糖肾方对糖尿病肾病蛋白聚糖介导肾脏脂质沉积的机制研究

项目名称： 糖肾方对糖尿病肾病蛋白聚糖介导肾脏脂质沉积的机制研究

项目编号： No.81473526

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 赵婷婷

作者单位： 中日友好医院

项目金额： 73万元

中文摘要： 肾脏脂质沉积是糖尿病肾病(diabetic nephropathy,DN)发生发展的重要因素。蛋白聚糖（Proteoglycan, PG）是细胞外基质重要成份，与中医津液密切相关，DN 病理情况下PG 异常升高，导致痰瘀互结。PG中糖胺聚糖链与脂蛋白通过静电力结合是导致脂质在组织沉积的关键因素。课题组前期研究发现，中药糖肾方能够延缓DN进展，减少肾脏脂质沉积，同时显著下调肾皮质PG表达。本研究拟从两种关键PG（decorin和biglycan）入手，通过构建无糖胺聚糖链的突变质粒，明确两者中糖胺聚糖链在肾脏固有细胞脂质沉积中的作用；继而采用db/db小鼠验证糖肾方降低其表达，减少肾脏脂质沉积，延缓DN进展的科学假说；在细胞和启动子水平明确药物对decorin/biglycan核心蛋白表达、糖链合成、结构及其与低密度脂蛋白亲和力的调控机制，从而阐释糖肾方益气养阴、化浊泄痰的科学内涵。

中文关键词： 糖肾方；2型糖尿病；脂质沉积；蛋白聚糖

英文摘要： Diabetic nephropathy (DN) is the leading cause of end stage renal disease. Lipotoxicity is one of major underlying mechanisms contributing to renal injury and the development of albuminuria in diabetic condition. Proteoglycans are the components of extracelluar matrix. They are covalently substituted with glycosaminoglycan (GAG) side chains which mediate lipidprotein retention by interacting with lipoproteins through ionic interaction. In the previous study, we found that Tangshen Formula (TSF) can significantly alleviate lipid accumulation in the kidney and delay DN progression. Meanwhile, proteoglyan expression and its GAG side synthesis in renal cortex were decreased markedly after TSF treatment. In the current proposal, we will investigate the effect of decorin and biglycan, the two proteoglycan, on the lipidprotein retention in renal cells by the plasmids with the site of GAG side conjuction mutated. The effect of TSF on the core protein of decorin and biglycan, GAGs chain synthetase molecular weight, disaccharide units, and low-density lipoprotein affinity are carried out in db/db mouse model and cells. In addition, the effect of TSF on regulating the activity of decorin/biglycan promoters is analyzed. The study will reveal the mechanism of TSF alleviates lipidprotein retention, which will provide scentific clues in clincal use in treating DN.

英文关键词： Tangshen Formula;Diabetic nephropathy;Lipid retention;Proteoglycan