Association of G-protein-coupled receptor kinase 4 haplotypes, but not HSD3B1 or PTP1B polymorphisms, with essential hypertension

Speirs, Helen J.L.; Katyk, K; Kumar, Natasha N.; Benjafield, Adam; Wang, William Y.S.; Morris, Brian J.

doi:10.1097/00004872-200405000-00014

Cited by 87 publications

(81 citation statements)

References 25 publications

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“…Although Wang et al and Bhatnagar et al analyzed T-rs1024323-C and T-rs1801058-C in hypertension, we selected subjects with PE. In addition, we observed an association of the T allele of the T-rs1024323-C variant with an elevation in DBP; this is also in agreement with the result found by Speirs et al 12 . These controversial results may be due to populationspecific differences in the extent of linkage disequilibrium between rs1024323 and a putative functional SNP, either in the GRK4 gene or in nearby regions.…”

Section: Characteristics Of Participantssupporting

confidence: 93%

“…Different sample sizes may also contribute to discrepant results. Compared with the study of 168 HTs and 312 NTs (Speirs et al 12 ), our sample sizes are considerably smaller. Several reasons may explain these inconsistent findings, including allelic heterogeneity, true variation in disease association between populations, modifying genetic and/or environmental factors, or statistically underpowered small sample sizes.…”

Section: Characteristics Of Participantsmentioning

confidence: 77%

“…Bengra et al 16 observed a significant association (P¼0.034) between GRK4 A486V and an Italian population of mildly hypertensive patients. Speirs et al 12 showed that the V allele of the A486V variant of GRK4-had an association with HT (P¼0.02). The V allele was also associated with an elevation in SBP (P¼0.002).…”

Section: Characteristics Of Participantsmentioning

confidence: 99%

“…The variant alleles (GRK4 Ala142Val and Ala486Val) have been associated with a higher risk of essential hypertension. [10][11][12] A TaqMan real-time allelic discrimination system eliminates the need for post-amplification steps and is less technically demanding and more rapid than conventional PCR. This report describes the use of TaqMan real-time allelic discrimination PCR, with minor groove binding probes, for single tube detection and genotyping of SNPs.…”

Section: Introductionmentioning

confidence: 99%

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G protein-coupled receptor kinase 4 gene variants are not associated with preeclampsia in Northern Han Chinese

Sun

Zhang

2010

Hypertens Res

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Genetic variations in preeclampsia (PE) may affect PE risk. The G protein-coupled receptor kinase 4 (GRK4) gene encodes a member of the Ser/Thr protein kinase family and has been linked to both genetic and acquired hypertension. The aim of this study was to investigate the association between polymorphisms (T-rs1024323-C and T-rs1801058-C) in GRK4 and PE in Northern Han Chinese. Using a case-control design, the association between the GRK4 exon-4 T-rs1024323-C and exon-13 T-rs1801058-C polymorphisms and the risk of PE in Northern Han Chinese was assessed in 105 individuals with PE and 103 age-and area-matched normotensive controls. Genotypes were determined by allelic discrimination. The odds ratio and 95% confidence interval were estimated by binary logistic regression. No association was found between the GRK4 polymorphisms (T-rs1024323-C and T-rs1801058-C) and PE, and there was also no relationship with the severity of PE. The risk of homozygous and heterozygous variant allele carriers of the analyzed single-nucleotide polymorphisms did not differ significantly from that of the homozygous wild-type allele carriers, even after adjustment for age, body mass index, (family) history of hypertension and smoking status. The GRK4 (T-rs1024323-C and T-rs1801058-C) polymorphisms were not associated with a risk of PE in the present Northern Han Chinese study group. Thus, the GRK4 polymorphisms do not seem to have an important role in PE in this population.

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Section: Characteristics Of Participantssupporting

confidence: 93%

Section: Characteristics Of Participantsmentioning

confidence: 77%

Section: Characteristics Of Participantsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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G protein-coupled receptor kinase 4 gene variants are not associated with preeclampsia in Northern Han Chinese

Sun

Zhang

2010

Hypertens Res

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“…5 However, SHRs have increased renal cortical membrane GRK4 expression relative to WKY rats. GRK4 polymorphisms (called FJ1 in Reference 24) are associated with hypertension in humans, [23][24][25][26] but there are no differences in the coding region of GRK4 in WKY rats and SHRs (unpublished data).…”

