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

Kidney Int. 2012 Apr;81(7):662-73. doi: 10.1038/ki.2011.443. Epub 2012 Jan 18.

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.

MeSH terms

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

Substances

  • 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