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
-
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
-
Peptidyl-Prolyl Isomerase F
-
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
-
Peptidyl-Prolyl Isomerase F
-
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