| Critical role of Nox4-based NADPH oxidase in glucose-induced oxidative stress in the kidney: implications in type 2 diabetic nephropathy. | |
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MedLine Citation:
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PMID: 20630933 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Molecular mechanisms underlying renal complications of diabetes remain unclear. We tested whether renal NADPH oxidase (Nox) 4 contributes to increased reactive oxygen species (ROS) generation and hyperactivation of redox-sensitive signaling pathways in diabetic nephropathy. Diabetic mice (db/db) (20 wk) and cultured mouse proximal tubule (MPT) cells exposed to high glucose (25 mmol/l, D-glucose) were studied. Expression (gene and protein) of Nox4, p22(phox), and p47(phox), but not Nox1 or Nox2, was increased in kidney cortex, but not medulla, from db/db vs. control mice (db/m) (P < 0.05). ROS generation, p38 mitogen-activated protein (MAP) kinase phosphorylation, and content of fibronectin and transforming growth factor (TGF)-β1/2 were increased in db/db vs. db/m (P < 0.01). High glucose increased expression of Nox4, but not other Noxes vs. normal glucose (P < 0.05). This was associated with increased NADPH oxidase activation and enhanced ROS production. Nox4 downregulation by small-interfering RNA and inhibition of Nox4 activity by GK-136901 (Nox1/4 inhibitor) attenuated d-glucose-induced NADPH oxidase-derived ROS generation. High d-glucose, but not l-glucose, stimulated phosphorylation of p38MAP kinase and increased expression of TGF-β1/2 and fibronectin, effects that were inhibited by SB-203580 (p38MAP kinase inhibitor). GK-136901 inhibited d-glucose-induced actions. Our data indicate that, in diabetic conditions: 1) renal Nox4 is upregulated in a cortex-specific manner, 2) MPT cells possess functionally active Nox4-based NADPH, 3) Nox4 is a major source of renal ROS, and 4) activation of profibrotic processes is mediated via Nox4-sensitive, p38MAP kinase-dependent pathways. These findings implicate Nox4-based NADPH oxidase in molecular mechanisms underlying fibrosis in type 2 diabetic nephropathy. |
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Authors:
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M Sedeek; G Callera; A Montezano; A Gutsol; F Heitz; C Szyndralewiez; P Page; C R J Kennedy; K D Burns; R M Touyz; R L Hébert |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-07-14 |
Journal Detail:
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Title: American journal of physiology. Renal physiology Volume: 299 ISSN: 1522-1466 ISO Abbreviation: Am. J. Physiol. Renal Physiol. Publication Date: 2010 Dec |
Date Detail:
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Created Date: 2010-12-08 Completed Date: 2011-01-10 Revised Date: 2011-04-28 |
Medline Journal Info:
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Nlm Unique ID: 100901990 Medline TA: Am J Physiol Renal Physiol Country: United States |
Other Details:
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Languages: eng Pagination: F1348-58 Citation Subset: IM |
Affiliation:
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Kidney Research Centre, Ottawa Hospital Research Institute and Deptartment of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cells, Cultured Cytochrome b Group / biosynthesis Diabetes Mellitus, Experimental / metabolism*, pathology Diabetic Nephropathies / metabolism*, pathology Fibrosis Glucose / pharmacology Kidney / metabolism* Male Mice NADPH Oxidase / biosynthesis, physiology* Oxidative Stress / drug effects Pyrazoles / pharmacology Pyridones / pharmacology RNA, Small Interfering / pharmacology Reactive Oxygen Species / metabolism p38 Mitogen-Activated Protein Kinases / drug effects |
| Grant Support | |
ID/Acronym/Agency:
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//Canadian Institutes of Health Research |
| Chemical | |
Reg. No./Substance:
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0/2-(2-chlorophenyl)-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo(4,3-c)pyridine-3,6(2H,5H)-dione; 0/Cytochrome b Group; 0/Pyrazoles; 0/Pyridones; 0/RNA, Small Interfering; 0/Reactive Oxygen Species; 50-99-7/Glucose; EC 1.6.-/Nox4 protein, mouse; EC 1.6.3.1/NADPH Oxidase; EC 1.6.3.1/neutrophil cytosolic factor 1; EC 1.6.3.1/p22(phox) protein, mouse; EC 2.7.11.24/p38 Mitogen-Activated Protein Kinases |
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