Hsu Y-H, Chen C-H, Hou C-C, Sue Y-M, Cheng C-Y, Cheng T-H, Lin H, Tsai W-L, Chan P, Chen T-H
Department of Internal Medicine, Nephrology Division, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan.
Kidney Int. 2008 Mar;73(5):578-87. doi: 10.1038/sj.ki.5002704. Epub 2007 Nov 21.
To study the protective effect of prostacyclin (PGI2) we increased PGI2 production by infected NRK-52E cells with an adenovirus carrying cyclooxygenase-1 and prostacyclin synthase. PGI2 overexpression protected these cells from gentamicin-induced apoptosis by reducing cleaved caspase-3 and caspase-9, cytochrome c, and decreasing generation of reactive oxygen species. Expression of the nuclear receptor of PGI2, peroxisome proliferator-activated receptor-alpha (PPARalpha), was reduced during gentamicin treatment of the cells, while its overexpression significantly inhibited gentamicin-induced apoptosis and the amount of cleaved caspase-3. Transformation with PPARalpha short interfering RNA abolished the protective effect of PGI2 overproduction in gentamicin-treated cells. The PPARalpha activator docosahexaenoic acid given to gentamicin-treated mice significantly reduced the number of apoptotic cells in renal cortex, but this protective effect was not seen in PPARalpha knockout mice. Our study suggests that increased endogenous PGI2 production protects renal tubular cells from gentamicin-induced apoptosis through a PPARalpha-signaling pathway.
为研究前列环素（PGI2）的保护作用，我们用携带环氧合酶-1和前列环素合酶的腺病毒感染NRK-52E细胞，以增加PGI2的生成。PGI2过表达通过减少裂解的半胱天冬酶-3和半胱天冬酶-9、细胞色素c以及降低活性氧的生成，保护这些细胞免受庆大霉素诱导的凋亡。在细胞用庆大霉素处理期间，PGI2的核受体过氧化物酶体增殖物激活受体α（PPARα）的表达降低，而其过表达显著抑制庆大霉素诱导的凋亡以及裂解的半胱天冬酶-3的量。用PPARα短干扰RNA转染消除了PGI2过表达在庆大霉素处理细胞中的保护作用。给予庆大霉素处理小鼠PPARα激活剂二十二碳六烯酸可显著减少肾皮质中凋亡细胞的数量，但在PPARα基因敲除小鼠中未观察到这种保护作用。我们的研究表明，内源性PGI2生成增加通过PPARα信号通路保护肾小管细胞免受庆大霉素诱导的凋亡。
