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

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.

• Authors: Hao Bao, Yan Ge, Shougang Zhuang, Lance D Dworkin, Zhihong Liu, Rujun Gong
• Journal: Kidney international (Kidney Int) Vol. 81 Issue 7 Pg. 662-73 (Apr 2012) ISSN: 1523-1755 [Electronic] United States
• PMID: 22258319 (Publication Type: Journal Article)

Chemical References

• 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione
• Anti-Inflammatory Agents, Non-Steroidal
• Cyclophilin D
• Mitochondrial Membrane Transport Proteins
• Mitochondrial Permeability Transition Pore
• PPIF protein, mouse
• Protein Kinase Inhibitors
• Thiadiazoles
• Diclofenac
• Adenosine Triphosphate
• Ptgs2 protein, mouse
• Cyclooxygenase 2
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, mouse
• Glycogen Synthase Kinase 3
• Cyclophilins

Topics

• Acute Kidney Injury (chemically induced, pathology, physiopathology, prevention & control)
• Adenosine Triphosphate (biosynthesis)
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (toxicity)
• Apoptosis (drug effects)
• Cell Survival (drug effects)
• Cyclooxygenase 2 (biosynthesis, deficiency, genetics)
• Cyclophilin D
• Cyclophilins (metabolism)
• Diclofenac (toxicity)
• Epithelial Cells (drug effects, pathology)
• Glycogen Synthase Kinase 3 (antagonists & inhibitors)
• Glycogen Synthase Kinase 3 beta
• Kidney Tubular Necrosis, Acute (chemically induced, pathology, physiopathology, prevention & control)
• Kidney Tubules (drug effects, pathology)
• Mice
• Mice, 129 Strain
• Mice, Inbred BALB C
• Mice, Knockout
• Mitochondrial Membrane Transport Proteins (drug effects, metabolism)
• Mitochondrial Permeability Transition Pore
• Necrosis
• Oxidation-Reduction
• Phosphorylation (drug effects)
• Protein Kinase Inhibitors (pharmacology)
• Thiadiazoles (pharmacology)