PGC-1α在硝基油酸抗氧化肾脏保护中的作用及机制的研究

项目名称： PGC-1α在硝基油酸抗氧化肾脏保护中的作用及机制的研究

项目编号： No.81200530

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学二处

项目作者： 王海萍

作者单位： 山东大学

项目金额： 23万元

中文摘要： 硝硝基油酸是新型内源性PPARγ激动剂，无明显副作用。申请者前期发现硝基油酸通过抗氧化减轻小鼠内毒素血症和Obese Zucker Rats大鼠模型的肾损伤，但具体作用机制不明确。PPARγ辅助激活因子（PGC-1α）可调节线粒体介导的氧化应激及细胞凋亡，我们预实验发现硝基油酸可阻断脂多糖（LPS）诱导的PGC-1α低表达，本研究将重复小鼠内毒素血症模型，检测PGC-1α及其介导的线粒体ROS生成和抗氧化能力在硝基油酸处理前后的变化；并在PGC-1α基因敲除小鼠中，观察硝基油酸是否仍对内毒素血症诱导的肾损伤有保护作用；然后予LPS处理人肾近端小管细胞，检测PGC-1α下游基因在硝基油酸处理前后的表达变化，以明确PGC-1α在硝基油酸抗氧化肾保护作用中的信号途径，及是否依赖PGC-1α/PPARγ通路所介导。本研究将为硝基油酸的抗氧化作用提供更有力的证据，为其临床开发应用提供更翔实的实验依据

中文关键词： 急性肾损伤；硝基油酸；PGC1-a；；

英文摘要： Nitro-oleic acid (OA-NO2) is identified as endogenous potent ligands for proxisome proliferator-activated receptor subtype-γ (PPARγ) with less side effects. We previous demonstrated that OA-NO2 improved endotoxin-induced acute renal failure in mice and kidney injury in Obese Zucker Rats via anti-oxidative stress. Based on these results, the present study is undertaken to explore the mechanism of the anti-oxidative stress of OA-NO2. Abundant evidence demonstrates that PPARγ ?coactivator-1 (PGC-1α) play an important role in the mitochondrial biogenesis and also the development of the acute kidney injury. We got a clue from the preliminary experiment that OA-NO2 remarkably blocked LPS-induced decrease expression of the PGC-1α. The present study repeat the endotoxin-induced acute renal failure model and test the expression of the PGC-1αand the renal ROS production with or without OA-NO2 treatment; Moreover, we test whether OA-NO2 still has renal protective effects in the endotoximia in PGC-1αknockout mice; In vitro study, we culture the human proximal tubule to study the detail signal pathway of the regulation of the PGC-1αin the anti-oxidative effects of the OA-NO2; At last, we study whether the regulation of the PGC-1αis dependant on the PPARγ/PGC-1αpathway.

英文关键词： acute kidney injury；nitro oleic acid；PGC1-a；；