| PKC-alpha mediates flow-stimulated superoxide production in thick ascending limbs. | |
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MedLine Citation:
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PMID: 20053794 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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We showed that luminal flow increases net superoxide (O(2)(-)) production via NADPH oxidase in thick ascending limbs. Protein kinase C (PKC) activates NADPH oxidase activity in phagocytes, cardiomyocytes, aortic endothelial cells, vascular smooth muscle cells, and renal mesangial cells. However, the flow-activated pathway that induces NADPH oxidase activity in thick ascending limbs is unclear. We hypothesized that PKC mediates flow-stimulated net O(2)(-) production by thick ascending limbs. Initiation of flow (20 nl/min) increased net O(2)(-) production from 4 +/- 1 to 61 +/- 12 AU/s (P < 0.007; n = 5). The NADPH oxidase inhibitor apocynin completely blocked the flow-induced increase in net O(2)(-) production (2 +/- 1 vs. 1 +/- 1 AU/s; P > 0.05; n = 5). Flow-stimulated O(2)(-) was also blocked in p47(phox)-deficient mice. We measured flow-stimulated PKC activity with a fluorescence resonance energy transfer (FRET)-based membrane-targeted PKC activity reporter and found that the FRET ratio increased from 0.87 +/- 0.02 to 0.96 +/- 0.04 AU (P < 0.05; n = 6). In the absence of flow, the PKC activator phorbol 12-myristate 13-acetate (200 nM) enhanced net O(2)(-) production from 5 +/- 2 to 92 +/- 6 AU/s (P < 0.001; n = 6). The PKC-alpha- and betaI-selective inhibitor Gö 6976 (100 nM) decreased flow-stimulated net O(2)(-) production from 54 +/- 15 to 2 +/- 1 AU/s (P < 0.04; n = 5). Flow-induced net O(2)(-) production was inhibited in thick ascending limbs transduced with dominant-negative (dn)PKC-alpha but not dnPKCbetaI or LacZ (Delta = 11 +/- 3 AU/s for dnPKCalpha, 55 +/- 7 AU/s for dnPKCbetaI, and 63 +/- 7 AU/s for LacZ; P < 0.001; n = 6). We concluded that flow stimulates net O(2)(-) production in thick ascending limbs via PKC-alpha-mediated activation of NADPH oxidase. |
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Authors:
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Nancy J Hong; Guillermo B Silva; Jeffrey L Garvin |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2010-01-06 |
Journal Detail:
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Title: American journal of physiology. Renal physiology Volume: 298 ISSN: 1522-1466 ISO Abbreviation: Am. J. Physiol. Renal Physiol. Publication Date: 2010 Apr |
Date Detail:
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Created Date: 2010-03-23 Completed Date: 2010-04-22 Revised Date: 2011-07-27 |
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: F885-91 Citation Subset: IM |
Affiliation:
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Department of Internal Medicine, Hypertension and Vascular Research Division, Henry Ford Hospital, 2799 West Grand Blvd., Detroit, MI 48202, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Gene Expression Regulation, Enzymologic Isoenzymes Kidney Medulla / metabolism Loop of Henle / metabolism* Male Mice Mice, Inbred C57BL NADPH Oxidase / genetics, metabolism Protein Kinase C / genetics, metabolism Protein Kinase C-alpha / metabolism* Rats Rats, Sprague-Dawley Superoxides / metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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HL-28982/HL/NHLBI NIH HHS; HL-70985/HL/NHLBI NIH HHS; HL-90550/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Isoenzymes; 11062-77-4/Superoxides; EC 1.6.3.1/NADPH Oxidase; EC 1.6.3.1/neutrophil cytosolic factor 1; EC 2.7.1.-/protein kinase C beta; EC 2.7.11.13/Protein Kinase C; EC 2.7.11.13/Protein Kinase C-alpha |
| Comments/Corrections | |
Comment In:
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Am J Physiol Renal Physiol. 2010 Apr;298(4):F883-4
[PMID:
20130124
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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