The long-term objective is to determine the interaction among the five dopamine receptors and other G protein-coupled receptors (GPCRs) in the regulation of renal electrolyte transport and blood pressure. The D3 dopamine receptor (D3R), by itself, or via its interaction, with other dopamine receptors (e.g., DIR) and other GPCRs (e.g., angiotensin type 1 receptor), regulates renal sodium transport and blood pressure. Deletion of the D3R gene (D3R-/-) results in saltsensitive hypertension that is associated with increased renal expression of sodium/hydrogen exchanger type 3 (NHE3[SLC9A3]), sodium chloride exchanger (NCC[SLC12A3]) and alpha subunit of the epithelial sodium channel (ENaC [SCNNl A ]). Preliminary data show that the D3R ubiquitinates NHE3 and that the ubiquitination of NHE3 is due to D3R-mediated inhibition of USP48, an ubiquitinase. The overall hypothesis of project 3 is that the hypertension in D3R-/- mice is caused by increased activity and expression of NHE3 and NCC;their increased expression is caused by decreased degradation due to deubiquitination by USP48.
Specific aim 1 will test the hypothesis that impaired D3R function, because of decreased expression (D3-/-) or because of constitutive desensitization by human GRK4 gamma variants (e.g., GRK4 gammpl42V), results in increased renal expression of NHE3 and NCC when NaCI intake is normal and increased renal expression of NCC and ENaC when NaCI intake is increased. The impaired ability of D3-/-mice to excrete sodium contributes to the development of hypertension.
Specific aim 2 will test the hypothesis that D3R inhibits USP4S activity, preventing the deubiquitination of NHE3 and NCC;this preserves their ubiquitination, resulting in increased degradation and therefore, decreased expression. Decreased expression of D3R, or impairment of D3R function by human GRK4gamma 142V, increases USP48 expression and activity, promotes the deubiquitination and prevents the degradation of NHE3 and NCC, thus, increasing their expression levels. Hypertension is a complex polygenic disease. However, based on our findings, GRK4 regulation of a limited number of GPCRs, and the downstream regulation of genes/proteins by GPCRs, e.g., D3R, makes a single gene, GRK4, a key contributor in the pathogenesis of essential hypertension.

Public Health Relevance

These studies will shed light on the genetic causes of human essential hypertension. Understanding the mechanisms by which hypertension develops when the function of a dopamine receptor Is impaired can lead to the development of strategies to prevent and treat hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL074940-10
Application #
8625324
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
10
Fiscal Year
2014
Total Cost
$387,058
Indirect Cost
$77,568
Name
University of Virginia
Department
Type
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Wang, Zheng; Zeng, Chunyu; Villar, Van Anthony M et al. (2016) Human GRK4γ142V Variant Promotes Angiotensin II Type I Receptor-Mediated Hypertension via Renal Histone Deacetylase Type 1 Inhibition. Hypertension 67:325-34
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
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
Jose, Pedro A; Felder, Robin A; Yang, Zhiwei et al. (2016) Gastrorenal Axis. Hypertension 67:1056-63
Zhang, Yanrong; Jiang, Xiaoliang; Qin, Chuan et al. (2016) Dopamine D2 receptors' effects on renal inflammation are mediated by regulation of PP2A function. Am J Physiol Renal Physiol 310:F128-34
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:
Carey, Robert M (2016) Resistant Hypertension: Mineralocorticoid Receptor Antagonist or Renal Denervation? Hypertension 67:278-80
Jose, Pedro A (2016) Gastrorenal communication: sniffing and tasting. Exp Physiol 101:457-8
Yang, S; Yang, Y; Yu, P et al. (2015) Dopamine D1 and D5 receptors differentially regulate oxidative stress through paraoxonase 2 in kidney cells. Free Radic Res 49:397-410
Wang, Zhen; Guan, Weiwei; Han, Yu et al. (2015) Stimulation of Dopamine D3 Receptor Attenuates Renal Ischemia-Reperfusion Injury via Increased Linkage With Gα12. Transplantation 99:2274-84

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