以自噬为靶点调控肾小管上皮细胞参与移植肾间质纤维化形成的作用机制及干预研究

移植肾间质纤维化是影响肾移植受者长期存活的关键因素，其机制至今不明。我们既往研究证实肿瘤坏死因子-alpha（TNF-a）可通过诱导肾小管上皮细胞-间充质细胞转分化（肾小管EMT）发生进而在移植肾间质纤维化形成中起重要作用。新近我们又发现在移植肾间质纤维化患者肾小管上皮细胞中自噬活性明显增加，而TNF-a却可抑制人肾小管上皮细胞中自噬相关蛋白p62表达。但对于自噬在移植肾间质纤维化形成中的确切作用及机制迄今国内外尚未见报道。据此我们提出：自噬活性失调可能通过调控肾小管EMT发生进而在移植肾间质纤维化形成中起关键作用。为验证该假说，本课题拟通过同种异体肾移植大鼠和正常人肾小管上皮细胞模型，以TNF-a为介质，探讨自噬在移植肾间质纤维化形成中的作用及机制。并在此基础上，深入探讨依维莫司在其中的防治作用及机制。本课题预期成果将为从调控自噬角度研发防治移植肾间质纤维化形成的措施提供新线索和靶标。

Renal allograft interstitial fibrosis is the key factor affecting the long-term survival of renal transplanted recipients, but the mechanism is still unknown. Our previous studies have shown that renal tubular epithelial-mesenchymal transdifferentiation (renal tubular EMT) induced by tumor necrosis factor-alpha (TNF-alpha) plays an important role in the formation of renal allograft interstitial fibrosis. Recently, we found that autophagy significantly increased in renal tubular epithelial cells in patients with renal allograft interstitial fibrosis. While in vitro studies showed that TNF-alpha could inhibit the expression of autophagy related protein——p62 in human renal tubular epithelial cells. However, the exact role and mechanism of autophagy in formation of renal allograft interstitial fibrosis has never been reported at home and abroad. Accordingly, we put forward the hypothesis: disorder of autophagy activity maybe play a critical role in the formation of renal allograft interstitial fibrosis through promoting renal tubular EMT. To verify this hypothesis, this project will investigate the effects and mechanisms of autophagy in the formation of renal allograft interstitial fibrosis mediated by TNF-alpha through a rat renal allograft transplantation model and the human renal tubular epithelial cells model. On this basis, we will in-depth study the effects and mechanisms of everolimus in the formation of renal allograft interstitial fibrosis. The expected results of this study will provide new clues and targets for prevention and treatment of renal allograft interstitial fibrosis from the regulation of autophagy activity point of view.