基于线粒体损伤诱导的氧化应激探讨补阳还五汤干预肾间质纤维化的机制研究

Renal interstitial fibrosis is a common pathological basis for the development of various renal diseases which led to end-stage renal failure. In recent years, many evidence showed that oxidative stress induced by renal tubular epithelial mitochondria injury was one of the main pathogenesis of renal interstitial fibrosis. The regulation of renal interstitial oxidative stress was expected to be a new intervention target for the prevention and treatment of renal interstitial fibrosis. From the perspective that mitochondrial damage induced oxidative stress, this project treated ROS/NF-κB/P38 MAPK as the starting point, combined with the key pathogenesis of deficiency of vital pneuma, static blood blocking collaterals, using benefiting qi for activating blood circulation as the principle of treatment, the buyang huanwu decoction as the research carrier, using the hypothesis that buyang huanwu decoction can regulating the mitochondrial autophagy of tubules epithelial cell , improving the mitochondrial damage and the renal interstitial oxidative stress, intervening the signal pathway transduction of ROS/NF-κB/P38 MAPK , as a result, intervening the renal interstitial fibrosis. This research also combined with vivo and vitro experiments, using biochemical, pathological, immunohistochemical and molecular biology technology, dynamicly observed the activation of oxidative stress and renal interstitial injury effect, explore the deep mechanism of buyang huanwu decoction on the intervention renal interstitial fibrosis.

肾间质纤维化是各种肾脏疾病发展至终末期肾衰竭的共同病理基础。近年来，诸多证据表明由肾小管上皮细胞损伤介导的氧化应激反应是导致肾间质纤维化的主要病机之一。因此，有效干预肾间质氧化应激的产生有望成为防治肾间质纤维化新的治疗手段。本研究从肾小管上皮细胞线粒体损伤诱导肾间质氧化应激这一视角，以ROS/NF-κB/P38MAPK为切入点，结合肾间质纤维化早期正气亏虚、脉络不利的关键病机，以补气活血为治疗原则，以补阳还五汤为研究载体，围绕“补阳还五汤可通过调控肾小管上皮细胞线粒体自噬反应，改善线粒体损伤状态，进而干预由肾间质氧化应激介导的ROS/NF-κB/P38MAPK信号转导，阻抑肾间质纤维化进展”这一假说，在体和离体实验相结合，从多层面结合生化、病理、免疫组化及分子生物学等技术，动态观察了线粒体损伤及氧化应激相关通路激活介导的肾间质损伤效应，探讨了补阳还五汤干预肾间质纤维化的深层机制。

肾间质纤维化是各种肾脏疾病发展至终末期肾衰竭的共同病理基础。近年来，诸多证据表明由肾小管上皮细胞损伤介导的氧化应激反应是导致肾间质纤维化的主要病机之一。因此，有效干预肾间质氧化应激的产生有望成为防治肾间质纤维化新的治疗手段。本研究从肾小管上皮细胞线粒体损伤诱导肾间质氧化应激这一视角，以ROS/NF-κB/P38MAPK为切入点，结合肾间质纤维化早期正气亏虚、脉络不利的关键病机，以补气活血为治疗原则，以补阳还五汤为研究载体，在体和离体实验相结合，从多层面结合生化、病理、免疫组化及分子生物学等技术，动态观察了线粒体损伤及氧化应激相关通路激活介导的肾间质损伤效应，证实了补阳还五汤能够改善UUO大鼠肾功能状态，减轻肾组织病理损伤程度，能够通过抑制线粒体诱导的氧化应激反应，调控PINK1/Parkin介导的线粒体自噬，从而抑制肾小管上皮细胞EMT进程，阻抑肾间质纤维化的进展，为后续防治肾间质纤维化进展研究提供了新的干预靶点。