Our goal is to provide a coherent mechanistic explanation for how the NaCl cotransporter (NCC) of the renal distal tubule is regulated in response to variation in potassium diet. Such a response is thought to play a central role in switching the mineralocorticoid hormone response of the kidney to either conserve sodium or excrete potassium, depending on whether aldosterone is induced by a change in dietary sodium or potassium. It is well known that NCC is up regulated by aldosterone in states of low Na diet and intravascular volume depletion. Remarkably, however, NCC is suppressed in high aldosterone states that accompany hyperkalemia or following ingestion of a potassium-rich diet. Perhaps even more surprising, NCC is activated following ingestion of a low potassium diet when aldosterone is kept low to minimize potassium secretion. While it is widely believed that the WNK-SPAK network of kinases functions as a physiological """"""""switch"""""""" to coordinate renal Na reabsorption and potassium secretion, current models fail to explain how NCC can be regulated by potassium diet independent of aldosterone. Our goal is to resolve this riddle with a new and testable model that explains how regulation of NCC can become uncoupled from aldosterone signals. We use animal models to test specific predictions of our proposed model to demonstrate that the mechanism is functionally relevant in the in vivo kidney. We then use the mpkDCT cell model and methods that manipulate critical components to carry out mechanistic tests of the model's predictions.
Our aim i s to fill a fundamental gap in the understanding of how renal Na transport is coordinated with potassium diet. We expect to answer the following specific questions: 1) What is the role of SPAK and WNK4 phosphorylation in activation of NCC in the kidney? 2) How do WNKs modulate SPAK-Dependent regulation of NCC?

Public Health Relevance

This work will study genes in the kidney well known to be involved in the regulation of blood pressure and potassium homeostasis. We will evaluate the mechanism whereby these genes affect the renal NaCl co-transporter's response to dietary potassium. This should provide insights that will help identify new drug targets for use in the treatment of hypertension. By studying the effect of potassium diet on sodium transport we hope to develop an explanation for the finding that high potassium diet reduces hypertension.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK032839-27
Application #
8515994
Study Section
Cellular and Molecular Biology of the Kidney Study Section (CMBK)
Program Officer
Mullins, Christopher V
Project Start
1984-03-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
27
Fiscal Year
2013
Total Cost
$297,353
Indirect Cost
$99,118
Name
University of Maryland Baltimore
Department
Physiology
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Wade, James B; Liu, Jie; Coleman, Richard et al. (2015) SPAK-mediated NCC regulation in response to low-K+ diet. Am J Physiol Renal Physiol 308:F923-31
Grimm, P Richard; Lazo-Fernandez, Yoskaly; Delpire, Eric et al. (2015) Integrated compensatory network is activated in the absence of NCC phosphorylation. J Clin Invest 125:2136-50
Li, Lijun; Garikepati, R Mayuri; Tsukerman, Susanna et al. (2013) Reduced ENaC activity and blood pressure in mice with genetic knockout of the insulin receptor in the renal collecting duct. Am J Physiol Renal Physiol 304:F279-88
Grimm, P Richard; Taneja, Tarvinder K; Liu, Jie et al. (2012) SPAK isoforms and OSR1 regulate sodium-chloride co-transporters in a nephron-specific manner. J Biol Chem 287:37673-90
Wade, James B; Fang, Liang; Coleman, Richard A et al. (2011) Differential regulation of ROMK (Kir1.1) in distal nephron segments by dietary potassium. Am J Physiol Renal Physiol 300:F1385-93
Liu, Wen; Schreck, Carlos; Coleman, Richard A et al. (2011) Role of NKCC in BK channel-mediated net K⁺ secretion in the CCD. Am J Physiol Renal Physiol 301:F1088-97
Wade, James B (2011) Statins affect AQP2 traffic. Am J Physiol Renal Physiol 301:F308
Welling, Paul A; Chang, Yen-Pei C; Delpire, Eric et al. (2010) Multigene kinase network, kidney transport, and salt in essential hypertension. Kidney Int 77:1063-9
Wang, Ying; O'Connell, Jeffrey R; McArdle, Patrick F et al. (2009) From the Cover: Whole-genome association study identifies STK39 as a hypertension susceptibility gene. Proc Natl Acad Sci U S A 106:226-31
Fang, Liang; Garuti, Rita; Kim, Bo-Young et al. (2009) The ARH adaptor protein regulates endocytosis of the ROMK potassium secretory channel in mouse kidney. J Clin Invest 119:3278-89

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