肾小管上皮细胞的损伤可触发自噬和间充质转分化（EMT）。但这两者之间的关系、调控机制和在肾脏纤维化中的意义不清楚。我们前期研究表明肾小管上皮细胞自噬和EMT的诱导呈细胞周期依赖性，G1/S停滞的细胞表现为自噬，G2/M期则为EMT，且抑制自噬可增加炎症因子释放，促进肾脏纤维化，提示调控自噬与EMT的关系可延缓纤维化的进程。本项目拟应用下调肾脏mTOR活性促进自噬和特异性敲除肾小管上皮细胞Atg5致自噬缺陷的小鼠慢性肾脏病模型，进一步证实抑制肾小管上皮细胞自噬可加速肾脏纤维化；沉默HK2细胞Atg5/Smad3，明确自噬和EMT转换的关系；通过体内外实验阐明mTOR通过调控细胞周期介导自噬和EMT的机制及对肾脏纤维化的影响；前瞻性观察自噬与慢性肾脏病临床及病理的相关性。本研究有助于揭示肾小管上皮细胞自噬与EMT的关系和调控机制，以及自噬调控纤维化的信号通路，为临床防治肾脏纤维化提供科学依据。

Autophagy and epithelial-mesenchymal transition (EMT) occur in renal epithelial cells after sublethal injury. However, the interaction and regulation of these two events and the role in renal fibrosis are largely unknown. Our preliminary data showed that inhibition of autophagy can accelerate the process of renal fibrosis. Epithelial cells G1/S arrest resulted in autophagy, whereas G2/M arrest led to EMT. Impairment of autophagy in epithelial cells increased the expression of profibrotic cytokines and promoted fibroblast proliferation and extracellular matrix accumulation. In this proposal, we will first examin if the reduction of autophagy by mTOR inhibitor or epithelial cells-specific deletion of autophagy related 5 (Atg5) is associated with renal fibrosis in mice unilatreral ureteral obstruction (UUO) and 5/6 nephrectomy. We will further explore the interaction between autophagy and EMT by downregulating Atg5/Smad3 with siRNA in HK2 cells, and the role of mTOR signal pathway in regulating autophagy and EMT both in vitro and in vivo. Finally, we will prospectively investigate correlation between autophagy and pathology and clinical outcome in chronic kidney disease. Our study will provide a scientific basis and new target site for prevention and treatment of renal fibrosis.