Hypertension (High blood pressure) affects 1 in 3 adults and is an independent risk factor for the development of cardiovascular disease and stroke. Salt-sensitive hypertension is prevalent in African Americans and the incidence of end-stage renal disease (ESRD) attributable to hypertension is 6-fold higher in African Americans when compared to whites. The etiology of salt-sensitive hypertension and the factors that lead to progression of hypertensive kidney injury remain poorly understood. Hv1 (encoded HVCN1) is a voltage-gated H+ channel which is required for maximal reactive oxygen species formation during the bacterial killing respiratory burst in immune cells. A number of recent studies have identified a role of Hv1 in non-immune tissues, including in the lung and spermatozoa. Our compelling preliminary data are the first to localize Hv1 to the kidney, where it its present on th apical membrane of medullary thick ascending limb (mTAL). Our hypothesis is that Hv1 contributes to the development of salt-sensitive hypertension and renal injury both by enhancing Na+ reabsorption in this nephron segment and by promoting reactive oxygen species formation. We hypothesize that through these mechanisms, augmented activity of Hv1 in the kidney of Dahl salt-sensitive rats contributes to the development of hypertension, oxidative stress and renal injury in this model. We will test our hypothesis in wild-type Dahl salt-sensitive, salt-resistant and Hv1 null-mutant Dahl salt-sensitive rats. Our hypothesis is supported by data indicating that Hv1 promotes reactive oxygen species production in mTAL, that Hv1 contributes to blood pressure elevation in Dahl salt-sensitive rats, and that Hv1 activation promotes the progression of renal injury. The + "- following hypothesis will be tested in our proposal: 1) H efflux via Hv1 drives O2 production by NADPH oxidase;2) Hv1 activity in mTAL enhances Na+ reabsorption in mTAL;3) Augmented Hv1 activity in Dahl salt-sensitive rats promotes the progression of renal disease in these animals.

Public Health Relevance

Salt-sensitive hypertension is prevalent in African Americans and the incidence of end-stage renal disease (ESRD) attributable to hypertension is 6-fold higher in African Americans when compared to whites. The etiology of salt-sensitive hypertension and the factors that lead to the development of hypertensive ESRD remain unknown. Studies in the current proposal focus on understanding the role of a novel renal ion channel, Hv1, toward the development of salt- sensitive hypertension and renal injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK099548-01A1
Application #
8758494
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Ketchum, Christian J
Project Start
2014-08-01
Project End
2019-03-30
Budget Start
2014-08-01
Budget End
2015-03-31
Support Year
1
Fiscal Year
2014
Total Cost
$302,167
Indirect Cost
$102,167
Name
Georgia Regents University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
O'Connor, Paul M (2014) A radical approach to balancing the tides of tubular flow. Am J Physiol Renal Physiol 307:F917-8