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Invited Review
1 Department of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, Peoples Republic of China
2 Futaba Kosei Hospital, Fukushima, Japan
3 Health Care Center, Fukushima University, Fukushima, Japan
4 Department of Medicine, Georgetown University Medical Center, Washington, District of Columbia
5 Department of Pathology, Medical Automation Center, University of Virginia Health Science Center, Charlottesville, Virginia
6 Institute for Nephrology and Hypertension, Departments of Pediatrics and Physiology and Biophysics, Georgetown University Medical Center, Washington, District of Columbia
Abnormalities in dopamine production and receptor function have been described in human essential hypertension and rodent models of genetic hypertension. Under normal conditions, D1-like receptors (D1 and D5) 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 D1-like receptor-mediated inhibition of epithelial sodium transport is impaired because of an uncoupling of the D1-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.
dopamine; D1 dopamine receptor; G protein-coupled receptor kinase type 4
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