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)
|