Primary (essential) hypertension affects 28 % of the adult population in the United States and leads to premature cardiovascular, cerebrovascular and renal disease. The overall goal of Project #2 is to understand the interactions among the major renal Na+ regulatory pathways (dopamine 1, [DIR], dopamine 3 [DSR], and angiotensin type 1 [AT1R] receptors) which are critical to the regulation of blood pressure in humans. In experimental animals, the renal renin-angiotensin system and the renal dopaminergic system independently, and in concert, regulate renal Na+ excretion, and defects in these pathways can lead to hypertension. We have reported that the hypertension in mice overexpressing the human G protein-coupled receptor kinase type 4 variant, GRK4 A142V is associated with decreased renal D1R expression and function and increased AT1R expression and function. A similar mechanism may be operating in human essential hypertension. Expression of GRK4 variants in cell lines replicates the D1R defect noted in human renal proximal tubule cells from hypertensive subjects. Inhibition of GRK4 function or expression normalizes D1R function in human renal proximal tubule cells/cell lines expressing GRK4 variants. Moreover, renal selective prevention of the expression of GRK4 in spontaneously hypertensive rats attenuates the development of hypertension. The uncoupling of D1R in hypertension impairs the inhibitory paracrine regulation by dopamine (DA) of renal Na+ transport in the proximal tubule and even more distal nephron segments. Because DA, via D1Rs and D3Rs, normally antagonizes the increase in Na+ reabsorption caused by angiotensin II, via AT1Rs, enhanced renal Na+ reabsorption In hypertension may be due to an unopposed AT1R action (by DA). The overall hypothesis of Project #2 is that AT1R-mediated antinatriuresis is opposed by D1Rs and D3Rs, acting in concert in normal human subjects, and that this protective mechanism is deficient in patients with essential hypertension.
Three specific aims will determine the interactions among D1Rs and D3Rs and AT1Rs and their consequences in terms of Na+ excretion: (1) to test the hypothesis that D3R activation induces natriuresis, in part, by an action in the renal proximal and distal tubule in normotensive but not in hypertensive human subjects;(2) to test the hypothesis that D1Rs and D3Rs act synergistically in the induction of natriuresis in normal human subjects but not in hypertensive subjects;and (3) to test the hypothesis that antinatriuresis in human hypertension is related to AT1R-mediated Na+ reabsorption that is unopposed by DA. Hypertension is a complex polygenic disease. However, based on our findings, GRK4 regulation of a limited number of G protein-coupled receptors (GPCRs), and the downstream regulation of genes/proteins by GPCRs, e.g., D1R, D3R, and AT1R, makes a single gene, GRK4, a key contributor in the pathogenesis of essential hypertension.

Public Health Relevance

These studies will provide clinical correlation with the biochemical findings of projects 1 and 3 on the genetic causes of human essential hypertension. Understanding the overall physiologic mechanisms that control blood pressure and sustain hypertension can aid in focusing research efforts into successful targeted therapeutic stratagies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL074940-10
Application #
8625322
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
$387,059
Indirect Cost
$77,569
Name
University of Virginia
Department
Type
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Armando, Ines; Konkalmatt, Prasad; Felder, Robin A et al. (2015) The renal dopaminergic system: novel diagnostic and therapeutic approaches in hypertension and kidney disease. Transl Res 165:505-11
Lee, Hewang; Abe, Yoshifusa; Lee, Icksoo et al. (2014) Increased mitochondrial activity in renal proximal tubule cells from young spontaneously hypertensive rats. Kidney Int 85:561-9
Gildea, John J; Shah, Ishan T; Van Sciver, Robert E et al. (2014) The cooperative roles of the dopamine receptors, D1R and D5R, on the regulation of renal sodium transport. Kidney Int 86:118-26
Yu, Peiying; Sun, Min; Villar, Van Anthony M et al. (2014) Differential dopamine receptor subtype regulation of adenylyl cyclases in lipid rafts in human embryonic kidney and renal proximal tubule cells. Cell Signal 26:2521-9
Chen, Ken; Fu, Chunjiang; Chen, Caiyu et al. (2014) Role of GRK4 in the regulation of arterial AT1 receptor in hypertension. Hypertension 63:289-96
Gildea, John J; Seaton, Joscelyn E; Victor, Ken G et al. (2014) Exosomal transfer from human renal proximal tubule cells to distal tubule and collecting duct cells. Clin Biochem 47:89-94
Yang, Yu; Cuevas, Santiago; Yang, Sufei et al. (2014) Sestrin2 decreases renal oxidative stress, lowers blood pressure, and mediates dopamine D2 receptor-induced inhibition of reactive oxygen species production. Hypertension 64:825-32
Jiang, Xiaoliang; Konkalmatt, Prasad; Yang, Yu et al. (2014) Single-nucleotide polymorphisms of the dopamine D2 receptor increase inflammation and fibrosis in human renal proximal tubule cells. Hypertension 63:e74-80
Yu, Peiying; Han, Weixing; Villar, Van Anthony M et al. (2014) Unique role of NADPH oxidase 5 in oxidative stress in human renal proximal tubule cells. Redox Biol 2:570-9
Armando, Ines; Villar, Van Anthony M; Jones, John E et al. (2014) Dopamine D3 receptor inhibits the ubiquitin-specific peptidase 48 to promote NHE3 degradation. FASEB J 28:1422-34

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