Section: Discussionmentioning

confidence: 99%

Amelioration of Genetic Hypertension by Suppression of Renal G Protein–Coupled Receptor Kinase Type 4 Expression

et al. 2006

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Abstract-Abnormalities in D 1 dopamine receptor function in the kidney are present in some types of human essential and rodent genetic hypertension. We hypothesize that increased activity of G protein-coupled receptor kinase type 4 (GRK4) causes the impaired renal D 1 receptor function in hypertension. We measured renal GRK4 and D 1 and serine-phosphorylated D 1 receptors and determined the effect of decreasing renal GRK4 protein by the chronic renal cortical interstitial infusion (4 weeks) of GRK4 antisense oligodeoxynucleotides (As-Odns) in conscious-uninephrectomized spontaneously hypertensive rats (SHRs) and their normotensive controls, Wistar-Kyoto (WKY) rats. Basal GRK4 expression and serine-phosphorylated D 1 receptors were Ϸ90% higher in SHRs than in WKY rats and were decreased to a greater extent in SHRs than in WKY rats with GRK4 As-Odns treatment. Basal renal D 1 receptor protein was similar in both rat strains. GRK4 As-Odns, but not scrambled oligodeoxynucleotides, increased sodium excretion and urine volume, attenuated the increase in arterial blood pressure with age, and decreased protein excretion in SHRs, effects that were not observed in WKY rats. These studies provide direct evidence of a crucial role of renal GRK4 in the D 1 receptor control of sodium excretion and blood pressure in genetic hypertension. The uncoupling of the D 1 -like receptor from its effector proteins in the kidney in hypertension is associated with increased phosphorylation of the D 1 receptor. 4,5 In human essential hypertension, single nucleotide polymorphisms of the G protein-coupled receptor (GPCR) kinase 4 (GRK4) are associated with constitutive phosphorylation and desensitization of the D 1 receptor in renal proximal tubules. 4 -6 These lead to sodium retention and hypertension. Indeed, transgenic mice expressing the GRK4 variant, GRK4␥A142V, develop hypertension that is associated with an impaired D 1 receptormediated natriuresis. 5 To determine whether aberrant GRK4 function contributes to the impaired renal D 1 receptor function in SHRs, we studied the renal expression of GRK4 and the effects of decreasing its expression in the kidney by a chronic renal cortical interstitial infusion of GRK4 antisense (As) oligodeoxynucleotides (Odns) in conscious SHRs and their normotensive controls, Wistar-Kyoto (WKY) rats. If an increased GRK4 activity in the kidney is responsible for the increased blood pressure in SHRs, this maneuver should improve D 1 receptor-mediated renal tubular handling of sodium and ameliorate the high blood pressure in SHRs without affecting these variables in WKY rats.

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Dopamine and Renal Function and Blood Pressure Regulation

Armando

Villar

José

2011

Comprehensive Physiology

104

215

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Dopamine is an important regulator of systemic blood pressure via multiple mechanisms. It affects fluid and electrolyte balance by its actions on renal hemodynamics and epithelial ion and water transport and by regulation of hormones and humoral agents. The kidney synthesizes dopamine from circulating or filtered L-DOPA independently from innervation. The major determinants of the renal tubular synthesis/release of dopamine are probably sodium intake and intracellular sodium. Dopamine exerts its actions via two families of cell surface receptors, D1-like receptors comprising D1R and D5R, and D2-like receptors comprising D2R, D3R, and D4R, and by interactions with other G protein-coupled receptors. D1-like receptors are linked to vasodilation, while the effect of D2-like receptors on the vasculature is variable and probably dependent upon the state of nerve activity. Dopamine secreted into the tubular lumen acts mainly via D1-like receptors in an autocrine/paracrine manner to regulate ion transport in the proximal and distal nephron. These effects are mediated mainly by tubular mechanisms and augmented by hemodynamic mechanisms. The natriuretic effect of D1-like receptors is caused by inhibition of ion transport in the apical and basolateral membranes. D2-like receptors participate in the inhibition of ion transport during conditions of euvolemia and moderate volume expansion. Dopamine also controls ion transport and blood pressure by regulating the production of reactive oxygen species and the inflammatory response. Essential hypertension is associated with abnormalities in dopamine production, receptor number, and/or posttranslational modification.

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Association of G-protein-coupled receptor kinase 4 haplotypes, but not HSD3B1 or PTP1B polymorphisms, with essential hypertension

Abstract: Genetic variation in GRK4gamma was associated with HT in the subjects studied.

Cited by 87 publications

References 25 publications

G protein-coupled receptor kinase 4 gene variants are not associated with preeclampsia in Northern Han Chinese

G protein-coupled receptor kinase 4 gene variants are not associated with preeclampsia in Northern Han Chinese

Amelioration of Genetic Hypertension by Suppression of Renal G Protein–Coupled Receptor Kinase Type 4 Expression

Dopamine and Renal Function and Blood Pressure Regulation

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