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; 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
Spector, David A; Yang, Qing; Klopouh, Leonid et al. (2008) The ROMK potassium channel is present in mammalian urinary tract epithelia and muscle. Am J Physiol Renal Physiol 295:F1658-65
Cunningham, Rochelle; Brazie, Marc; Kanumuru, Srilatha et al. (2007) Sodium-hydrogen exchanger regulatory factor-1 interacts with mouse urate transporter 1 to regulate renal proximal tubule uric acid transport. J Am Soc Nephrol 18:1419-25
Spector, David A; Yang, Qing; Wade, James B (2007) High urea and creatinine concentrations and urea transporter B in mammalian urinary tract tissues. Am J Physiol Renal Physiol 292:F467-74
Alewine, Christine; Olsen, Olav; Wade, James B et al. (2006) TIP-1 has PDZ scaffold antagonist activity. Mol Biol Cell 17:4200-11

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