Hypertension and salt sensitivity are major contributors to human morbidity and mortality. However, there has been slow progress in the understanding of the etiology or the link between personal genetics, biochemical regulation, and environmental influences. Our work has shown that two renal regulatory pathways that counter-regulate sodium reabsorption in the renal tubule, namely, dopamine (inhibitory) and angiotensin (stimulatory), are central in the etiology of hypertension and salt sensitivity. We have reported that increased activity of G protein-coupled receptor kinase type 4 (GRK4), because of activating variants, directly causes the dysregulation of dopamine receptors, as well as the angiotensin receptors, in renal proximal tubule cells (RPTCs) from humans with essential hypertension. In animal models, transgenic mice over expressing GRK4y wild-type gene are normotensive, while GRK4Y 142V transgenic mice are hypertensive and salt-sensitive, while GRK4y486V transgenic mice are salt-sensitive. The overall objective of this program project is the study of novel mechanisms of trans-regulation, including protein degradation, between the dopamine and angiotensin receptors in renal tubule cells. These novel mechanisms will be examined in novel mouse models, and in humans in whom in vivo renal functional studies will be correlated with studies in freshly voided renal tubule cells obtained from the same individual. Supported by administrative, analytical, and animal core laboratories, Project 1 will test the hypothesis that novel spatiotemporal interactions between and among dopaminergic and angiotensin receptors and several key regulatory proteins (DiR, D5R, ATiR, and GRK4) occur in lipid rafts and are regulated by the interaction between caveolin-1 and GRK4 in human RPTCs. We also hypothesize that the facilitatory effect of caveolin-1 on DiR function is impaired by GRK4 gene variants. Project 2 will test the hypothesis that ATiR-mediated antinatriuresis is opposed by DiRs and D3RS, acting in concert in normal human subjects, and that this protective mechanism is deficient in patients with essential hypertension. The physiologic responses to selective dopaminergic and angiotensin system stimulation from a specific subject will be correlated with single renal cell physiological responses from the urine-derived cells obtained from the same subject. This will enable us to correlate renal functional responses with renal cellular studies in the same subject. Project 3 will test the hypothesis that the hypertension that occurs with decreased D3R expression or function (caused by GRK4 gene variants) is due to increased activity and expression of NHE3, NCC, and ENaC;their increased expression is caused by decreased degradation due to their deubiquitination (a.k.a. deubiquitinylation) by USP48. This basic and translational grant application will delineate new insights into the interactions between the dopaminergic and renin-angiotensin systems and provide new insight that will lead to new therapeutic approaches.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL074940-10
Application #
8625320
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
OH, Youngsuk
Project Start
2004-04-01
Project End
2014-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
10
Fiscal Year
2014
Total Cost
$1,935,291
Indirect Cost
$387,843
Name
University of Virginia
Department
Pathology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
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
Yatabe, Midori Sasaki; Iwahori, Toshiyuki; Watanabe, Ami et al. (2017) Urinary Sodium-to-Potassium Ratio Tracks the Changes in Salt Intake during an Experimental Feeding Study Using Standardized Low-Salt and High-Salt Meals among Healthy Japanese Volunteers. Nutrients 9:
Konkalmatt, Prasad R; Asico, Laureano D; Zhang, Yanrong et al. (2016) Renal rescue of dopamine D2 receptor function reverses renal injury and high blood pressure. JCI Insight 1:
Jose, Pedro A (2016) Gastrorenal communication: sniffing and tasting. Exp Physiol 101:457-8
Wang, Zheng; Zeng, Chunyu; Villar, Van Anthony M et al. (2016) Human GRK4?142V Variant Promotes Angiotensin II Type I Receptor-Mediated Hypertension via Renal Histone Deacetylase Type 1 Inhibition. Hypertension 67:325-34
Carey, Robert M (2016) Resistant Hypertension: Mineralocorticoid Receptor Antagonist or Renal Denervation? Hypertension 67:278-80
Jose, Pedro A; Yang, Zhiwei; Zeng, Chunyu et al. (2016) The importance of the gastrorenal axis in the control of body sodium homeostasis. Exp Physiol 101:465-70
Jose, Pedro A; Felder, Robin A; Yang, Zhiwei et al. (2016) Gastrorenal Axis. Hypertension 67:1056-63
Sanada, H; Yoneda, M; Yatabe, J et al. (2016) Common variants of the G protein-coupled receptor type 4 are associated with human essential hypertension and predict the blood pressure response to angiotensin receptor blockade. Pharmacogenomics J 16:3-9
Yu, Changqing; Chen, Jianghua; Guan, Weiwei et al. (2015) Activation of the D4 dopamine receptor attenuates proliferation and migration of vascular smooth muscle cells through downregulation of AT1a receptor expression. Hypertens Res 38:588-96

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