Control of Renal Na and K Excretion

描述（由申请人提供）：我们将研究肾脏Na和K排泄及其相互作用的潜在控制机制。为此，我们将带来几个互补的方法来解决这个问题，包括在体内微灌注的远曲小管，电生理分析的连接小管和集合管，并在完整的肾脏表面膜蛋白的定量。我们将采用这些技术的条件下，饮食中的钠和钾的摄入量的变化，激素状态的改变和几种疾病的状态及其治疗。拟议中的研究将测试几个相关的假设，这一规定的性质。首先，在远曲小管（NaCl共转运或NCC）和醛固酮敏感的远端肾单位，包括连接小管和集合管（Na（ENaC）和K ROMK）通道）的转运蛋白的改变是最重要的运输机制参与这种调节。第二，Na平衡的变化会引起NCC和ENaC的平行变化，K平衡的变化会引起ENaC和ROMK的平行变化，但NCC和ENaC的变化是反平行的。第三，肾素-血管紧张素-醛固酮轴是参与这种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地刺激NCC而有助于整体调节。我们也将利用这些方法来探讨家族性高钾血症性高血压（FHHt）的疾病。具体来说，我们将研究WNK激酶的作用-这是突变的某些形式的FHHt -在调节钠和钾排泄。结果将提供深入了解肾单位的两个部分，以及两种循环激素，如何合作，以保持钠和钾平衡，面对一系列的饮食挑战和病理损伤。

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.