4-benzyl-2-methyl-1-2-4-thiadiazolidine-3-5-dione and Necrosis

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.

Topics: Acute Kidney Injury; Adenosine Triphosphate; Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Cell Survival; Cyclooxygenase 2; Cyclophilins; Diclofenac; Epithelial Cells; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Kidney Tubular Necrosis, Acute; Kidney Tubules; Mice; Mice, 129 Strain; Mice, Inbred BALB C; Mice, Knockout; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Necrosis; Oxidation-Reduction; Peptidyl-Prolyl Isomerase F; Phosphorylation; Protein Kinase Inhibitors; Thiadiazoles