-receptor tyrosine kinase, c-Src, EGF receptor and extracellular signal-regulated kinases (ERK) in aorta and kidney, which was accompanied by the increase in plasma concentration and urinary excretion of isoprostanes and H2O2. Blood pressure and renal Na+,K+-ATPase activity were higher, whereas urinary sodium excretion was lower in animals receiving leptin. The effects of leptin on renal Na+,K+-ATPase, natriuresis and blood pressure were abolished by NADPH oxidase inhibitor, apocynin, Src kinase inhibitor, PP2, EGF receptor inhibitor, AG1478, protein farnesyltransferase inhibitor, manumycin A, and ERK inhibitor, PD98059. In contrast, inhibitors of insulin-like growth factor-1 and platelet-derived growth factor receptors, AG1024 and AG1295, respectively, only slightly reduced ERK phosphorylation and had no effect on blood pressure in rats receiving leptin. These data indicate that: (1) experimental hyperleptinemia is associated with oxidative stress and c-Src-dependent transactivation of the EGF receptor, which stimulates ERK in vascular wall and the kidney, (2) overactivity of EGF receptor-ERK pathway contributes to leptin-induced hypertension by stimulating renal Na+,K+-ATPase and reducing sodium excretion, (3) inhibitors of c-Src, EGF receptor and ERK may be considered as a novel therapy for hypertension associated with hyperleptinemia, e.g. in patients with obesity and metabolic syndrome.
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PMID:Transactivation of epidermal growth factor receptor in vascular and renal systems in rats with experimental hyperleptinemia: role in leptin-induced hypertension. 1828 56

The phagocyte NADPH oxidase (NOX2) is critical for the bactericidal activity of phagocytic cells and plays a major role in innate immunity. We showed recently that NOX2 activity in mouse dendritic cells (DCs) prevents acidification of phagosomes, promoting antigen cross-presentation. In order to investigate the role of NOX2 in the regulation of the phagosomal pH in human DCs, we analyzed the production of reactive oxygen species (ROS) and the phagosomal/endosomal pH in monocyte-derived DCs and macrophages (M(diameter)s) from healthy donors or patients with chronic granulomatous disease (CGD). As expected, we found that human M(diameter)s acidify their phagosomes more efficiently than human DCs. Accordingly, the expression of the vacuolar proton ATPase (V-H(+)-ATPase) was higher in M(diameter)s than in DCs. Phagosomal ROS production, however, was also higher in M(diameter)s than in DCs, due to higher levels of gp91phox expression and recruitment to phagosomes. In contrast, in the absence of active NOX2, the phagosomal and endosomal pH decreased. Both in the presence of a NOX2 inhibitor and in DCs derived from patients with CGD, the cross-presentation of 2 model tumor antigens was impaired. We conclude that NOX2 activity participates in the regulation of the phagosomal and endosomal pH in human DCs, and is required for efficient antigen cross-presentation.
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PMID:NADPH oxidase controls phagosomal pH and antigen cross-presentation in human dendritic cells. 1902 53

