G protein-coupled receptor kinase 4 gene variants in human essential hypertension

Robin A. Felder, Hironobu Sanada, Jing Xu, Pei Ying Yu, Zheng Wang, Hidetsuna Watanabe, Laureano D. Asico, Wei Wang, Shaopeng Zheng, Ikuyo Yamaguchi, Scott M. Williams, James Gainer, Nancy J. Brown, Debra Hazen-Martin, Lee Jun C. Wong, Jean E. Robillard, Robert M. Carey, Gilbert M. Eisner, Pedro A. Jose

Research output: Contribution to journalArticlepeer-review

218 Scopus citations

Abstract

Essential hypertension has a heritability as high as 30-50%, but its genetic cause(s) has not been determined despite intensive investigation. The renal dopaminergic system exerts a pivotal role in maintaining fluid and electrolyte balance and participates in the pathogenesis of genetic hypertension. In genetic hypertension, the ability of dopamine and D1-like agonists to increase urinary sodium excretion is impaired. A defective coupling between the D1 dopamine receptor and the G protein/effector enzyme complex in the proximal tubule of the kidney is the cause of the impaired renal dopaminergic action in genetic rodent and human essential hypertension. We now report that, in human essential hypertension, single nucleotide polymorphisms of a G protein-coupled receptor kinase, GRK4γ increase G protein-coupled receptor kinase (GRK) activity and cause the serine phosphorylation and uncoupling of the D1 receptor from its G protein/effector enzyme complex in the renal proximal tubule and in transfected Chinese hamster ovary cells. Moreover, expressing GRK4γA142V but not the wild-type gene in transgenic mice produces hypertension and impairs the diuretic and natriuretic but not the hypotensive effects of D1-like agonist stimulation. These findings provide a mechanism for the D1 receptor coupling defect in the kidney and may explain the inability of the kidney to properly excrete sodium in genetic hypertension.

Original languageEnglish (US)
Pages (from-to)3872-3877
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number6
DOIs
StatePublished - Mar 19 2002

ASJC Scopus subject areas

  • General

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