Control of Renal Na and K Excretion

控制肾脏钠和钾的排泄

基本信息

批准号：
8694529
负责人：
LAWRENCE G PALMER
金额：
$ 59.78万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8694529
关键词：
Acute Adrenergic Agonists Agonist Aldosterone Angiotensin II Angiotensins Autonomic nervous system Biotinylation Chronic Corticosterone Defect Diet Disease Distal Distal convoluted renal tubule structure Diuretics Duct (organ) structure Endocrine system Equilibrium Excretory function Familial disease Goals Health Homeostasis Hormones Hypertension In Situ Infusion procedures Intake Ions KCNJ1 gene Kidney Measurement Measures Mediating Membrane Proteins Methods Mineralocorticoid Receptor Mus Mutate Nature Nephrons Neurotransmitters Phosphotransferases Physiological Plasma Proteins Rattus Regulation Renin Research Role SLC12A3 gene Salts Signal Transduction Simulate Surface Techniques Testing Transgenes Transport Process Up-Regulation epithelial Na+ channel in vivo insight mutant osmotic minipump patch clamp public health relevance response salt balance

项目摘要

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.

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控制机制。为此，我们将为问题带来几种互补方法，包括远端曲折小管的体内微灌注，连接小管和收集管道的电生理分析以及完整肾脏中表面膜蛋白的量化。我们将在饮食中NA和K摄入变化的条件下采用这些技术，激素状态的改变以及几种疾病状态及其治疗方法。拟议的研究将检验有关该法规性质的几个相关假设。首先，在延伸曲折小管（NaCl共晶或NCC）以及醛固酮敏感的远端肾单位中的转运蛋白改变，包括连接小管和收集管道（NA（NA（ENAC）和K ROMK））是最重要的运输机制在此法规中。其次，NA平衡的变化将导致NCC和ENAC的平行变化，而K平衡的变化会导致ENAC和ROMK的平行变化，但NCC和ENAC的反平行变化。第三，肾素 - 血管紧张素 - 醛固酮轴是参与该调节的关键激素系统，主要由醛固酮控制ENAC，而Angiotensin II进行了NCC。第四，自主神经系统通过选择性刺激NCC来促进整体调节。我们还将使用这些方法来研究家族性高钾血高血压（FHHT）的疾病。具体而言，我们将研究WNK激酶的作用 - 这些激酶以某些形式的FHHT突变 - 在Na和K排泄的调节中。结果将提供有关肾单位的两个部分以及两种循环激素如何合作，以在面对一系列饮食挑战和病理侮辱的情况下保持NA和K平衡。