药源性肾损害临床常见，目前缺乏保护肾脏的有效药物。顺铂是引起肾损害的常见药物，可致肾缺血缺氧和氧化损伤。肾细胞可通过低氧诱导因子1(HIF-1)介导线粒体自噬抵御缺氧和氧化损伤。三七总皂苷（PNS）可保护顺铂肾损害且不抑制顺铂抗肿瘤效应。本课题组发现PNS 可保护顺铂肾损害，减轻肾小管上皮细胞线粒体损伤和增多线粒体自噬体，升高肾LC3Ⅱ、HIF-1α、BNIP3、Beclin-1和Atg5蛋白表达；提示PNS可增强HIF-1α介导的线粒体自噬而保护顺铂肾损害。本项目拟建立体内、体外顺铂肾损害模型，以PNS、HIF-1α抑制剂干预，了解不同时间点肾小管上皮细胞的线粒体自噬活性、线粒体功能与形态、ROS含量等，以及LC3、HIF-1α、BNIP3、Beclin-1蛋白表达、mRNA表达等，从HIF-1/BNIP3/Beclin-1通路调控的线粒体自噬探讨PNS保护顺铂肾损害的作用机制。

Drug-induced renal damage is common in clinical, and there have not been effective drug to protect kidney presently. Cisplatin is one of the common drugs which cause renal damage, it can induce kidney ischemia, hypoxia and oxidative damage. Kidney cells can resist hypoxia and oxidative damage through mitophagy mediated by hypoxia-inducible factor 1(HIF-1). Panax Notoginsenosides (PNS) can protect against cisplatin-induced renal damage and not inhibit cisplatin’s antitumor effect. We found that PNS could protect against cisplatin-induced nephrotoxicity, reduced the mitochondria damage and increasing mitochondrial autophagy in rat renal tubular epithelial cells, elevated the protein expression of LC3, HIF-1α, BNIP3, Beclin-1 and Atg5 in renal tissue, these results suggest that PNS can enhance mitophagy mediated by HIF-1αand protect against cisplatin-induced nephrotoxicity. This project intends to establish rat model and cellular model of cisplatin-induced nephrotoxicity, intervening with PNS and HIF-1α inhibitor, then determine the mitophagy activity, mitochondrial function and morphology, reactive oxygen species content, detect the protein expression of LC3, HIF-1α, BNIP3 and Beclin-1, detect the expression of HIF-1αmRNA in renal tubular epithelial cell at different time points. Furthermore, we will clarify the molecular mechanisms of PNS protection against cisplatin-induced nephrotoxicity through the mitophagy regulated by HIF-1/BNIP3/Beclin-1 pathway.