糖尿病肾病（DN）是糖尿病最严重的并发症之一，其发病机制尚未充分阐明并缺乏有效治疗措施。研究表明肾小管上皮细胞的上皮-间充质转化（EMT）是DN肾纤维化的重要发病机制之一，而自噬在EMT的发生中起重要作用，但机制不甚清楚。最新研究显示，提高细胞自噬水平能促进EMT始动因子Snail1的降解，进而抑制EMT的发生。申请者及课题组前期结果表明E2F1/EZH2/Beclin-1通路可能与DN的发生发展密切相关，推测该通路可能介导了高糖对自噬的抑制以及对EMT的诱导作用。本项目将以肾小管上皮细胞、糖尿病小鼠及E2F1基因敲除小鼠为研究对象，在体内和体外深入研究高糖是否通过E2F1/EZH2/Beclin-1通路抑制自噬，促进EMT，并探讨白藜芦醇是否可通过调控E2F1/EZH2/Beclin-1通路的效应发挥抗纤维化作用，为进一步阐明DN发病机制、寻找有效药物分子靶标提供实验依据。

Diabetic nephropathy (DN) is one of the most serious complications of diabetes. The pathogenesis of DN has not yet been well elucidated and it is lack of effective measures to treat DN. Research indicates that epithelial-mesenchymal transition in renal tubular epithelial cells is one of important pathogenesis of renal fibrosis associated with DN. Moreover, autophagy plays an important role in the occurrence of EMT, but the exact mechanism is unclear. Recent studies have shown that improve the level of autophagy could promote the degradation of Snail1, which is well known as a master regulators of EMT, and thus suppress the occurrence of EMT. Previous experiment results of the applicant and our research group revealed that E2F1/EZH2/Beclin-1 pathway was close related to the occurrence and development of DN, speculating a mediator role of this pathway on high glucose-induced autophagy suppression and EMT. At present research, renal tubular epithelial cells, diabetic mice and E2F1 gene knockout mice will be served as study subjects to further investigate whether E2F1/EZH2/Beclin-1 pathway mediates high glucose-induced autophagy suppression and EMT in vivo and in vitro and to explore whether this pathway and its biological effect mediates anti-fibrosis effect of resveratrol. This research may be helpful to further clarify the pathogenesis of DN and to provide experimental basis in looking for effective drug molecular targets.