Kang Dae Sik, Kwon Chae Hwa, Park Ji Yeon, Kim Jae Ho, Woo Jae Suk, Jung Jin Sup, Kim Yong Keun
Department of Physiology, College of Medicine, Pusan National University, Pusan, 602-739, Korea.
Toxicol Appl Pharmacol. 2006 Nov 1;216(3):426-35. doi: 10.1016/j.taap.2006.06.008. Epub 2006 Jun 27.
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.
过氧化物酶体增殖物激活受体γ（PPARγ）配体15d - PGJ2可诱导肾近端小管细胞死亡。然而，其潜在的分子机制仍不明晰。本研究旨在探讨活性氧（ROS）、丝裂原活化蛋白激酶和核因子κB（NF - κB）在15d - PGJ2诱导的负鼠肾（OK）细胞死亡中的作用。用15d - PGJ2处理OK细胞导致浓度和时间依赖性的细胞死亡，这主要归因于细胞凋亡。15d - PGJ2增加了ROS的产生，而过氧化氢酶和N - 乙酰半胱氨酸可抑制该效应。这些抗氧化剂也可防止15d - PGJ2诱导的细胞死亡，表明细胞死亡与ROS生成有关。PPARγ拮抗剂GW9662不能防止15d - PGJ2诱导的细胞死亡。15d - PGJ2引起细胞外信号调节激酶（ERK）的短暂激活。然而，ERK上游激酶MEK的抑制剂（PD98059和U0126）并未改变15d - PGJ2诱导的细胞死亡。用组成型活性MEK和显性负性MEK转染对细胞死亡无影响。15d - PGJ2抑制NF - κB转录活性，同时伴有NF - κB亚基p65核转位的抑制和DNA结合受损。用NF - κB特异性抑制剂吡咯烷二硫代氨基甲酸盐抑制NF - κB以及用IκBα（S32A/36A）转染导致细胞死亡。这些结果表明，5d - PGJ2诱导的OK细胞死亡与ROS产生和NF - κB抑制有关，但与丝裂原活化蛋白激酶（MAPK）激活无关。
