The genetic causes of salt sensitivity in humans are not well known. The kidney is critical to the overall fluid and electrolyte balance and long-term regulation of blood pressure (BP). Therefore, the pathogenesis of salt sensitivity must involve an inability to decrease sodium transport and increase sodium excretion when the sodium load is increased. Variants of the human G protein-coupled receptor kinase type 4 (hGRK) genes that regulates a limited number of G protein-coupled receptors, are associated with essential hypertension in several ethnic groups. Expression of the hGRK4g486V variant in mice causes salt sensitivity depending on the genetic background. Preliminary data suggest that the orphan receptor GPR83 may counteract the salt- sensitive producing effect of hGRK4g 486V, the expression of which is dependent on the genetic background and may explain ethnic-related differences in salt sensitivity. This project will test the overall novel hypothesis that salt sensitivity imparted by hGRK4g 486V is due to decreased expression/function of the orphan receptor GPR83 that results in an imbalance in natriuretic (dopamine D1 receptor, D1R) and antinatriuretic (angiotensin type 1 receptor, AT1R) systems which increases BP.
Specific Aim 1 will test the hypothesis that GPR83 function is necessary to maintain a normal blood pressure under conditions of sodium excess and that lack or decreased GPR83 function will have the least effect on mice in a salt-resistant background.
This Specific Aim 1 will also clarify the effects of GRK4 and D1R on the regulation of GPR83 expression.
Specific Aim 2 will test the hypothesis that the protective effects of GPR83 are mediated by negative regulation of AT1R and positive regulation of D1R functions.
This Specific Aim will clarify the cellular mechanisms involved in the regulation of these functions.
Specific Aim 3 will test the hypothesis that GPR83 function is impaired by hGRK4g486V and that the ability to impair GPR83 function is dependent on the proportion of "salt sensitivity" and "salt resistance" genes. In mice with a predominant salt-sensitive background renal GPR83 is necessary to maintain normal blood pressure even when sodium intake is not increased. These studies will be able to determine, for the first time, the role of the interaction of "salt sensitivity" and "salt resistance" genes in the pathogenesis o essential hypertension. The identification of a novel salt resistance gene, i.e., GPR83, may lead to the development of drugs that target its expression and function.
Salt sensitivity is associated with increased cardiovascular risk, even if the blood pressure does not reach hypertensive levels. Mortality and morbidity are both higher in hypertensive subjects and in salt-sensitive normotensive subjects than in salt-resistant normotensive subjects. The molecular mechanisms causing salt sensitivity in humans are poorly understood. These studies may lead to the identification of a novel salt resistance gene and may lead to the development of drugs that target its expression and function.
|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|
|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|
|Arnaldo, Francis B; Villar, Van Anthony M; Konkalmatt, Prasad R et al. (2014) D1-like dopamine receptors downregulate Na+-K+-ATPase activity and increase cAMP production in the posterior gills of the blue crab Callinectes sapidus. Am J Physiol Regul Integr Comp Physiol 307:R634-42|
|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|
|Wang, Shaoxiong; Lu, Xi; Yang, Jian et al. (2014) Regulation of renalase expression by D5 dopamine receptors in rat renal proximal tubule cells. Am J Physiol Renal Physiol 306:F588-96|
|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|
Showing the most recent 10 out of 49 publications