The G Protein–Coupled Receptor Kinase 4 Gene Affects Blood Pressure in Young Normotensive Twins

Zhu, Haidong; Lu, Yanhui; Wang, Xiaoling; Treiber, Frank A.; Harshfield, Gregory A.; Snieder, Harold; Dong, Yanbin

doi:10.1016/j.amjhyper.2005.07.007

Cited by 30 publications

(24 citation statements)

References 25 publications

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“…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.…”

Section: Impaired Renal D 1 Receptor and Hypertensionmentioning

confidence: 99%

The dopaminergic system in hypertension

et al. 2007

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Dopamine plays an important role in the pathogenesis of hypertension by regulating epithelial sodium transport, vascular smooth muscle contractility and production of reactive oxygen species and by interacting with the renin-angiotensin and sympathetic nervous systems. Dopamine receptors are classified into D(1)-like (D(1) and D(5)) and D(2)-like (D(2), D(3) and D(4)) subtypes based on their structure and pharmacology. Each of the dopamine receptor subtypes participates in the regulation of blood pressure by mechanisms specific for the subtype. Some receptors regulate blood pressure by influencing the central and/or peripheral nervous system; others influence epithelial transport and regulate the secretion and receptors of several humoral agents. This review summarizes the physiology of the different dopamine receptors in the regulation of blood pressure, and the relationship between dopamine receptor subtypes and hypertension.

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Section: Impaired Renal D 1 Receptor and Hypertensionmentioning

confidence: 99%

The dopaminergic system in hypertension

et al. 2007

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“…Zhu et al 47 determined the association of GRK4 variants (65L, 142V, and 486V) with blood pressure in black and white American twin subjects. Single-locus analyses revealed a significant interaction and a dose effect between 65L and age for systolic blood pressure.…”

Section: Grk4 Polymorphisms and Hypertensionmentioning

confidence: 99%

“…Individuals who are homozygous for the 65L-142V-A486 haplotype have a 1.05-mm Hg steeper increase in systolic blood pressure per year of increase in age compared with those homozygous for the most common R65-A142-A486 haplotype. 47 In black adolescents with GRK4 65L, mental stress causes an increase in blood pressure and a decrease in sodium excretion. One study, however, did not find an association of GRK4 486V with the top fifth percentile of diastolic blood pressure of subjects with white European ancestry.…”

Section: Grk4 Polymorphisms and Hypertensionmentioning

confidence: 99%

G Protein–Coupled Receptor Kinase 4

Zeng

Villar²,

Eisner³

et al. 2008

Hypertension

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N early 30% of middle-aged Americans have hypertension, but the prevalence is higher in non-Hispanic blacks and individuals Ͼ60 years of age (65%). 1 There is a direct and quantitative relationship between higher blood pressure values and mortality. Although 30% to 50% is thought to be heritable, the genetic cause(s) of essential hypertension has been difficult to identify. More than 1 gene is undoubtedly involved, because Mendelian dominant and recessive traits are not readily discernible in hypertensive subjects, except in those with monogenic forms of hypertension. Moreover, in any hypertensive individual, risk-predisposing genes are engaged in a complex network of gene-gene and geneenvironment interactions. 2,3 The kidney plays a major role in the long-term regulation of blood pressure, and abnormal sodium chloride metabolism is frequently encountered in hypertension. Therefore, many studies have focused on the abnormal renal handling of sodium chloride in the pathogenesis of essential hypertension. 2,4 Approximately 50% of subjects with essential hypertension are sodium chloride sensitive. 5 Indeed, humans with salt-sensitive hypertension have increased sodium transport in the renal proximal tubule and medullary thick ascending limb, although distal tubular mechanisms may also be involved. 6 The sodium retention in hypertension is because of enhanced sodium transport, per se, and/or a failure to respond appropriately to signals that decrease sodium transport. Sodium transport is regulated by natriuretic and antinatriuretic hormones and humoral agents, such as dopamine and angiotensin, which exert their effects via G protein-coupled receptors (GPCRs). Activation of certain postjunctional dopamine receptor subtypes (D 1 R, D 3 R, D 4 R, and D 5 R) and the angiotensin type 2 receptor inhibit, whereas activation of the postjunctional D 2 R and angiotensin type 1 receptor (AT 1 R) increase sodium transport. 2,7 GPCR Kinase FamilyThe GPCR kinases (GRKs) are a 7-member family of serine/threonine protein kinases characterized by their ability to phosphorylate or modify and desensitize agonist-occupied cell surface membrane GPCRs. GRKs 1 and 7 belong to the rhodopsin family; GRKs 2 and 3 belong to the ␤-adrenergic receptor kinase family, and GRKs 4, 5, and 6 belong to the GRK4 family (Table 1). GRKs 1 and 7 are expressed exclusively in rods and cones, respectively, in the retina. GRKs 2, 3, 5, and 6 are ubiquitously expressed, whereas GRK4 expression is limited (see below). 8 Overexpression of GRK2, GRK3, and especially GRK5 in human embryonic kidney cells desensitizes the D 1 R. 9 GRK activity and GRK2 expression are increased in lymphocytes of patients with essential hypertension and spontaneously hypertensive rats (SHRs). 10 Overexpression of GRK2 in vascular smooth muscles in mice produces hypertension and impairs the vasodilatory action of ␤-adrenergic receptors. 11 The vasoconstrictor response to angiotensin II is also impaired in these mice, which is at odds with the increased reactivity and sensitivity to an...

