Ciglitazone induces apoptosis via activation of p38 MAPK and AIF nuclear translocation mediated by reactive oxygen species and Ca(2+) in opossum kidney cells

• Published in: Toxicology (Amsterdam) 2009-03, Vol.257 (1-2), p.1
• Main Authors: Kwon, Chae Hwa, Park, Ji Yeon, Kim, Thae Hyun, Woo, Jae Suk, Kim, Yong Keun
• Format: Article
• Language: English
• Subjects: Active Transport, Cell Nucleus; Animals; Antioxidants - pharmacology; Apoptosis - drug effects; Apoptosis Inducing Factor - genetics; Apoptosis Inducing Factor - metabolism; Calcium - metabolism; Calcium Channel Blockers - pharmacology; Cells, Cultured; Chelating Agents - pharmacology; Chromans - pharmacology; Dose-Response Relationship, Drug; Egtazic Acid - pharmacology; Enzyme Activation; Epithelial Cells - drug effects; Epithelial Cells - enzymology; Epithelial Cells - pathology; Hypoglycemic Agents - toxicity; Kidney - drug effects; Kidney - enzymology; Kidney - pathology; Lanthanum - pharmacology; Membrane Potential, Mitochondrial - drug effects; Mitochondria - drug effects; Mitochondria - metabolism; Opossums; p38 Mitogen-Activated Protein Kinases - genetics; p38 Mitogen-Activated Protein Kinases - metabolism; PPAR gamma - agonists; Reactive Oxygen Species - metabolism; RNA Interference; RNA, Small Interfering - metabolism; Thiazolidinediones - toxicity; Time Factors; Transfection
• ISSN: 0300-483X
• DOI: 10.1016/j.tox.2008.11.019

We have previously demonstrated that the synthetic peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist ciglitazone induces apoptosis accompanied by activation of p38 mitogen-activated protein kinase (MAPK) and nuclear translocation of apoptosis inducing factor (AIF) in opossum kidney (OK) renal epithelial cells. However, the precise mechanism by which ciglitazone induces activation of p38 MAPK and the role of AIF in the induction of the apoptosis are not defined. This study was therefore undertaken to determine whether the roles of reactive oxygen species (ROS) generation and intracellular Ca(2+) in the ciglitazone-induced activation of p38 MAPK and whether AIF nuclear translocation is responsible for the ciglitazone-induced apoptosis in OK renal epithelial cells. Ciglitazone caused generation of ROS and an increase in intracellular Ca(2+). Ciglitazone-induced cell death was reduced by the antioxidant Trolox, the Ca(2+) chelator EGTA, and the store-operated Ca(2+) channels (SOCC) blocker lanthanum chloride (La(3+)), indicating involvement of ROS and Ca(2+) in the ciglitazone-induced cell death. Ciglitazone-induced intracellular Ca(2+) increase was decreased by Trolox, while ROS generation was not affected by EGTA and La(3+), suggesting that ROS generation promote the increase of intracellular Ca(2+). Transfection of small interfering RNA (siRNA) of p38 MAPK or vector expressing microRNA (miRNA) of AIF prevented the ciglitazone-induced cell death. Activation of p38 MAPK, mitochondrial membrane depolarization, and AIF nuclear translocation induced by ciglitazone were inhibited by Trolox, EGTA and La(3+). Taken together, these results suggest that ROS-dependent intracellular Ca(2+) increase is responsible for activation of p38 MAPK and nuclear translocation of AIF by ciglitazone.