The importance of G protein-coupled receptor kinase 4 (GRK4) in pathogenesis of salt sensitivity, salt sensitive hypertension and response to antihypertensive treatment

International Journal of Molecular Sciences
B Rayner, Raj Ramesar

Abstract

Salt sensitivity is probably caused by either a hereditary or acquired defect of salt excretion by the kidney, and it is reasonable to consider that this is the basis for differences in hypertension between black and white people. Dopamine acts in an autocrine/paracrine fashion to promote natriuresis in the proximal tubule and thick ascending loop of Henle. G-protein receptor kinases (or GRKs) are serine and threonine kinases that phosphorylate G protein-coupled receptors in response to agonist stimulation and uncouple the dopamine receptor from its G protein. This results in a desensitisation process that protects the cell from repeated agonist exposure. GRK4 activity is increased in spontaneously hypertensive rats, and infusion of GRK4 antisense oligonucleotides attenuates the increase in blood pressure (BP). This functional defect is replicated in the proximal tubule by expression of GRK4 variants namely p.Arg65Leu, p.Ala142Val and p.Val486Ala, in cell lines, with the p.Ala142Val showing the most activity. In humans, GRK4 polymorphisms were shown to be associated with essential hypertension in Australia, BP regulation in young adults, low renin hypertension in Japan and impaired stress-induced Na excretion in normotensive bl...Continue Reading

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Citations

Sep 16, 2015·Pharmacogenomics·Matthew J Sorrentino, Peter H O'Donnell
Feb 13, 2017·Free Radical Biology & Medicine·Zhenyu DiaoXiaoyan Wang
Jul 9, 2016·Journal of the American Heart Association·Jian YangChunyu Zeng
Apr 6, 2016·Hypertension·Pedro A JoseGilbert M Eisner
Jan 31, 2019·Clinical and Experimental Hypertension : CHE·Dongdong SunChunyu Zeng
Mar 16, 2019·Physiological Genomics·Elizabeth A SwansonDavid H Ellison
Aug 7, 2017·Current Hypertension Reports·Andrew C TiuVan Anthony M Villar
Jul 1, 2015·Current Opinion in Nephrology and Hypertension·Pedro A Jose, Dominic Raj
Jul 3, 2015·The Journal of Biological Chemistry·Samantha J AllenKevin J Lumb
Feb 7, 2019·The Pharmacogenomics Journal·Santiago CuevasPedro A Jose
Dec 2, 2020·International Journal of Molecular Sciences·Victor J MartinezAndrew C Tiu

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Methods Mentioned

BETA
antisense oligonucleotides

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