Control of Renal Na and K Excretion

描述(由申请人提供)：我们将研究控制肾脏钠和钾排泄的潜在机制及其相互作用。为此，我们将提出几种互补的方法来解决这个问题，包括远端曲小管的体内微灌流，连接小管和集合管的电生理分析，以及完整肾脏表面膜蛋白的定量。我们将在饮食钠和钾摄入量变化、激素状态变化以及几种疾病状态及其治疗的条件下使用这些技术。拟议的研究将检验关于这一规定性质的几个相关假设。首先，包括连接小管和集合管(Na(ENaC)和K ROMK通道)在内的远端曲管转运体(氯化钠共转运体或NCC)和对醛固酮敏感的远端肾单位转运体的改变是参与这一调控的最重要的转运体机制。第二，Na平衡的变化会导致NCC和ENaC的平行变化，而K平衡的变化会产生ENaC和ROMK的平行变化，而NCC和ENaC的变化是反平行的。第三，肾素-血管紧张素-醛固酮轴是参与这一调节的关键激素系统，ENaC主要由醛固酮控制，NCC由血管紧张素II控制。第四，自主神经系统通过选择性刺激NCC参与整体调节。我们还将利用这些方法来研究家族性高钾性高血压(FHHt)的疾病。具体地说，我们将研究WNK激酶--在某些形式的FHHt中发生突变--在调节Na和K排泄中的作用。这一结果将让我们深入了解肾单位的两个部分，以及两种循环激素，如何在面对一系列饮食挑战和病理性侮辱时，保持钠和钾的平衡。

DESCRIPTION (provided by applicant): We will investigate the mechanisms underlying control of renal Na and K excretion and their interactions. To this end, we will bring several complementary approaches to the problem, including in vivo microperfusion of distal convoluted tubules, electrophysiological analysis of connecting tubules and collecting ducts, and quantification of surface membrane proteins in the intact kidney. We will employ these techniques under conditions of changes in dietary Na and K intake, alterations in hormone status and several disease states and their treatments. The proposed research will test several related hypotheses on the nature of this regulation. First, alterations in transporters in the distl convoluted tubule (NaCl cotransport or NCC) and in the aldosterone-sensitive distal nephron, comprising the connecting tubule and collecting ducts (Na (ENaC) and K ROMK) channels) are the most important transport mechanisms involved in this regulation. Second, changes in Na balance will produce parallel changes in NCC and ENaC, while changes in K balance produce parallel changes in ENaC and ROMK, but antiparallel changes in NCC and ENaC. Third, the renin-angiotensin- aldosterone axis is a key hormonal system involved in this regulation, with ENaC controlled mainly by aldosterone, and NCC by angiotensin II. Fourth, the autonomic nervous system contributes to the overall regulation by selectively stimulating NCC. We will also use these approaches to investigate to the disorder of Familial Hyperkalemic Hypertension (FHHt). Specifically, we will examine the roles of WNK kinases - which are mutated in some forms of FHHt - in the regulation of Na and K excretion. The results will provide insight into how two segments of the nephron, together with two circulating hormones, cooperate in order to maintain Na and K balance in the face of a range of dietary challenges and pathological insults.