Previously, we have demonstrated that leptin increases blood pressure (BP) in the rats through two oxidative stress-dependent mechanisms: stimulation of extracellular signal-regulated kinases (ERK) by H(2)O(2) and scavenging of nitric oxide (NO) by superoxide (O(2-.)). Herein, we examined if renal glutathione system and antioxidant enzymes determine the mechanism of prohypertensive effect of leptin. Leptin administered at 0.5 mg/kg/day for 4 or 8 days increased BP and renal Na(+),K(+)-ATPase activity and reduced fractional sodium excretion; these effects were prevented by NADPH oxidase inhibitor, apocynin. Superoxide scavenger, tempol, abolished the effect of leptin on BP and renal Na(+) pump in rats receiving leptin for 8 days, whereas ERK inhibitor, PD98059, was effective in animals treated with leptin for 4 days. Leptin administered for 4 days decreased glutathione (GSH) and increased glutathione disulfide (GSSG) in the kidney. In animals receiving leptin for 8 days GSH returned to normal level, which was accompanied by up-regulation of gamma-glutamylcysteine synthetase (gamma-GCS), a rate-limiting enzyme of the GSH biosynthetic pathway. In addition, superoxide dismutase (SOD) activity was decreased, whereas glutathione peroxidase (GPx) was increased in rats receiving leptin for 8 days. Cotreatment with gamma-GCS inhibitor, buthionine sulfoximine (BSO), accelerated, whereas GSH precursor, N-acetylcysteine (NAC), attenuated leptin-induced changes in gamma-GCS, SOD, and GPx. In addition, coadministration of BSO changed the mechanism of BP elevation from H(2)O(2)-ERK to (O(2-.))-NO dependent in animals receiving leptin for 4 days, whereas NAC had the opposite effect in rats treated with leptin for 8 days. These results suggest that initial change in GSH redox status induces decrease in SOD/GPx ratio, which results in greater amount of (O)2-.)) versus H(2)O(2) in later phase of leptin treatment, thus shifting the mechanism of BP elevation from H(2)O(2)-ERK to (O(2-.))-NO dependent.
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PMID:Renal antioxidant enzymes and glutathione redox status in leptin-induced hypertension. 1869 Apr 14

Earlier we reported defects in D1 receptor function in renal proximal tubules (RPTs) of aged Fischer 344 (F344) and obese Zucker rats. However, the defects in the receptor function in RPTs of obese Zucker rats do not pass onto primary cultures of RPTs from these animals. Here, we determined whether the defects in D1 receptor function in RPTs of aged F344 rats pass onto the primary cultures. RPTs from aged (24-mo) and adult (6-mo) F344 rats were grown into primary cultures. The microscopic studies showed that cells in cultures from adult and old rats were healthy as determined by the shape and size of the cells and nuclei. D1 receptor agonist SKF-38393 produced inhibition of (86)Rb (rubidium) uptake, index of Na-K-ATPase activity, in cells from adult rats, but this was reduced in old rats. Also, SKF-38393 increased the [(35)S]GTPgammaS binding, index of receptor activation, in the membranes of cells from adult rats but to a lesser extent from old rats. Furthermore, there was a downward trend in the levels of D1 receptor numbers and in the receptor proteins in old rats. Interestingly, gp(91phox) subunit of NADPH oxidase and cellular protein carbonyl levels (oxidative stress marker) were higher in cultures from old rats. These results show that RPTs from adult and old F344 rats grow into epithelial cells in cultures. Furthermore, cells in cultures from old rats are at a higher level of oxidative stress, which may be contributing to the reduced D1 receptor function in the cells from old compared with adult rats.
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PMID:Renal proximal tubules from old Fischer 344 rats grow into epithelial cells in cultures and exhibit increased oxidative stress and reduced D1 receptor function. 1879 49

