胆汁酸受体FXR在肾脏水钠代谢调节中的作用及机制

项目名称： 胆汁酸受体FXR在肾脏水钠代谢调节中的作用及机制

项目编号： No.81200511

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： 张晓燕

作者单位： 深圳大学

项目金额： 25万元

中文摘要： 肾脏在水钠代谢稳态中发挥中心的调节作用。抗利尿激素和醛固酮分别通过结合集合管上皮细胞V2受体及盐皮质激素受体，控制水通道-2及钠通道表达，从而调控水、钠重吸收。胆汁酸受体（FXR）是胆汁酸合成及转运的重要调节因子，在肝脏和小肠高表达。我们的前期研究表明FXR在肾脏特别是集合管高表达；与野生型相比，FXR基因敲除小鼠在高盐饮食时24小时尿量显著增加。最近的报道也显示FXR内源激动剂鹅去氧胆酸可通过抑制11β-羟基类固醇脱氢酶2活性，增加水钠重吸收，以上研究均提示FXR可能在集合管水钠转运调节中有重要作用。本课题将通过体内、外实验探讨其对水钠代谢的影响。内容一将使用FXR基因缺失小鼠探讨其在肾脏水钠代谢调节中的作用；内容二将在培养的集合管上皮细胞研究FXR调控水钠转运的分子机制。本课题的开展不仅为阐明肾脏水钠稳态调控的机制提供实验依据，也可能为肝肾综合征等常见水钠代谢紊乱疾病的治疗提供新思路。

中文关键词： 胆汁酸受体；基因敲除；水钠重吸收；高渗；细胞凋亡

英文摘要： The kidney is the central organ in the regulation of water and salt homeostatis. Antidiuretic hormone (ADH) and aldosterone control water and salt reabsorption by activation of V2 receptor and mineralocorticoid receptor localized in the epithelial cell of the collecting ducts, controlling the expression of aquaporin 2 (AQP2) and sodium channel ENaC. Bile acid receptor (FXR), highly expressed in the liver and small intestine, is a vital regulatory factor in the synthesis and transport of bile acids. Our previously study showed that FXR abundantly expressed in the kidney, especially in the collecting duct. In addition, FXR knockout mice exhibited more 24-hour urine volume than wide type mice after treated with a high salt diet. Recently, several groups have reported that chenodeoxycholic acid (CDCA), an endogenous activator of FXR, can increase the reabsorption of water and salt by inhibiting the activity of 11beta-hydroxysteroid dehydrogenase (11β-HSD2). These findings suggest that FXR may play an important role in water and salt reabsorption in the collecting ducts. The present study is designed to clarify the role of FXR in renal water and salt metabolism. We will first study the role of FXR in the water and salt reabsorption by using FXR gene knockout mice. Secondly, we will define the molecular mechanisms by

英文关键词： bile acid receptor；gene knockout；water and sodium reabsorption；hypertonicity；cell apoptosis