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.
The kidney has to maintain the correct amounts of both Na and K salts in the body by excreting them at appropriate rates. In the proposed research we will examine how these ions can be regulated separately by focusing on two different segments of the kidney, two different targets (mechanisms of transport), and three different effectors (hormones and neurotransmitters). The proposed studies will help us to understand how salt balance is regulated in both health and disease.