Biomechanical Regulation of Renal Ion Transporters

描述（由申请人提供）：肾小管流速的变化使肾小管上皮细胞受到剪切应力和静水压力的变化，最终影响细胞功能。远端肾单位，特别是皮质集合管（CCD），由2种主要细胞类型组成：钠吸收主细胞（70%）和酸碱转运闰间细胞（30%）。主细胞具有顶端上皮钠通道（ENaCs），其在经上皮钠吸收中发挥关键作用。插层细胞的酸碱转运分别由位于β-和α-插层细胞的顶端阴离子交换剂和质子泵介导。兔CCD响应于流量增加，Na吸收增加以及碳酸氢盐分泌减少。该申请将解决ENaC激活的流量依赖性机制，从而扩展当前资助期内开始的研究，并启动旨在探索质子和碳酸氢盐运输流量调节机制的调查。拟议的研究将利用CCD，培养的上皮细胞和爪蟾卵母细胞，以确定流动增加ENaC开放概率的机制。在兔CCD中进行的研究将解决血流减少净碳酸氢盐分泌的机制。这些拟议的研究应提供新的信息，在CCD的钠和酸/碱运输的监管。

DESCRIPTION (provided by applicant): Variability in renal tubular flow rates subject tubular epithelial cells to changes in shear stress and hydrostatic pressure that ultimately affects cellular function. The distal nephron, and specifically the cortical collecting duct (CCD), is comprised of 2 major cell types: Na-absorbing principal cells (70%) and acid-base transporting intercalated cells (30%). Principal cells possess apical epithelial Na channels (ENaCs), which have a key role in transepithelial Na absorption. Acid-base transport by intercalated cells is mediated by apical anion exchangers and proton pumps localized to beta-and alpha-intercalated cells, respectively. Rabbit CCDs respond to an increase in flow with an increase in Na absorption as well as a reduction in bicarbonate secretion. This application will address mechanisms underlying flow-dependence of ENaC activation, and thus extend studies begun in the current funding period, and initiate an investigation directed at exploring mechanisms underlying flow-regulation of proton and bicarbonate transport. Proposed studies will utilize CCDs, cultured epithelial cells and Xenopus oocytes to determine mechanisms by which flow increases ENaC open probability. Studies in rabbit CCDs will address mechanisms by which flow reduces net bicarbonate secretion. These proposed studies should provide new information regarding the regulation of Na and acid/base transport in the CCD.