Functional genomics of the dopaminergic system in hypertension.
Abnormalities in dopamine production and receptor function have been described in human essential hypertension and rodent models of genetic hypertension. Under normal conditions, D(1)-like receptors (D(1) and D(5)) inhibit sodium transport in the kidney and intestine. However, in the Dahl salt-sensitive and spontaneously hypertensive rats (SHRs) and in humans with essential hypertension, the D(1)-like receptor-mediated inhibition of epithelial sodium transport is impaired because of an uncoupling of the D(1)-like receptor from its G protein/effector complex. The uncoupling is receptor specific, organ selective, nephron-segment specific, precedes the onset of hypertension, and cosegregates with the hypertensive phenotype. The defective transduction of the renal dopaminergic signal is caused by activating variants of G protein-coupled receptor kinase type 4 (GRK4: R65L, A142V, A486V). The GRK4 locus is linked to and GRK4 gene variants are associated with human essential hypertension, especially in salt-sensitive hypertensive subjects. Indeed, the presence of three or more GRK4 variants impairs the natriuretic response to dopaminergic stimulation in humans. In genetically hypertensive rats, renal inhibition of GRK4 expression ameliorates the hypertension. In mice, overexpression of GRK4 variants causes hypertension either with or without salt sensitivity according to the variant. GRK4 gene variants, by preventing the natriuretic function of the dopaminergic system and by allowing the antinatriuretic factors (e.g., angiotensin II type 1 receptor) to predominate, may be responsible for salt sensitivity. Subclasses of hypertension may occur because of additional perturbations caused by variants of other genes, the quantitative interaction of which may vary depending upon the genetic background.
Zeng
Chunyu
C
Department of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, People's Republic of China.
Sanada
Hironobu
H
Watanabe
Hidetsuna
H
Eisner
Gilbert M
GM
Felder
Robin A
RA
Jose
Pedro A
PA
D000818:Animals; D019898:Autocrine Communication / Q000502:physiology; D004298:Dopamine / Q000378:metabolism* / Q000502:physiology*; D023281:Genomics / Q000379:methods*; D006801:Humans; D006973:Hypertension / Q000235:genetics / Q000503:physiopathology*; D019899:Paracrine Communication / Q000502:physiology
D004298:Dopamine