Oxidative stress causes changes in angiotensin (Ang) type 1 receptor (AT1R) function, which contributes to hypertension. Ang II affects blood pressure via maintenance of sodium homeostasis by regulating renal Na(+) absorption through its effects on Na/K-ATPase (NKA). At low concentrations, Ang II stimulates NKA; higher concentrations inhibit the enzyme. We examined the effect of oxidative stress on renal AT1R function involved in biphasic regulation of NKA. Male Sprague-Dawley rats received tap water (control) and 30 mmol/L of L-buthionine sulfoximine (BSO), an oxidant, with and without 1 mmol/L of Tempol (antioxidant) for 2 weeks. BSO-treated rats exhibited increased oxidative stress, AT1R upregulation, and hypertension. In proximal tubules from control rats, Ang II exerted a biphasic effect on NKA activity, causing stimulation of the enzyme at picomolar and inhibition at micromolar concentrations. However, in BSO-treated rats, Ang II caused stimulation of NKA at both of the concentrations. The effect of Ang II was abolished by the AT1R antagonist candesartan and the mitogen-activated protein kinase inhibitor UO126, whereas the Ang type 2 receptor antagonist PD-123319 and NO synthase inhibitor N(G)-nitro-L-arginine methyl ester had no effect. The inhibitory effect of Ang II was sensitive to candesartan and N(G)-nitro-L-arginine methyl ester, whereas PD-123319 and UO126 had no effect. In BSO-treated rats, Ang II showed exaggerated stimulation of NKA, mitogen-activated protein kinase, proline-rich-tyrosine kinase 2, and NADPH oxidase but failed to activate NO signaling. Tempol reduced oxidative stress, normalized AT1R signaling, unmasked the biphasic effect on NKA, and reduced blood pressure in BSO-treated rats. In conclusion, oxidative stress-mediated AT1R upregulation caused a loss of NKA biphasic response and hypertension. Tempol normalized AT1R signaling and blood pressure.
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PMID:Loss of biphasic effect on Na/K-ATPase activity by angiotensin II involves defective angiotensin type 1 receptor-nitric oxide signaling. 1895 61

Endosome trafficking and function require acidification by the vacuolar ATPase (V-ATPase). Electrogenic proton (H+) transport reduces the pH and creates a net positive charge in the endosomal lumen. Concomitant chloride (Cl-) influx has been proposed to occur via ClC Cl-=H+ exchangers. This maintains charge balance and drives Cl- accumulation, which may itself be critical to endosome function. Production of reactive oxygen species (ROS) in response to cytokines occurs within specialized endosomes that form in response to receptor occupation. ROS production requires an NADPH oxidase (Nox) and the ClC-3 Cl-=H+ exchanger. Like the V-ATPase, Nox activity is highly electrogenic, but separates charge with an opposite polarity (lumen negative). Here we review established paradigms of early endosomal ion transport focusing on the relation between the V-ATPase and ClC proteins. Electrophysiologic constraints on Nox-mediated vesicular ROS production are then considered. The potential for ClC-3 to participate in charge neutralization of both proton (V-ATPase) and electron (Nox) transport is discussed. It is proposed that uncompensated charge separation generated by Nox enzymatic activity could be used to drive secondary transport into negatively charged vesicles. Further experimentation will be necessary to establish firmly the biochemistry and functional implications of endosomal ROS production.
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PMID:Electrophysiology of reactive oxygen production in signaling endosomes. 1920 39

Mitochondrial dysfunction may play a role in the pathogenesis of several renal diseases. Although functional roles and metabolic demands differ among tubule segments, relatively little is known about the properties of mitochondria in different parts of the nephron. Clinically, the proximal tubule seems particularly vulnerable to mitochondrial toxicity. In this study, we used multiphoton imaging of live rat kidney slices to investigate differences in mitochondrial function along the nephron. The mitochondrial membrane potential was markedly higher in distal than proximal tubules. Inhibition of respiration rapidly collapsed the membrane potential in proximal tubules, but potential was better maintained in distal tubules. Inhibition of the F1F(o)-ATPase abolished this difference, suggesting that maintenance of potential via ATPase activity is more effective in distal than proximal tubules. Immunostaining revealed that the ratio of the expression of ATPase to IF1, an endogenous inhibitor of the mitochondrial ATPase, was lower in proximal tubules than in distal tubules. Production of reactive oxygen species was higher in proximal than distal cells, but inhibition of NADPH oxidase eliminated this difference. Glutathione levels were higher in proximal tubules. Overall, mitochondria in the proximal tubules were in a more oxidized state than those in the distal tubules. In summary, there are axial differences in mitochondrial function along the nephron, which may contribute to the pattern and pathophysiology of some forms of renal injury.
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PMID:Multiphoton imaging reveals differences in mitochondrial function between nephron segments. 1947 Jun 68

