| Inhibition of glycogen synthase kinase-3β prevents NSAID-induced acute kidney injury. | |
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MedLine Citation:
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PMID: 22258319 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Clinical use of nonsteroidal anti-inflammatory drugs (NSAIDs) like diclofenac (DCLF) is limited by multiple adverse effects, including renal toxicity leading to acute kidney injury. In mice with DCLF-induced nephrotoxicity, TDZD-8, a selective glycogen synthase kinase (GSK)3β inhibitor, improved acute kidney dysfunction and ameliorated tubular necrosis and apoptosis associated with induced cortical expression of cyclooxygenase-2 (COX-2) and prostaglandin E2. This renoprotective effect was blunted but still largely preserved in COX-2-null mice, suggesting that other GSK3β targets beyond COX-2 functioned in renal protection. Indeed, TDZD-8 diminished the mitochondrial permeability transition in DCLF-injured kidneys. In vitro, GSK3β inhibition reinstated viability and suppressed necrosis and apoptosis in DCLF-stimulated tubular epithelial cells. DCLF elicited oxidative stress, enhanced the activity of the redox-sensitive GSK3β, and promoted a mitochondrial permeability transition by interacting with cyclophilin D, a key component of the mitochondrial permeability transition pore. TDZD-8 blocked GSK3β activity and prevented GSK3β-mediated cyclophilin D phosphorylation and the ensuing mitochondrial permeability transition, concomitant with normalization of intracellular ATP. Conversely, ectopic expression of a constitutively active GSK3β abolished the effects of TDZD-8. Hence, inhibition of GSK3β ameliorates NSAID-induced acute kidney injury by induction of renal cortical COX-2 and direct inhibition of the mitochondrial permeability transition.Kidney International advance online publication, 18 January 2012; doi:10.1038/ki.2011.443. |
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Authors:
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Hao Bao; Yan Ge; Shougang Zhuang; Lance D Dworkin; Zhihong Liu; Rujun Gong |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-1-18 |
Journal Detail:
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Title: Kidney international Volume: - ISSN: 1523-1755 ISO Abbreviation: - Publication Date: 2012 Jan |
Date Detail:
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Created Date: 2012-1-19 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0323470 Medline TA: Kidney Int Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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1] Research Institute of Nephrology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China [2] Division of Kidney Disease and Hypertension, Department of Medicine, Brown University School of Medicine, Providence, Rhode Island, USA. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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