基于ILK信号通路探讨芪地糖肾方干预糖尿病肾病足细胞EMT作用机制研究

Podocyte impairment induced proteinuria is the critical influencing factor of Diabetic Nephropathy (DN) progression. Epithelial-mesenchymal transition (EMT) is a reversible process before podocyte cell exfoliation and apoptosis. For podocyte protecting, inhibiting EMT is of great importance. ILK plays an important role in EMT signaling transduction. Our previous studies have show that Qi-Di-Tang-Shen Formula can reduce proteinuria in DN patients and experimental rats, as well as alleviate podocyte impairment. Based on this we presume that Qi-Di-Tang-Shen formula can regulate the EMT and reduce podocyte impairment by controlling downstream the ILK signal pathway. To verify the above hypothesis，we in order to utilizing specific gene mutation knock-in and high glucose to create EMT model. Our study can clarify the podocyte protection mechanism of Qi-Di-Tang-Shen formula. And provide a new target of DN treatment of traditional Chinese medicine.

足细胞损伤导致的蛋白尿是糖尿病肾病(DN)进展的关键，上皮－间质转分化（EMT）是足细胞发生脱落和（或）凋亡前的早期可逆过程,为延缓糖尿病肾病的防治提供了重要切入点和突破口。ILK是介导EMT的关键信号通路。前期研究表明：芪地糖肾方可降低DN蛋白尿，减轻足细胞损伤。基于此我们提出芪地糖肾方通过调节足细胞ILK信号通路，抑制足细胞EMT，保护足细胞作用的假说。拟采用db/db自发2型DN小鼠模型、制备高糖诱导的EMT模型，从整体和细胞水平观察芪地糖肾方对ILK信号通路和足细胞上皮－间质转分化的影响，为阐明芪地糖肾方保护足细胞作用机制和临床防治DN蛋白尿提供理论依据。

糖尿病肾脏病（diabetic kidney disease, DKD）是糖尿病常见且严重的微血管并发症之一，临床以蛋白尿及肾脏纤维化改变为主，晚期可进展至终末期肾脏病（end stage renal disease，ESRD）。足细胞损伤是导致DKD蛋白尿产生和肾脏纤维化的关键因素。上皮－间质转分化（epithelial-mesenchymal transition，EMT）为足细胞发生脱落凋亡前的早期可逆过程，对足细胞EMT干预是DKD防治的重要切入点和突破口，整合素链接酶ILK是介导EMT的关键，肾小球中ILK主要在足细胞表达，是调节足细胞EMT关键因子。中医药治疗DKD肾脏纤维化优势显著。精损络痹是DKD核心病机，精损即肾精虚损，络痹即因虚至滞，湿、瘀、浊痹阻肾络化生癥瘕。导师柳红芳教授根据多年临床经验拟填精通络方芪地糖肾方（专利号：CN 107714817 A），本团队前期研究表明芪地糖肾方可降低DKD临床患者蛋白尿，保护足细胞，改善肾脏纤维化。我们认为芪地糖肾方是通过保护足细胞从而降低蛋白尿改善肾脏纤维化，而足细胞EMT是引起纤维化的关键因素，ILK又是足细胞EMT的关键因子，基于此我们提出芪地糖肾方通过调节ILK介导的足细胞EMT，从而改善DKD肾脏纤维化的假设。本研究为阐明芪地糖肾方改善DKD肾脏纤维化的作用机制提供理论支持。