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Inhibition of glycogen synthase kinase-3β prevents NSAID-induced acute kidney injury.

Authors :
Bao H
Ge Y
Zhuang S
Dworkin LD
Liu Z
Gong R
Bao, Hao
Ge, Yan
Zhuang, Shougang
Dworkin, Lance D
Liu, Zhihong
Gong, Rujun
Source :
Kidney International. Apr2012, Vol. 81 Issue 7, p662-673. 12p.
Publication Year :
2012

Abstract

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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00852538
Volume :
81
Issue :
7
Database :
Academic Search Index
Journal :
Kidney International
Publication Type :
Academic Journal
Accession number :
104535607
Full Text :
https://doi.org/10.1038/ki.2011.443