肾结石形成中CaSR对大鼠髓袢升支粗段管周膜氯通道的调控

Hypercalcinuria is the main risk factor of nephrolithiasis and closely related with renal salt and Ca2+ transport. However, our understanding of its pathogenesis is quite incomplete. The gain-of-function mutation of Calcium-Sensing-Receptor (CaSR) gene which has been considered as a candidate gene of kidney stone in the basolateral membrane in the TAL of kidney could inhibit the reabsorption of NaCl and Ca2+. Our previous work showed that the stimulation of CaSR could inhibit the activities of the basolateral 10pS Cl channels which play an important role in renal salt and Ca2+ transport in the TALs of rat kidney. So we supposed that the stimulation of CaSR may cause hypercalcinuria which could increase the incidence of kidney stone through inhibiting the basolateral 10pS Cl channels in the TAL of kidney.According to this hypothesis,we plan to study the regulation of CaSR on the Cl- channels in the formation of hypercalcinuria and kidney stones and the effect of CaSR on hypercalcinuria and kidneys stones through calcuim oxalate (CaOx)rat models. Furthermore, we will also use single channel patch clamp technique and molecular biology technique to investigate the machanism of the mudulation of CaSR on the basolateral 10pS Cl channels in the TAL. This program will advance our understanding of the ion transport in the TAL ,provide a new roadmap for the pathogenesis of nephrolithiasis and expore a new way to prevent and cure kidney stones.

高钙尿是肾结石形成的主要危险因素，其发生与肾脏水盐代谢及Ca2+重吸收密切相关,具体发病机制目前尚不清楚。大鼠肾脏髓袢升支粗段TAL管周膜钙敏感受体CaSR基因功能获得性突变能抑制NaCl及Ca2+的重吸收，被认为是肾结石形成的候选基因。本项目组前期工作已经证实，CaSR激活后能抑制TAL管周膜10pS氯通道，而后者在肾脏水盐代谢及钙平衡中起着重要的作用。我们提出假说：CaSR激活后通过抑制10pS氯通道的活性，抑制NaCl及Ca2+的重吸收，形成高钙尿，增加肾结石的几率。本项目拟利用草酸钙肾结石大鼠模型，在体研究肾结石形成中，CaSR对氯通道的调控，及对高钙尿进而肾结石的影响，并利用单通道膜片钳技术、分子生物学技术，进一步研究CaSR对10pS氯通道的调控机制。本课题的完成将深入阐明TAL离子转运，为明确肾结石的发病机制提供新思路，为防治肾结石开拓新途径。