肝X受体通过调节肾小球脂代谢参与2型糖尿病肾病的机制研究

项目名称： 肝X受体通过调节肾小球脂代谢参与2型糖尿病肾病的机制研究

项目编号： No.81200536

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学二处

项目作者： 孔晓牧

作者单位： 中日友好医院

项目金额： 25万元

中文摘要： 糖尿病肾病（DN）是导致终末期肾病的主要病因，肾小球脂代谢异常导致的脂毒性与DN发病有重要关系。研究表明，肝X受体（LXRs）包括LXRα和LXRβ在维持肾脏脂代谢稳态中具有重要作用。我们前期的研究发现LXRs激动剂处理2型糖尿病db/db小鼠12周可加重白蛋白尿、肾小球硬化，伴随脂代谢合成通路的激活。由此，我们推测LXRα和LXRβ可能通过调节肾脏脂代谢途径参与2型DN的发生。为验证上述假说，我们计划：1）探讨LXRα和LXRβ非选择性激动剂处理、LXRα或LXRβ基因缺陷对db/db小鼠DN发病的影响；2）LXRs激动剂与抑制剂对高糖处理的野生型和原代培养的LXRα或LXRβ敲除肾小球细胞（足细胞和系膜细胞）生长、细胞外基质蛋白合成及脂代谢通路的改变。本课题的开展将有助于阐明DN的发生发展机制，为临床防治和新药研发提供新思路。

中文关键词： 肝X受体；2型糖尿病；糖尿病肾病；；

英文摘要： Diabetic nephropathy (DN) is the leading cause of end stage renal disease. Glomerular lipotoxicity is one of major underlying mechanisms contributing to glomerular injury and the development of albuminuria in diabetic condition. Liver X receptors (LXRs) play an important role in maintaining lipid homeostasis in kidney by modulating cholesterol efflux and triglycerides biosynthesis. It has been previously reported that renal LXRs were upregulated in the kidneys of type 2 diabetic mice. Our previous work found that type 2 diabetic db/db mice exhibited a significant increase in albuminuria, a worsened glomerulosclerosis, and an enhanced lipogenesis after the treatment with a non-selective LXRs agonist T0901317 for 12 weeks, suggesting aberrant activation of LXRs may result in the pathogenesis of diabetic nephropathy. The present study was designed to clarify the role of both LXRα and LXRβ in diabetic renal complications. The specific aim #1 will determine the effect of LXR activation (LXRs agonists) and inactivation (LXRα or LXRβ gene deficiency) on albuminuria, glomerular fibrosis and renal lipid metabolism in db/db mice. Specific aim #2 will examine the role of LXRs in high glucose-induced lipotoxicity and extracellular matrix production in cultured renal cells with or without LXRα and LXRβ gene ablation in the p

英文关键词： Liver X receptor；Type 2 diabetes；Diabetic nephropathy；；