Chemerin通过P38MAPK途径介导糖尿病肾病及硫辛酸干预研究

Diabetic nephropathy is the most main microvascular complications of diabetes, which is a major threat to public health. Adipokine chemerin, a novel adipocyte-secreted factor was implicated in diabetic nephropathy progression. However, the precise mechanism of diabetic nephropathy by adipokine chemerin in diabetes has not been clarified. On the other hand, lipoic acid, an antioxidant has been attracting particular attention because of the protective effect on diabetic nephropathy. Recently, chemerin and lipoic acid were shown to be associated with p38 Mitogen-activated protein kinase-fibronectin (P38MAPK) signal pathway and inflammation in diabetic nephropathy. In contrast to the established role of chemerin and lipoic acid in P38MAPK signal pathway or inflammation, its molecular mechanisms remain elusive. Previously, we have found that chemerin and its receptor was observed to be higher expressed in kidney of diabetic rats, which preliminarily proved the correlation between chemerin and diabetic nephropathy. On this basis, this project will provide insights into the link between chemerin, p38MAPK, NF-κB signal pathway and inflammation through vivo and vitro experiments; lipoic acid intervention will be also involved in this study. Furthermore, we will explore its possible molecular mechanisms that can lead to the identification of a new target for diabetic nephropathy.

糖尿病肾病是糖尿病最主要的微血管并发症，是威胁公众健康的重大问题。最近有研究表明新发现的脂肪因子chemerin可能与糖尿病肾病的发生发展相关。另外，硫辛酸作为一种抗氧化营养素，在糖尿病肾病中的保护作用也越来越受到关注。最近研究提示chemerin引起的炎症损伤可能与P38MAPK信号通路有关，我们的前期工作观察到chemerin及其受体在糖尿病大鼠肾脏中表达增加，初步证明了chemerin与糖尿病肾病的相关性，但确切的作用机制尚不清楚。在前期工作基础上，本项目将通过体内及体外实验，分别从基因及蛋白水平求证chemerin对糖尿病肾病P38MAPK及其下游NF-κB信号通路相关的炎症因子的影响作用，以及硫辛酸干预对以上影响的抑制作用，以期寻求预防及治疗糖尿病肾病的新靶点。

糖尿病肾病是糖尿病常见且严重的微血管并发症，但其确切发病机制至今尚未阐明。最近发现脂肪因子chemerin可能与糖尿病肾病的发生发展相关。另外，硫辛酸作为一种抗氧化剂，在糖尿病肾病中的保护作用也越来越受到关注。本项目探讨chemerin对糖尿病肾病及P38MAPK信号通路的影响，以及硫辛酸的干预作用。通过单侧肾切除及STZ诱导建立糖尿病肾病大鼠模型。采用全自动生化仪测定空腹血糖 (FBG)，尿素氮(BUN)和肌酐（Cr）；采用放射免疫法测定24小时尿蛋白排泄率。RT-PCR法及western blot法测定 chemerin及P38MAPK的表达。于体外实验中Western blot法检测chemerin及硫辛酸对人肾小球系膜细胞中P38-MAPK、NF-κB及TGF-β蛋白表达的影响。结果发现动物实验中，糖尿病肾病组肌酐、尿素氮、尿微量白蛋白排泄率均明显高于对照组，硫辛酸组上述指标明显下降。糖尿病肾病组chemerin 及P38MAPK表达量明显增加；硫辛酸干预后上述指标下降。在体外实验中，chemerin刺激人肾小球系膜细胞，P38MAPK及其下游NF-κB信号通路表达显著增加；硫辛酸干预后能够明显抑制以上蛋白的表达。提示chemerin通过激活P38-MAPK及其下游NF-κB信号通路，影响糖尿病肾病的发生发展，而硫辛酸对以上过程具有抑制作用。本项目为寻求治疗糖尿病肾病的新靶点提供方向。