Kidney injury molecular（KIM-1)介导肾小管上皮细胞自噬在糖尿病肾病肾间质纤维化中的作用

Diabetic nephropathy is a serious complication of diabetes, which is one of the main cause of end-stage renal disease (ESRD).Renal interstitial fibrosis is the common pathological characteristic，and hypoxia is one of the major factors involved in the development of interstitial fibrosis in diabetic nephropathy. Under hypoxic conditions, the activation of autophagy increases, which can lead to tubular epithelial cell apoptosis and promote renal interstitial fibrosis. KIM-1 is an early stage kidney injury indicator, but recent studies showed that KIM-1 can induce tubular epithelial cells into semiprofessional phagocytes. The expression of KIM-1 increases in diabetic nephropathy，but relationship between KIM-1 mediated autophagy and renal interstitial fibrosis is not clear. Our preliminary experimental results showed the KIM-1 was involved in diabetic nephropathy through mediating autophagy as a downstream factor of hypoxia inducible factor-1.In order to investigate the role of KIM-1 mediated tubular epithelial cells autophagy in interstitial fibrosis in diabetic nephropathy，this study was designed to detect KIM-1 mediated autophagy levels in cell，animal models and clinical specimens. And apply intervention measures to curb the KIM-1 signaling pathway to investigate the role of KIM-1 mediated autophagy in interstitial fibrosis in diabetic nephropathy, and provide new targets and ideas for the prevention and treatment of diabetic nephropathy，which has important theoretical significance and application value.

糖尿病肾病是糖尿病常见的并发症，也是导致终末期肾脏病（ESRD）的主要病因之一。肾间质纤维化是ESRD 共同的病理学特点，缺氧是促进糖尿病肾病肾间质纤维化的主要因素之一。缺氧环境下，细胞自噬水平增高，而细胞自体吞噬可导致肾小管细胞凋亡，促进肾间质纤维化。肾损伤分子-1(KIM-1)虽被用作早期肾脏损伤的指标，近来研究表明KIM-1具有介导肾小管上皮细胞向"半专业"吞噬细胞转化的功能。在糖尿病肾病中KIM-1表达增高，但其介导的自体吞噬与缺氧导致的肾间质纤维化之间的关系尚不明确。我们的前期实验结果显示，KIM-1作为缺氧诱导因子调控的下游因子，很可能通过介导细胞自噬参与糖尿病肾病肾间质纤维化，本研究将通过检测细胞、动物模型和临床标本中KIM-1 介导的自体吞噬水平，同时应用干预措施抑制KIM-1相关信号通路，探讨其在缺氧所致糖尿病肾病肾间质纤维化中的作用，具有重要的理论意义和应用价值。

糖尿病肾病（DN）是导致终末期肾脏病的主要病因之一，肾小管间质病变在DN的早期就已发生且与肾功能进展密切相关。因此阐明DN肾小管间质纤维化的机制，寻找延缓DN进展的有效方法越来越受到重视。肾损伤分子-1(KIM-1) 是一种敏感性和特异性都较高的肾小管损伤标志物，近年的研究发现其还是一种有功能的分子，可能参与了肾小管的损伤和修复。KIM-1在急性肾损伤中发挥促进损伤修复的作用，而其长期高表达可促进肾小管间质纤维化，加速肾脏病进展。目前尚无相关研究探讨KIM-1在DN发生发展中的作用及机制，我们应用高糖刺激体外培养的肾小管上皮细胞，模拟DN患者肾小管上皮细胞所处的高糖环境，并用KIM-1 siRNA抑制KIM-1的表达，研究KIM-1对肾小管上皮细胞内自噬体形成，表达自噬标记蛋白、炎症因子和纤维化因子的影响。结果提示高糖环境下人肾小管上皮细胞（HK2）内自噬体形成数量及表达自噬标记蛋白微管相关蛋白l轻链3II型（LC3II）增加，下调KIM-1表达能显著抑制高糖条件下HK2细胞自噬体的形成及LC3II的表达。高糖环境下肾小管上皮细胞表达单核细胞趋化因子（MCP-1）、纤维连接蛋白（FN）及I型胶原（COL-1）增加，下调KIM-1表达可降低MCP-1及纤维化因子的表达。提示KIM-1可能通过增加细胞自噬、促进炎症因子及纤维化因子表达增加参与DN的进展。