核受体LXRβ对肾脏集合管上皮水通道蛋白AQP2的调节机制

项目名称： 核受体LXRβ对肾脏集合管上皮水通道蛋白AQP2的调节机制

项目编号： No.31500940

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 生物科学

项目作者： 赵滢滢

作者单位： 深圳大学

项目金额： 20万元

中文摘要： 肾脏集合管上皮细胞管腔面分布的水通道Aquaporin2(AQP2)对尿液浓缩和机体水平衡的维持发挥至关重要的作用。AQP2蛋白水平及其在管腔面的分布量直接影响机体产生的尿量。细胞通过出胞和胞吞改变管腔面AQP2的数量来调节集合管对水的通透性，而AQP2泛素化在其膜转运过程中发挥重要作用。前期研究发现核受体LXRβ可以通过增加中枢抗利尿激素的释放促进肾对水的重吸收，其机制可能和集合管上皮细胞中AQP2蛋白增加相关。但近期发现，离体原代细胞培养下LXRβ激活可以对AQP2进行转录后调节，且此调节很可能通过影响其泛素化来实现。鉴此，本课题将重点探讨：(1) 核受体LXRβ上调肾脏集合管上皮细胞中AQP2蛋白水平的机制；(2) LXRβ如何通过影响AQP2泛素化来改变细胞对水的通透性。本课题的开展将对阐明肾脏水重吸收调控机制提供重要的实验依据，并为水代谢异常疾病的治疗及药物开发提供相关思路。

中文关键词： 集合管；水通道；核受体；水平衡；泛素化

英文摘要： The kidney play important role in regulating body water homeostasis. Water channels (Aquaporins, AQPs) located in the apical and basolateral membrane of epithelial cells along renal tubules are essential for water reabsorption and urine concentration. Apical accumulation of Aquaporin2 (AQP2) of renal collecting duct will increases the water permeability and lead to urine concentration. Among all renal water channels, AQP2 expression is regulated by circulating arginine vasopressin (AVP). Liver X Receptors (LXRs) are well-known for their role in lipid homeostasis. Our previous study suggests nuclear receptor LXRβ is also a key receptor in controlling water balance with targets in AVP system. LXRβ can induce AVP expression in hypothalamus and lead to water reabsorption in kidney. Our present data showed that activation of LXRβ increased the protein level of AQP2 via affecting it’s ubiquitination in primary cultured mouse inner medullary duct cells. It suggests that beside the above mentioned central AVP mechanisms, LXRβ possess a peripheral nephrogenic mechanism in regulating water balance through direct regulating AQP2 in renal collecting duct. In contrast to the well-established AVP mediated regulation in protein level and protein phosphorylation, LXRβ regulation of AQPs via post-transcriptional modification is poorly understood. To improve our understanding of basic mechanism, we propose to: (1) characterized how LXRβ regulating AQP2 protein level in collecting duct principle cell; (2) identified the pathway responsible for LXRβ activation induced AQPs ubiquitination stasis change. Detailed knowledge of the molecular mechanisms for AQP2 regulation would provide new therapeutic targets for water balance disorders in patients.

英文关键词： collecting duct;Aquaporin;nuclear receptor;water homeostasis;ubiquitination