肾小管上皮细胞（TECs）受损后可停滞于G2/M期，释放炎症因子，促进肾脏纤维化。我们前期研究表明特异性近端TECs的Atg5基因失活可增加G2/M期停滞，且依赖于Atg5的自噬功能。此外，Atg5基因失活小鼠的肾脏炎症因子水平明显高于野生型小鼠，提示TECs自噬缺陷可加重炎症反应。但其机制尚不清楚。本项目拟利用上述小鼠及雷帕霉素增强自噬的慢性肾病模型，进一步证实TECs自噬、肾脏炎症反应与纤维化的关系；分别应用上述小鼠原代TECs，上调/沉默/变异HK-2细胞Atg5和药物改变细胞周期等方法，探讨Ang II刺激下炎症因子合成和NF-κB/NLRP3信号通路活化及协同效应，研究Atg5介导的TECs自噬靶向降解和抑制炎症信号通路的关键分子；前瞻性观察自噬与慢性肾脏病临床及病理的联系。本研究有助于揭示TECs自噬调控肾脏炎症反应，减缓纤维化的作用和机制，为临床防治肾脏纤维化提供科学依据。

G2/M-arrested tubular epithelial cells (TECs) after injury showed increased release of inflammation and contributed to renal fibrosis. Our previous study demonstrated that Atg5 deficient proximal tubular epithelial cells enhanced cell cycle arrest at G2/M, and this Atg5-mediated effect was autophagy-dependent. Moreover, kidney tissue of Atg5-/- mice showed a significant increase in protein levels of inflammatory cytokines as compared with those in wild-type mice, suggesting autophagy deficiency aggravate renal inflammation. However, the mechanism(s) were unknown. In this proposal, to further study the relationship among TECs autophagy, inflammation and renal fibrosis, mice models of chronic kidney nephropathy was induced in littermate Atg5+/+ and Atg5-/- mice with or without rapamycin treatment. Primary TECs from Atg5+/+ and Atg5-/- mice, upregulating/downregulating/mutation Atg5 in HK-2 cells, and regulating cell cycle in HK-2 cells were used to investigate the effects of Atg5-mediated TECs autophagy in the release of inflammation, activation of NF-κB/NLRP3 signal pathways induced by Ang II, and explore whether autophagy play a role in degradation key molecules of NF-κB/NLRP3 signal pathways. 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 inflammation and fibrosis.