Journal article
G protein-coupled receptor kinase 4 gene variants in human essential hypertension
Proceedings of the National Academy of Sciences - PNAS, Vol.99(6), pp.3872-3877
03/19/2002
DOI: 10.1073/pnas.062694599
PMCID: PMC122616
PMID: 11904438
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.
Details
- Title: Subtitle
- G protein-coupled receptor kinase 4 gene variants in human essential hypertension
- Creators
- Robin A. Felder - University of Virginia Health SystemHironobu Sanada - University of Virginia Health SystemJing Xu - Georgetown University Medical CenterPei-Ying Yu - Georgetown University Medical CenterZheng Wang - Georgetown University Medical CenterHidetsuna Watanabe - University of Virginia Health SystemLaureano D. Asico - University of Virginia Health SystemWei Wang - Georgetown University Medical CenterShaopeng Zheng - Georgetown University Medical CenterIkuyo Yamaguchi - Georgetown University Medical CenterScott M. Williams - Meharry Medical CollegeJames Gainer - Vanderbilt University Medical CenterNancy J. Brown - Vanderbilt University Medical CenterDebra Hazen-Martin - Medical University of South CarolinaLee-Jun C. Wong - Georgetown University Medical CenterJean E. Robillard - University of Michigan Medical SchoolRobert M. Carey - University of Virginia Health SystemGilbert M. Eisner - Georgetown University Medical CenterPedro A. Jose - Georgetown University Medical Center
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.99(6), pp.3872-3877
- DOI
- 10.1073/pnas.062694599
- PMID
- 11904438
- PMCID
- PMC122616
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Publisher
- The National Academy of Sciences
- Number of pages
- 6
- Language
- English
- Date published
- 03/19/2002
- Academic Unit
- Molecular Physiology and Biophysics; Nephrology, Dialysis and Transplantation; Stead Family Department of Pediatrics; Medicine Administration
- Record Identifier
- 9984773401402771
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