G protein-coupled kinase type 4 (GRK4) gene variants (R65L, A142V, and A486V) selectively desensitizes the dopamine-1 receptor (DIR) and not the D5R, which upregulates the angiotensin type 1 receptor (ATIR). The net result of a desensitized DIR (natriuretic) and upregulated ATIR (antinatriuretic) is a net sodium reabsorption by the kidney. However, the molecular mechanisms responsible for DIR desensitization, ATIR upregulation, and the integration of these two pathways on net sodium metabolism are not well understood. We hypothesize that the membrane localization and ultimate activity of the DIR, D5R, and ATIR are regulated by oligomerization and spatial orientation via scaffolding proteins (e.g. caveolin-l (CAV1)), which ultimately regulate their interaction with intracellular second messengers. Specifically, GRK4 binds to caveolin-l (CAV1) which is interrupted by the presence of gene variants. We further hypothesize that a molecular trimeric D1R/CAV1/GRK4 association may be necessary for dopaminergic inhibition of NaKATPase activity via intracellular internalization in conjunction with adapter protein-2 (AP-2).
Specific Aim 1 will examine the spatiotemporal transregulation of the DIR, D5R, ATIR, and CAV1 and their link to intracellular second messengers. In order to increase the relevance of our studies to human physiology and pathophysiology, we will study these phenomenon in 60 human renal proximal tubular cells (RPTCs) lines that have been genotyped for GRK4 variants.
Specific Aim 2 will study spatiotemporal transregulation of the DIR, D5R, ATIR, and CAVIand their effect on the activity of the principal sodium transporters in human RPTCs NaKATPase and NHE3. The study of the effect of gene variants of GKR4 on the single RPTC physiology representing wide genetic diversity will improve our understanding of how the renal proximal tubule controls renal sodium excretion, and lead to potential novel therapeutic targets for the development of targeted and personalized antihypertensive therapeutics.

Public Health Relevance

Understanding the dynamic relationships between two key sodium regulatory pathways in the kidney is essential to deciphering the basic etiology of hypertension and salt sensitivity, major causes of common serious diseases. Since these diseases disproportionatly effect low income populations, effective targeted treatments are needed to reduce the burden on medicaid and medicare reciptients.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Virginia
United States
Zip Code
Li, Fengmin; Yang, Jian; Villar, Van Anthony M et al. (2018) Loss of renal SNX5 results in impaired IDE activity and insulin resistance in mice. Diabetologia 61:727-737
Wang, Xiaoyan; Villar, Van Anthony; Tiu, Andrew et al. (2018) Dopamine D2 receptor upregulates leptin and IL-6 in adipocytes. J Lipid Res 59:607-614
Luo, Hao; Chen, Caiyu; Guo, Li et al. (2018) Exposure to Maternal Diabetes Mellitus Causes Renal Dopamine D1 Receptor Dysfunction and Hypertension in Adult Rat Offspring. Hypertension 72:962-970
Wu, Gengze; Jose, Pedro A; Zeng, Chunyu (2018) Noncoding RNAs in the Regulatory Network of Hypertension. Hypertension 72:1047-1059
Asico, Laureano D; Cuevas, Santiago; Ma, Xiaobo et al. (2018) Nephron segment-specific gene expression using AAV vectors. Biochem Biophys Res Commun 497:19-24
Muntner, Paul; Whelton, Paul K; Woodward, Mark et al. (2018) A Comparison of the 2017 American College of Cardiology/American Heart Association Blood Pressure Guideline and the 2017 American Diabetes Association Diabetes and Hypertension Position Statement for U.S. Adults With Diabetes. Diabetes Care 41:2322-2329
Ye, Zhengmeng; Lu, Xi; Deng, Yi et al. (2018) In Utero Exposure to Fine Particulate Matter Causes Hypertension Due to Impaired Renal Dopamine D1 Receptor in Offspring. Cell Physiol Biochem 46:148-159
Yang, Yang; Chen, Caiyu; Fu, Chunjiang et al. (2018) Angiotensin II type 2 receptor inhibits expression and function of insulin receptor in rat renal proximal tubule cells. J Am Soc Hypertens 12:135-145
Tiu, Andrew C; Bishop, Michael D; Asico, Laureano D et al. (2017) Primary Pediatric Hypertension: Current Understanding and Emerging Concepts. Curr Hypertens Rep 19:70
Diao, Zhenyu; Asico, Laureano D; Villar, Van Anthony M et al. (2017) Increased renal oxidative stress in salt-sensitive human GRK4?486V transgenic mice. Free Radic Biol Med 106:80-90

Showing the most recent 10 out of 123 publications