血管生长素2调控足细胞穿胞在糖尿病肾病早期白蛋白尿中的作用及其机制

Albuminuria is an independent risk factor leading to the progression of diabetic nephropathy, but the mechanism is not clear. Podocytes can transfer the albumin completely by transcytosis mediated by receptor FcRn. Our previous studies demonstrated the transcytosis of albumin by podocytes was increased by high glucose, but the regulation mechanism is unknow. The expression of angiopoietin 2 was upregulated both in diabetic nephropathy patients and mice. The transcytosis of the albumin could be inhibited by angiopoietin 2 siRNA in vitro. These data indicated that the transcytosis of albumin regulated by angiopoietin 2 might be the potential mechanism of albuminuria during the early stage of diabetes. It was thought that serum glucocorticoid-inducible kinase 1 (SGK1) may be an important molecule factor which mediates the biological effects of Ang-2, however, the role of the SGK1 in the development of albuminuria during the early stage of diabetes is not clear. We will establish transcytosis model in vitro, podocyte specific FcRn knockout mice and angiopoietin 2 heterozygous knockout mice in vivo to explore the role of albumin trancytosis mechanism in the development of albuminuria, and investigate the regulation role of angiopoietin 2/SGK1.

白蛋白尿是糖尿病肾脏病（DN）持续进展的独立危险因素，但其发病机制未明。研究证实，足细胞在受体FcRn介导下，可通过穿胞作用将白蛋白转运至细胞外。我们的前期研究发现，高糖可增强足细胞对白蛋白的穿胞作用，但机制尚不清楚。血管生长素2（Ang-2）在2型糖尿病肾病患者及DN小鼠肾组织表达明显升高，而体外抑制Ang-2可降低足细胞对白蛋白的穿胞，这提示Ang-2可能通过调控穿胞作用参与DN早期白蛋白尿的发生。新近研究发现，血清和糖皮质激素诱导蛋白激酶1 (SGK1)可能是介导Ang-2生物学效应的重要分子，但其在DN早期白蛋白尿中的作用机制尚不明确。本课题组拟采用体外穿胞模型、足细胞特异性FcRn基因敲除小鼠及Ang-2功能性基因敲除小鼠模型，探讨足细胞穿胞在DN早期白蛋白尿发病机制中的作用，并阐明Ang-2-SGK1信号通路调控白蛋白在足细胞穿胞的分子机制。

糖尿病肾病（DN）是严重危害人类健康的疾病，白蛋白尿是DN的首发临床表现，也是糖尿病肾脏病持续进展的独立危险因素，但具体机制不详。本研究通过体外和体内实验，观察了高糖及糖尿病环境下肾脏细胞对白蛋白的穿胞情况，结果发现:（1）高糖条件下，洛沙坦可能通过抑制Angiopoietin-2/IL-18通路，减少了肾小球足细胞对白蛋白穿胞，减少了糖尿病肾病早期白蛋白尿的生成；（2）高糖条件下，洛沙坦可能通过抑制caveolin1，抑制白蛋白穿胞，减少了糖尿病肾病早期白蛋白尿的生成；（3） 高糖条件下，洛沙坦可能通过抑制Angiopoietin-2/IL-18通路，抑制白蛋白穿胞，减少了糖尿病肾病早期白蛋白尿的生成；（4）高糖条件下，褐藻多糖硫酸酯可能通过抑制Angiopoietin 2/caveolin 1通路，增加了肾小管上皮细胞对白蛋白穿胞，减少了糖尿病肾病早期白蛋白尿的生成。这些研究结果对糖尿病肾病发病机制提供了新的线索；对寻找早期干预和治疗白蛋白尿的方法，提供了新的靶点。