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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK099284-04
Application #
9284457
Study Section
Kidney Molecular Biology and Genitourinary Organ Development (KMBD)
Program Officer
Ketchum, Christian J
Project Start
2014-06-01
Project End
2019-05-31
Budget Start
2017-06-01
Budget End
2019-05-31
Support Year
4
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Physiology
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
Yang, Lei; Xu, Shuhua; Guo, Xiaoyun et al. (2018) Regulation of renal Na transporters in response to dietary K. Am J Physiol Renal Physiol 315:F1032-F1041
Palmer, Lawrence G (2017) Epithelial transport in The Journal of General Physiology. J Gen Physiol 149:897-909
Frindt, Gustavo; Yang, Lei; Uchida, Shinichi et al. (2017) Responses of distal nephron Na+ transporters to acute volume depletion and hyperkalemia. Am J Physiol Renal Physiol 313:F62-F73
Yang, Lei; Frindt, Gustavo; Lang, Florian et al. (2017) SGK1-dependent ENaC processing and trafficking in mice with high dietary K intake and elevated aldosterone. Am J Physiol Renal Physiol 312:F65-F76
Han, Jaeyong; Lee, Seung Hun; Giebisch, Gerhard et al. (2016) Potassium Channelopathies and Gastrointestinal Ulceration. Gut Liver 10:881-889
Frindt, Gustavo; Gravotta, Diego; Palmer, Lawrence G (2016) Regulation of ENaC trafficking in rat kidney. J Gen Physiol 147:217-27
Dong, Ke; Yan, Qingshang; Lu, Ming et al. (2016) Romk1 Knockout Mice Do Not Produce Bartter Phenotype but Exhibit Impaired K Excretion. J Biol Chem 291:5259-69
Alexander, Stephen Ph; Kelly, Eamonn; Marrion, Neil et al. (2015) The Concise Guide to PHARMACOLOGY 2015/16: Overview. Br J Pharmacol 172:5729-43
Gleason, Catherine E; Frindt, Gustavo; Cheng, Chih-Jen et al. (2015) mTORC2 regulates renal tubule sodium uptake by promoting ENaC activity. J Clin Invest 125:117-28
Guo, Xiaoyun; Li, Zezhi; Zhang, Chen et al. (2015) Down-regulation of PRKCB1 expression in Han Chinese patients with subsyndromal symptomatic depression. J Psychiatr Res 69:1-6

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