NOD2调控Snail表达介导糖尿病肾病足细胞EMT的作用机制

Epithelial-mesenchymal transition (EMT) of podocyte plays a crucial role in the development of proteinuria in diabetic nephropathy (DN). Snail is the key transcriptional factor that initiates EMT. However, the mechanism of Snail activation and how Snail induces EMT in DN is still unclear. Our previous study has shown that, in DN mice model, over-expression of innate immune receptor NOD2 can aggravate proteinuria and renal injury. The results of our pre-experiments suggested that, in samples from DN patients and mice model, NOD2 up-regulation was associated with EMT of podocyte. What’s more, silence of NOD2 gene in cultured podocyte could significantly inhibit high glucose-induced Snail expression and EMT. Based on these results, we propose that NOD2 may promote Snail-induced EMT of podocyte in DN and aggravate renal damage. We will use samples from DN patients, animal models and cultured podocyte to investigate: 1. The relationship between NOD2 and Snail-induced EMT of podocyte; 2. The role of NOD2 in Snail regulation; 3. The effect of NOD2 gene knockdown on EMT of podocyte and diabetic renal injury. We will discuss the mechanism of EMT from the perspective of innate immune reaction, which may provide us new target for the treatment of diabetic nephropathy.

足细胞上皮-间质转分化（EMT）是糖尿病肾病（DN）发生蛋白尿的重要机制之一。Snail是启动EMT的关键转录因子，但DN时Snail活化并促进EMT的原因并不清楚。我们前期发现，DN小鼠模型中固有免疫受体NOD2过表达可加重蛋白尿及肾损伤。预实验结果提示：DN患者及小鼠模型肾皮质中NOD2表达上调与足细胞EMT相关；体外培养的足细胞中，干扰NOD2表达能明显抑制高糖诱导的Snail过表达及EMT过程。因此我们提出以下科学假设：在DN足细胞中，NOD2可促进Snail介导的EMT从而加重肾损伤。本课题拟从患者标本、动物及细胞水平观察：1.NOD2与Snail介导的足细胞EMT的关系。2.NOD2调控Snail的分子机制。3.干预NOD2对足细胞EMT及DN肾脏损伤的作用。本课题从固有免疫角度探讨足细胞EMT的发生机制，有望为探索糖尿病肾病治疗的新靶点提供依据。

研究表明足细胞上皮间质转分化（EMT）是糖尿病肾病（DN）发生蛋白尿的重要机制之一。Snail可调控EMT相关蛋白的转录过程，是启动足细胞EMT的关键因子，而NOD2过表达可能是促进足细胞EMT的重要因素。我们提出以下科学假设：在DN足细胞中，NOD2表达上调可促进足细胞Snail介导的EMT从而加重DN肾损伤。主要研究内容为通过患者标本、动物模型及体外培养的足细胞观察：1、NOD2与Snail介导的DN足细胞EMT的关系。2、NOD2调控Snail的分子机制。3、干预NOD2表达对足细胞EMT及DN肾脏损伤的作用。我们的研究发现：1、高糖增加NOD2及Snail表达、促进足细胞转分化。2、转染shRNA干扰NOD2表达后给予高糖刺激，人肾小球足细胞中Snail及EMT相关蛋白表达显著下降。3、转染shRNA干扰Snail表达后用MDP活化NOD2，Snail表达升高表明NOD2为调控Snail表达的上游分子，同时人肾小球足细胞中EMT相关蛋白的表达变化具有统计学意义（P<0.05）。4、小鼠模型中敲除NOD2后的DN小鼠的组织损伤程度明显减轻，验证了NOD2与DN肾小球组织损伤有关。上述研究成果有望为探索糖尿病肾病治疗的新靶点提供依据。