Ciglitazone induces caspase-independent apoptosis via p38-dependent AIF nuclear translocation in renal epithelial cells.
Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists have been reported to induce apoptosis in a variety of cell types including renal proximal epithelial cells. However, the underlying mechanism of cell death induced by PPARgamma agonists has not been clearly defined in renal proximal tubular cells. This study was therefore undertaken to determine the mechanism by which ciglitazone, a synthetic PPARgamma agonist, induces apoptosis in opossum kidney (OK) cells, an established renal epithelial cell line. Ciglitazone treatment induced apoptotic cell death in a dose- and time-dependent manner. Ciglitazone caused a transient activation of ERK and sustained activation of p38 MAP kinase. Ciglitazone-mediated cell death was attenuated by the p38 inhibitor SB203580 and transfection of dominant-negative form of p38, but not by the MEK inhibitor U0126, indicating that p38 MAP kinase activation is involved in the ciglitazone-induced cell death. Although ciglitazone-induced caspase-3 activation, the ciglitazone-mediated cell death was not affected by the caspase-3 inhibitor DEVD-CHO. Ciglitazone-induced mitochondrial membrane depolarization and apoptosis-inducing factor (AIF) nuclear translocation and these effects were prevented by the p38 inhibitor. These results suggest that ciglitazone induces caspase-independent apoptosis through p38 MAP kinase-dependent AIF nuclear translocation in OK renal epithelial cells.
Kwon
Chae Hwa
CH
Department of Physiology, College of Medicine, Pusan National University, Pusan 602-739, Republic of Korea.
Yoon
Chang Soo
CS
Kim
Yong Keun
YK
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051033:Apoptosis Inducing Factor / Q000378:metabolism*; D015153:Blotting, Western; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology; D002995:Clofibric Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D058607:Fibric Acids; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D016193:G1 Phase / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D007684:Kidney Tubules / Q000166:cytology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009893:Opossums; D047495:PPAR gamma / Q000819:agonists; D011725:Pyridines / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology*; D000077288:Troglitazone; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D051033:Apoptosis Inducing Factor; D002839:Chromans; D058607:Fibric Acids; D007093:Imidazoles; D047495:PPAR gamma; D011725:Pyridines; D045162:Thiazolidinediones; D002995:Clofibric Acid; D048051:p38 Mitogen-Activated Protein Kinases; C019304:ciprofibrate; D000077288:Troglitazone; C093642:SB 203580; C039671:ciglitazone