15-deoxy-Delta12,14-prostaglandin J2 induces renal epithelial cell death through NF-kappaB-dependent and MAPK-independent mechanism.
The peroxisome proliferator-activated receptor-gamma (PPARgamma) ligand 15d-PGJ2 induces cell death in renal proximal tubular cells. However, the underlying molecular mechanism(s) remains unidentified. The present study was undertaken to examine the roles of reactive oxygen species (ROS), mitogen-activated protein kinase, and NF-kappaB in opossum kidney (OK) cell death induced by 15d-PGJ2. Treatment of OK cells with 15d-PGJ2 resulted in a concentration- and time-dependent cell death, which was largely attributed to apoptosis. 15d-PGJ2 increased ROS production and the effect was inhibited by catalase and N-acetylcysteine. The 15d-PGJ2-induced cell death was also prevented by these antioxidants, suggesting that the cell death was associated with ROS generation. The PPARgamma antagonist GW9662 did not prevent the 15d-PGJ2-induced cell death. 15d-PGJ2 caused a transient activation of extracellular signal-regulated kinase (ERK). However, inhibitors (PD98059 and U0126) of MEK, an ERK upstream kinase, did not alter the 15d-PGJ2-induced cell death. Transfection with constitutively active MEK and dominant-negative MEK had no effect on the cell death. 15d-PGJ2 inhibited the NF-kappaB transcriptional activity, which was accompanied by an inhibition of nuclear translocation of the NF-kappaB subunit p65 and impairment in DNA binding. Inhibition of NF-kappaB with a NF-kappaB specific inhibitor pyrrolidinecarbodithioate and transfection with IkappaBalpha (S32A/36A) caused cell death. These results suggest that the 5d-PGJ2-induced OK cell death was associated with ROS production and NF-kappaB inhibition, but not with MAPK activation.
Kang
Dae Sik
DS
Department of Physiology, College of Medicine, Pusan National University, Pusan, 602-739, Korea.
Kwon
Chae Hwa
CH
Park
Ji Yeon
JY
Kim
Jae Ho
JH
Woo
Jae Suk
JS
Jung
Jin Sup
JS
Kim
Yong Keun
YK
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D006690:Bisbenzimidazole; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D024202:Electrophoretic Mobility Shift Assay; D004847:Epithelial Cells / Q000187:drug effects*; D005434:Flow Cytometry; D017930:Genes, Reporter / Q000187:drug effects; D007668:Kidney / Q000166:cytology / Q000187:drug effects*; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D016328:NF-kappa B / Q000502:physiology*; D009893:Opossums / Q000502:physiology*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D014162:Transfection
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D020928:Mitogen-Activated Protein Kinases; D006690:Bisbenzimidazole; D015230:Prostaglandin D2