G-PROTEIN-COUPLED RECEPTOR KINASE GENE VARIANTS AND HYPERTENSION

University Of Virginia Charlottesville, Charlottesville VA

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Abstract

The renal dopaminergic system participates in the pathogenesis of genetic hypertension. In human essential hypertension, single nucleotide polymorphisms (SNPs) of a G protein-coupled receptor kinase, GRK4, increase GRK activity and cause the serine phosphorylation and uncoupling of the D1 receptor from its effector proteins in proximal tubule cells, effects of which are mimicked in Chinese hamster ovary (CHO) cells. Moreover, expressing GRK4-gamma- A142V but not the wild type gene in mice produces hypertension and impairs the diuretic and natriuretic but not the hypotensive effects of D1-like agonist stimulation. Our primary hypothesis is that GRK4-gamma variants are responsible for the D1 receptor coupling defect in the kidney and cause the inability of the kidney to properly excrete sodium in genetic hypertension. Essential hypertension is a heterogeneous disease in which both genetics and environment contribute to elevate blood pressure. Many diseases, including essential hypertension, have their genesis during development. Sodium intake, early in life in humans and animals, without impairing growth, affects adult blood pressure. Our secondary hypothesis is that alterations in sodium intake affect the development of hypertension in transgenic mice carrying the GRK4-gamma gene variants. Indeed, the overall hypothesis of this program project is that expression of disease in the young depends upon developmental steps made early in life in response to external and internal environmental challenges. Specific aim 1 will determine in transgenic mice the interactions of GRK4-gamma-A142V, with age and sodium intake on blood pressure elevation and whether the effect of GRK4-gamma-A142V is receptor, renal, and nephron segment specific. Specific aim 2 will determine whether transgenic mice carrying more than one GRK4-gamma gene variant develop a hypertension that is more severe than those carrying only one GRK4-gamma gene variant. The significant interaction GRK4 SNPs in hypertension was greater in the presence of more than one GRK4 SNP. In CHO cells, the expression of more than GRK4-gamma gene variant impairs D1 receptor function to a greater extent than that noted in CHO cells expressing only one GRK4-gamma gene variant. Specific aim 3 will determine whether GRK4-gamma gene variants affect blood pressure in D1 and D5 knockout mice. This aim will test the hypothesis that GRK4-gamma regulates D1 but not D5 receptors. These studies should elucidate the mechanisms by which GRK4-gamma gene variants promote the development of genetic hypertension and determine whether GRK4-gamma is a salt-sensitivity gene. The identification of individuals with a salt-sensitivity gene could form thescientific basis of sodium restriction in a selected target population.