Cardiovascular disease is the leading cause of death in the United States. Systemic arterial hypertension (or simply hypertension) is a major risk factor for the development of cardiovascular disease. Aldosterone and desoxycorticosterone (DOC) are mineralocorticoids that cause hypertension through increased urinary sodium (Na) retention and hypokalemic metabolic alkalosis through greater urinary acidification. Mineralocorticoids affect distal nephron and collecting duct (CD) ion transport to achieve these effects. The CD expresses at least two isoforms of H,K-ATPases, HK1 and HK2, that participate in acid secretion by the CD. Our recent studies also show that chronic DOC pivalate (DOCP) administration stimulates renal Na retention, weight gain, and metabolic alkalosis that are dependent on the presence of H,K-ATPases. Specifically, mice that lack both H,KATPases (HK1,2 -/-) failed to develop significant Na retention or metabolic alkalosis in response to DOCP stimulation. Comparison of the response of the single HK1 -/- to the double HK1,2 -/- strongly suggests an important physiological role for the H,K-ATPase HK2 isoform in the response to DOCP. Therefore, our central hypotheses are that: A) the H,K-ATPase HK2 isoform is critical for the chronic action of mineralocorticoids to produce renal Na retention, cause hypokalemic metabolic alkalosis, and increase blood pressure (BP); and that B) dietary K loading abolishes or attenuates mineralocorticoid action on Na retention and electrolyte abnormalities, which are dependent on the induction of the H,K-ATPase HK2 isoform in the kidney. We propose the following specific aims: 1) to determine the role of the H,K-ATPase HK2 isoform in the ion transport response to chronic mineralocorticoid treatment; 2) to determine the role of H,K-ATPase HK2 isoform in the regulation of blood pressure and the contribution of K intake and hypokalemia to these changes; 3) to determine if the differences in WT and HK2 KO animals in response to DOCP administration reflect a renal phenotype. We will test the novel physiological hypothesis that the H,K-ATPase HK2 isoform has an important role in Na homeostasis, volume regulation and BP control. As such, we have developed an integrated approach that combines whole animal metabolic balance studies, in vitro microperfusion, state-ofthe- art radiotelemetry measurement of BP, and renal transplantation to examine the physiological significance of HK2 stimulation by mineralocorticoids.

Public Health Relevance

These studies have direct relevance to our understanding of electrolyte disorders such as hypokalemia and metabolic alkalosis, which are potentially lethal disorders that are frequently seen in the veteran population. In addition, this research will provide a better understanding of the fundamental mechanisms of sodium regulation by the kidney. Excessive sodium absorption mediated by aldosterone and mineralocorticoids predictably leads to hypertension that is prevalent in the veteran population. Hypertension is a major cause of death among veterans due to the development of cardiovascular disease and the high incidence of stroke in hypertensive patients. These diseases are the leading cause of death among veterans as well as the general population of the United States. These studies examine a novel mechanism for renal sodium retention by mineralocorticoids and aldosterone. This proposal should identify new targets for drug therapy and intervention to more effectively control renal sodium regulation and hypertension that is so prevalent in the veteran population.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX001472-03
Application #
8762426
Study Section
Nephrology (NEPH)
Project Start
2012-10-01
Project End
2016-09-30
Budget Start
2014-10-01
Budget End
2015-09-30
Support Year
3
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Veterans Health Administration
Department
Type
DUNS #
097378632
City
Gainesville
State
FL
Country
United States
Zip Code
32608
Welch, Amanda K; Jeanette Lynch, I; Gumz, Michelle L et al. (2016) Aldosterone alters the chromatin structure of the murine endothelin-1 gene. Life Sci 159:121-126
Gumz, Michelle L; Rabinowitz, Lawrence; Wingo, Charles S (2015) An Integrated View of Potassium Homeostasis. N Engl J Med 373:60-72
Wingo, Charles S (2013) Introduction: potassium homeostasis in humans: our current understanding. Semin Nephrol 33:205-6
Welch, Amanda; Maroz, Natallia; Wingo, Charles S (2013) Hyperkalemia: getting to the heart of the matter. Nephrol Dial Transplant 28:15-6
Giebisch, Gerhard H; Wingo, Charles S (2013) Renal potassium homeostasis: a short historical perspective. Semin Nephrol 33:209-14
Asmar, Abdo; Mohandas, Rajesh; Wingo, Charles S (2012) A physiologic-based approach to the treatment of a patient with hypokalemia. Am J Kidney Dis 60:492-7
Greenlee, Megan M; Lynch, I Jeanette; Gumz, Michelle L et al. (2011) Mineralocorticoids stimulate the activity and expression of renal H+,K+-ATPases. J Am Soc Nephrol 22:49-58
Wingo, Charles S; Greenlee, Megan M (2011) Progesterone: not just a sex hormone anymore? Kidney Int 80:231-3