The G Protein-Coupled Receptor Kinase 4 Gene Modulates Stress-Induced Sodium Excretion in Black Normotensive Adolescents

Abstract

Approximately 20 -40% of adolescents have shown a reduction of urinary sodium excretion (U Na V) in response to blood pressure (BP) increase during behavioral stress. G protein-coupled receptor kinase 4 (GRK4) mediates the pressure and natriuresis relation. The present study investigated the impact of GRK4 genetic variants on U Na V under stress. A total of 664 normotensive adolescents including whites and blacks (17.6 Ϯ 3.3 yrs, 43.4% blacks) were recruited. Participants were subjected to a stress-protocol including three 10-min tasks (a social competence interview, a virtual reality car driving simulation test, and a video game challenge), concluded by a urine collection. Three functional polymorphisms including R65L, A142V and A486V were genotyped. Given blacks compared with whites had significantly higher systolic BP (SBP) levels during rest (p Ͻ 0.001) and stress (p Յ 0.001), there was no statistical difference in U Na V in response to stress between the two ethnic groups. In blacks, compared with R65R homozygotes, individuals with R65L or L65L genotype had significantly lower levels of stress-induced U Na V (8.42 Ϯ 0.63 versus 9.85 Ϯ 0.37 mEq/h, p ϭ 0.01). In summary, BP elevation seems uncoupled with U Na V increase during behavioral stress in black adolescents. The 65L allele of the GRK4 gene is associated with stress-induced U Na V reduction, suggesting impaired sodium handling in affected black youth. E ssential hypertension is determined by gene and environment interactions, and has its origin in childhood. Blood pressure (BP) increase during a sustained period of behavioral stress is typically accompanied by a compensatory increase in urinary sodium excretion (U Na V) (1,2). Our previous data show that an inadequate compensatory increase in U Na V in response to stress occurs in 20 -40% of adolescents aged 15-19 y (Harshfield et al. Annual Meeting of Society of Behavioral Medicine, April 13-16, 2005, Boston), which may predict the development of hypertension (1,2). In particular, we have recently demonstrated that U Na V in response to stress is a heritable phenotype in a multi-ethnic cohort of adolescents (Ge et al., Annual meeting of the American Society of Human Genetics, October 25-29, 2005, Salt Lake City). However, no candidate gene association study has been performed to date. Dopamine enhances renal sodium excretion, diuresis and natriuresis via dopamine receptors D (DRD) in the renal proximal tubules (3-5). G protein-coupled receptor kinase 4 (GRK4) regulates DRD1 phosphorylation, desensitization and internalization (6,7). Although functional single nucleotide polymorphisms (SNPs) of the GRK4 gene have been associated with hypertension in adult populations (8 -11), the impact of these variants on sodium homeostasis in humans remains unknown. Thus we conducted association analyses of the GRK4 polymorphisms in relation to stress-induced U Na V in a sample of young normotensive white and black twins. METHODS Study population.A total of 664 normotensive twin subjects including whites a...

Potential Dopamine-1 Receptor Stimulation in Hypertension Management

“…Transgenic mice expressing human GRK4γ 486 V are normotensive on a normal-salt diet and become hypertensive on a high-salt diet [90•]. Transgenic mice expressing human GRK4γ 65 L are normotensive on both normal and high salt intake, but in African American adolescent males carrying this variant, mental stress increases blood pressure and decreases sodium excretion [99]. Salt-sensitive hypertensive Japanese patients carrying at least three GRK4 gene variants have an impaired natriuretic response to a dopaminergic drug [100].…”

The dopaminergic system in hypertension

“…The GRK4 locus on human chromosome 4p16.3 is linked with hypertension [88][89][90][91]. The increase in BP with age in white and African Americans is associated with GRK4 65L [92] and the increase in BP and decrease in sodium excretion with mental stress is associated with GRK4 65L in adolescent African Americans [93]. GRK4 486V, by itself [82] or in conjunction with GRK4 65L and GRK4 142V [83], is associated with salt sensitivity.…”

G-protein-coupled receptor kinase 4 polymorphisms predict blood pressure response to dietary modification in Black patients with mild-to-moderate hypertension

“…16 The R65L aminoacid substitution was also associated with impaired stress-induced sodium excretion in Black normotensive men. 17 In a preliminary unpublished study in South Africans, we found the variant T allele of the A142V SNP to be significantly more frequent in Blacks compared with Whites (73 vs 23%, respectively) (Rayner et al, unpublished data). With this in mind we decided to study the effects of the A142V and R65L SNPs on the BP response to dietary intervention in the study performed previously.…”