Abstract
Essential hypertension is caused by the interaction of genetic, behavioral, and environmental factors. Abnormalities in the regulation of renal ion transport cause essential hypertension. The renal dopaminergic system, which inhibits sodium transport in all the nephron segments, is responsible for at least 50% of renal sodium excretion under conditions of moderate sodium excess. Dopaminergic signals are transduced by two families of receptors that belong to the G protein-coupled receptor (GPCR) superfamily. D(1)-like receptors (D(1)R and D(5)R) stimulate, while D2-like receptors (D(2)R, D(3)R, and D(4)R) inhibit adenylyl cyclases. The dopamine receptor subtypes, themselves, or by their interactions, regulate renal sodium transport and blood pressure. We review the role of the D(1)R and D(3)R and their interaction in the natriuresis associated with volume expansion. The D(1)R- and D(3)R-mediated inhibition of renal sodium transport involves PKA and PKC-dependent and -independent mechanisms. The D(3)R also increases the degradation of NHE3 via USP-mediated ubiquitinylation. Although deletion of Drd1 and Drd3 in mice causes hypertension, DRD1 polymorphisms are not always associated with human essential hypertension and polymorphisms in DRD3 are not associated with human essential hypertension. The impaired D(1)R and D(3)R function in hypertension is related to their hyper-phosphorylation; GRK4γ isoforms, R65L, A142V, and A486V, hyper-phosphorylate and desensitize D(1)R and D(3)R. The GRK4 locus is linked to and GRK4 variants are associated with high blood pressure in humans. Thus, GRK4, by itself, and by regulating genes related to the control of blood pressure may explain the "apparent" polygenic nature of essential hypertension.