| AMP-activated protein kinase (AMPK) negatively regulates Nox4-dependent activation of p53 and epithelial cell apoptosis in diabetes. | |
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MedLine Citation:
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PMID: 20861022 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Diabetes and high glucose (HG) increase the generation of NADPH oxidase-derived reactive oxygen species and induce apoptosis of glomerular epithelial cells (podocytes). Loss of podocytes contributes to albuminuria, a major risk factor for progression of kidney disease. Here, we show that HG inactivates AMP-activated protein kinase (AMPK), up-regulates Nox4, enhances NADPH oxidase activity, and induces podocyte apoptosis. Activation of AMPK blocked HG-induced expression of Nox4, NADPH oxidase activity, and apoptosis. We also identified the tumor suppressor protein p53 as a mediator of podocyte apoptosis in cells exposed to HG. Inactivation of AMPK by HG up-regulated the expression and phosphorylation of p53, and p53 acted downstream of Nox4. To investigate the mechanism of podocyte apoptosis in vivo, we used OVE26 mice, a model of type 1 diabetes. Glomeruli isolated from these mice showed decreased phosphorylation of AMPK and enhanced expression of Nox4 and p53. Pharmacologic activation of AMPK by 5-aminoimidazole-4-carboxamide-1-riboside in OVE26 mice attenuated Nox4 and p53 expression. Administration of 5-aminoimidazole-4-carboxamide-1-riboside also prevented renal hypertrophy, glomerular basement thickening, foot process effacement, and podocyte loss, resulting in marked reduction in albuminuria. Our results uncover a novel function of AMPK that integrates metabolic input to Nox4 and provide new insight for activation of p53 to induce podocyte apoptosis. The data indicate the potential therapeutic utility of AMPK activators to block Nox4 and reactive oxygen species generation and to reduce urinary albumin excretion in type 1 diabetes. |
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Authors:
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Assaad A Eid; Bridget M Ford; Karen Block; Balakuntalam S Kasinath; Yves Gorin; Goutam Ghosh-Choudhury; Jeffrey L Barnes; Hanna E Abboud |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-09-22 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 285 ISSN: 1083-351X ISO Abbreviation: J. Biol. Chem. Publication Date: 2010 Nov |
Date Detail:
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Created Date: 2010-11-24 Completed Date: 2010-12-30 Revised Date: 2011-12-21 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 37503-12 Citation Subset: IM |
Affiliation:
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Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78229-3900, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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AMP-Activated Protein Kinases
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genetics,
metabolism* Animals Apoptosis* Diabetes Mellitus / enzymology, genetics*, metabolism, physiopathology Disease Models, Animal Down-Regulation* Female Gene Expression Regulation Glucose / genetics Humans Male Mice NADPH Oxidase Phosphorylation Podocytes / cytology*, metabolism Tumor Suppressor Protein p53 / genetics*, metabolism |
| Grant Support | |
ID/Acronym/Agency:
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CA131272/CA/NCI NIH HHS; DK-R01-078971/DK/NIDDK NIH HHS; DK061597/DK/NIDDK NIH HHS; R01 DK050190-11/DK/NIDDK NIH HHS; R01 DK077295-05/DK/NIDDK NIH HHS; R01 DK078971-04/DK/NIDDK NIH HHS; R01 DK079996/DK/NIDDK NIH HHS; R01 DK079996-02/DK/NIDDK NIH HHS; R01 DK080106/DK/NIDDK NIH HHS; R01 DK080106-02/DK/NIDDK NIH HHS; R01 DK50190/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Tumor Suppressor Protein p53; 50-99-7/Glucose; EC 1.6.-/Nox4 protein, mouse; EC 1.6.3.1/NADPH Oxidase; EC 2.7.11.1/AMP-Activated Protein Kinases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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