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“…trols 33 and from a twin study of 934 black (44.2%) and white (55.8) normotensive American adolescents. 34 In a study of 184 newly diagnosed and untreated hypertensive Japanese, 35 mutation of GRK4 reduced the natriuretic response to dopaminergic stimulation. We did not find any association of blood pressure and renal sodium handling with GRK4 or the interaction between GRK4 and DRD1.…”

Section: Staessen Et Al Blood Pressure Sodium Handling Drd1 and Grk4mentioning

confidence: 99%

Blood Pressure and Renal Sodium Handling in Relation to Genetic Variation in the DRD1 Promoter and GRK4

et al. 2008

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Abstract-Activation of type-1 dopamine receptors (DRD1) reduces renal sodium reabsorption. In a family-based random sample of 611 untreated whites (women, 45.0%; mean age, 38.6 years), we measured blood pressure (BP). We used the endogenous lithium clearance to assess fractional sodium excretion (FE Na ) and proximal (RNa prox ) and distal (RNa dist ) tubular sodium reabsorption. We investigated multivariate-adjusted associations with the DRD1 promoter (AϪ48G, GϪ94A, and CϪ800T) and GRK4 (Ala142Val Key Words: blood pressure Ⅲ clinical genetics Ⅲ dopamine receptor gene Ⅲ GRK4 Ⅲ lithium clearance Ⅲ population science Ⅲ tubular transport D opamine reduces sodium reabsorption in the proximal renal tubules via activation of dopamine type-1 (DRD1) receptors, which leads to inhibition of sodium transporters, including the Na,H-exchanger and Na,K-ATPase. 1 The DRD1 promoter harbors several single-nucleotide polymorphisms (SNPs), 2 which influence the expression of the gene. Dopamine exerts its actions via G protein-coupled receptors, which in turn are under control of G protein-coupled receptor kinases (GRKs). 1 Amino-acid changing polymorphisms in one particular member of this family, GRK4, cause hyperphosphorylation, desensitization, and internalization of the DRD1 receptor and enhance the expression of the angiotensin II type-1 receptor. 1 The genes encoding DRD1 and GRK4 localize to chromosomes 5q35.1 3 and 4p16.3, 4 respectively. The GRK4 gene locus is embedded in a cluster on chromosome 4p16, which is associated with hypertension 5,6 and also includes ␣-adducin (ADD1). To our knowledge, there are no studies showing significant genome-wide linkage of hypertension with the DRD1 locus, although a genome-scan meta-analysis 7 identified 5q as a suggestive region.Measuring the clearance of endogenous lithium provides a way of estimating sodium handling in the proximal and postproximal nephron. 8,9 Expressing the renal clearance of endogenous lithium as a fraction of creatinine clearance provides a measure of tubular sodium reabsorption that is standardized for the glomerular filtration rate. 8,9 The fractional excretion of lithium (FE Li ) is a noninvasive marker of proximal tubular sodium handling and the proportion of sodium escaping reabsorption in the proximal segment of the nephron. FE Li also allows the calculation of the fractional distal reabsorption of sodium (RNa dist ). To our knowledge, no prior study addressed the possible association of these renal

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The G Protein–Coupled Receptor Kinase 4 Gene Affects Blood Pressure in Young Normotensive Twins

Abstract: Our data indicate that the R65L polymorphism of the GRK4 gene plays a role in BP regulation in adolescents and young adults.

Cited by 30 publications

References 25 publications

The dopaminergic system in hypertension

The dopaminergic system in hypertension

G Protein–Coupled Receptor Kinase 4

Blood Pressure and Renal Sodium Handling in Relation to Genetic Variation in the DRD1 Promoter and GRK4

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