Angiotensin II (Ang II) inhibits the cardiac sarcolemmal Na(+)-K(+) pump via protein kinase (PK)C-dependent activation of NADPH oxidase. We examined whether this is mediated by oxidative modification of the pump subunits. We detected glutathionylation of beta(1), but not alpha(1), subunits in rabbit ventricular myocytes at baseline. beta(1) Subunit glutathionylation was increased by peroxynitrite (ONOO(-)), paraquat, or activation of NADPH oxidase by Ang II. Increased glutathionylation was associated with decreased alpha(1)/beta(1) subunit coimmunoprecipitation. Glutathionylation was reversed after addition of superoxide dismutase. Glutaredoxin 1, which catalyzes deglutathionylation, coimmunoprecipitated with beta(1) subunit and, when included in patch pipette solutions, abolished paraquat-induced inhibition of myocyte Na(+)-K(+) pump current (I(p)). Cysteine (Cys46) of the beta(1) subunit was the likely candidate for glutathionylation. We expressed Na(+)-K(+) pump alpha(1) subunits with wild-type or Cys46-mutated beta(1) subunits in Xenopus oocytes. ONOO(-) induced glutathionylation of beta(1) subunit and a decrease in Na(+)-K(+) pump turnover number. This was eliminated by mutation of Cys46. ONOO(-) also induced glutathionylation of the Na(+)-K(+) ATPase beta(1) subunit from pig kidney. This was associated with a approximately 2-fold decrease in the rate-limiting E(2)-->E(1) conformational change of the pump, as determined by RH421 fluorescence. We propose that kinase-dependent regulation of the Na(+)-K(+) pump occurs via glutathionylation of its beta(1) subunit at Cys46. These findings have implications for pathophysiological conditions characterized by neurohormonal dysregulation, myocardial oxidative stress and raised myocyte Na(+) levels.
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PMID:Reversible oxidative modification: a key mechanism of Na+-K+ pump regulation. 1954 13

Ion homeostasis is essential for plant cell resistance to salt stress. Under salt stress, to avoid cellular damage and nutrient deficiency, plant cells need to maintain adequate K nutrition and a favorable K to Na ratio in the cytosol. Recent observations revealed that both nitric oxide (NO) and hydrogen peroxide (H(2)O(2)) act as signaling molecules to regulate K to Na ratio in calluses from Populus euphratica under salt stress. Evidence indicated that NO mediating H(2)O(2) causes salt resistance via the action of plasma membrane H(+)-ATPase but that activity of plasma membrane NADPH oxidase is dependent on NO. Our study demonstrated the signaling transduction pathway. In this addendum, we proposed a testable hypothesis for NO function in regulation of H(2)O(2) mediating salt resistance.
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PMID:Role of nitric oxide and hydrogen peroxide during the salt resistance response. 1970 88

Our previous studies showed that nitric oxide (NO) fails to inhibit migration of smooth muscle cells (SMC) exposed to high glucose (HG) because of oxidation of the most reactive cysteine, cysteine-674, on the sarco/endoplasmic reticulum ATPase, preventing its S-glutathiolation, thus blocking NO action. This study further addresses the sources of the oxidants responsible for the failure of NO to inhibit SMC migration in HG. NADPH oxidases are the major source of reactive oxygen species (ROS) in SMC. We used small interfering RNA or dominant-negative adenoviral vectors to target components of NADPH oxidase to study their individual roles by measuring serum-induced migration in the presence or absence of NO. In HG, the mRNA levels of Nox1 and Nox4 and the protein level of Nox4 were increased; knocking down Nox1 or Nox4 attenuated the ROS production and restored the inhibition of SMC migration by NO. Blockade of the activation of Rac1 or p47(phox) inhibited serum-induced migration and restored the inhibition of migration by NO. These data indicate that NADPH oxidases are responsible for the failure of NO to inhibit SMC migration caused by HG.
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PMID:NADPH oxidases are responsible for the failure of nitric oxide to inhibit migration of smooth muscle cells exposed to high glucose. 1973 35


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