Functional genomics of the dopaminergic system in hypertension

Abstract

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 (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 D 1-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 saltsensitive 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; D 1 dopamine receptor; G protein-coupled receptor kinase type 4 THE LONG-TERM REGULATION of blood pressure rests on renal and nonrenal mechanisms (22, 34, 41,82,85,138,143,172). The sympathetic nervous (48,91,133,198,240) and the reninangiotensin (48,62,64,81,82,122,132,143,171,205,221) systems have been shown to be important in the pathogenesis of essential hypertension, including that associated with obesity (43). However, there are several counter-regulatory pathways (39,76,135,142,169,174,184,205,219) (e.g., dopamine pathway), aberrations of which are involved in the pathogenesis of essential hypertension (3, 4, 8-18, 20, 21, 23-26, 29-33, 35, 37, 42, 44-46, 52-60, 67-70, 73-75, 77, 79, 80, 84, 86, 93-95, 97-103, 106-111, 114, 116, 118, 119, 124, 126-128, 130, 131, 136, 140, 141, 144-146, 148-156, 159-161, 163-166, 176-179, 182, 183, 186, 189, 192, 193, 195, 197, 203, 207, 209-216, 218, 224, 226-239), including that associated with obesity (16, 37,201). Dopamine can regulate blood pressure by renal and nonrenal mechanisms (e.g., intestines and central nervous system) (93,130,131,207) that also involve the renin-angiotensin system (12, 29, 46,209,211,212,226,235,236).Because the kidney is important in the long-term regu...

Redox Control of Renal Function and Hypertension

“…Dopaminergic system (DS)/sympathetic nervous system. Dopamine is produced locally in the proximal tubule cells and, after binding to D1 and D5 receptors, inhibits sodium absorption, thereby promoting natriuresis (381). Downstream signaling is mediated through G-protein subunits that are activated by G protein-coupled receptor kinase type 4 (GRK-4).…”

Genetics of arterial hypertension and hypotension

“…From human and animal studies, there is evidence for a renal dopamine receptor-or better signalling defect-in hypertension. Studies in the D 1 receptor protein, G proteins, adenylyl cyclases, phospholipase C, sodium transporters or the sodium pump revealed no causal abnormalities, so far (for review of the renal dopaminergic system in hypertension see Zeng et al 2004). Since the hypertensive phenotype with respect to renal dopamine signalling resembles processes observed in uncontrolled receptor desensitization, Felder et al (2002) studied D 1 receptor desensitization processes and observed an enhanced phosphorylation of the receptor protein at serine residues, which was attributed to an enhanced activity of the G protein-coupled receptor kinase 4 (GRK4).…”

“…Transgenic mice, overexpressing the GRK4γ isoform with the 142Val variant, exhibited increases in mean blood pressure by ∼30 mmHg compared to mice overexpressing the human wildtype variant . Mice overexpressing the GRK4 486Val variant were initally normotensive but developed hypertension on a sodium diet (Zeng et al 2004).…”

“…These results were confirmed in white Australians for the 486Val polymorphism, and were extended to several haplotypes that included the Arg65Leu and the Ala142Val variants . Results published in abstract form indicate that GRK4 variants also affect the risk for hypertension in black African and Japanese populations (Zeng et al 2004).…”

Increased responsiveness to JNK1/2 mediates the enhanced H2O2-induced stimulation of Cl−/HCO3− exchanger activity in immortalized renal proximal tubular epithelial cells from the SHR

“…One reason for the development and maintenance of this form of hypertension is the reduced capacity of the kidneys to excrete water and salts in appropriate relation to the intake [1]. In parallel with sodium, chloride is reabsorbed as the main accompanying anion and NaCl reabsorption regulation is critical in renal NaCl balance, which in turn controls extracellular volume and blood pressure [2]. About 50-70% of the filtered chloride is reabsorbed in the proximal tubule (PT) [3].…”