{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T01:04:13Z","timestamp":1789779853315,"version":"4.0.1"},"reference-count":24,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2015,3,12]],"date-time":"2015-03-12T00:00:00Z","timestamp":1426118400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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 black men. In South Africa, GRK4 polymorphisms are more common in people of African descent, associated with impaired Na excretion in normotensive African people, and predict blood pressure response to Na restriction in African patients with mild to moderate essential hypertension. The therapeutic importance of the GRK4 single nucleotide polymorphisms (SNPs) was emphasised in the African American Study of Kidney Disease (AASK) where African-Americans with hypertensive nephrosclerosis were randomised to receive amlodipine, ramipril or metoprolol. Men with the p.Ala142Val genotype were less likely to respond to metoprolol, especially if they also had the p.Arg65Leu variant. Furthermore, in the analysis of response to treatment in two major hypertension studies, the 65Leu\/142Val heterozygote predicted a significantly decreased response to atenolol treatment, and the 65Leu\/142Val heterozygote and 486Val homozygote were associated in an additive fashion with adverse cardiovascular outcomes, independent of BP. In conclusion, there is considerable evidence that GRK4 variants are linked to impaired Na excretion, hypertension in animal models and humans, therapeutic response to dietary Na restriction and response to antihypertensive drugs. It may also underlie the difference in hypertension between different geographically derived population groups, and form a basis for pharmacogenomic approaches to treatment of hypertension.<\/jats:p>","DOI":"10.3390\/ijms16035741","type":"journal-article","created":{"date-parts":[[2015,3,12]],"date-time":"2015-03-12T11:30:24Z","timestamp":1426159824000},"page":"5741-5749","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["The Importance of G Protein-Coupled Receptor Kinase 4 (GRK4) in Pathogenesis of Salt Sensitivity, Salt Sensitive Hypertension and Response to Antihypertensive Treatment"],"prefix":"10.3390","volume":"16","author":[{"given":"Brian","family":"Rayner","sequence":"first","affiliation":[{"name":"Division of Nephrology and Hypertension, University of Cape Town, Cape Town 7925, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raj","family":"Ramesar","sequence":"additional","affiliation":[{"name":"MRC Human Genetics Research Unit, Division of Human Genetics, Institute of Infectious Diseases and Molecular Medicine, Faculty of Health Sciences, University of Cape Town,  Cape Town 7925, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2015,3,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1161\/01.HYP.27.3.481","article-title":"Salt sensitivity of blood pressure in humans","volume":"27","author":"Weinberger","year":"1996","journal-title":"Hypertension"},{"key":"ref_2","first-page":"555","article-title":"Differences in response to sodium administration in normotensive white and black subjects","volume":"90","author":"Luft","year":"1977","journal-title":"J. Lab. Clin. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1161\/01.CIR.0000158136.76824.04","article-title":"State of disparities in cardiovascular health in the United States","volume":"1111","author":"Mensah","year":"2005","journal-title":"Circulation"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1161\/HYPERTENSIONAHA.110.161950","article-title":"Health behaviors and racial disparity in blood pressure control in the National Health and Nutrition Examination Survey","volume":"57","author":"Redmond","year":"2011","journal-title":"Hypertension"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1212","DOI":"10.1161\/HYPERTENSIONAHA.113.02989","article-title":"Racial differences in sensitivity of blood pressure to aldosterone","volume":"63","author":"Tu","year":"2014","journal-title":"Hypertension"},{"key":"ref_6","first-page":"594","article-title":"Screening for primary aldosteronism\u2014Normal ranges for aldosterone and renin in three South African groups","volume":"91","author":"Rayner","year":"2001","journal-title":"S. Afr. Med. J."},{"key":"ref_7","first-page":"14","article-title":"Renal physiology","volume":"Chapter 2","author":"Johnson","year":"2014","journal-title":"Comprehensive Clinical Nephrology"},{"key":"ref_8","first-page":"579","article-title":"Inherited disorders of sodium and water metabolism","volume":"Chapter 49","author":"Johnson","year":"2014","journal-title":"Comprehensive Clinical Nephrology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1097\/HJH.0b013e32832104b1","article-title":"Ethnic differences in proximal and distal tubular sodium reabsorbtion are heritable in black and white populations","volume":"27","author":"Bochud","year":"2009","journal-title":"J. Hypertens."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1146\/annurev.physiol.62.1.621","article-title":"Intrarenal dopamine: A key signal in the interactive regulation of sodium metabolism","volume":"62","author":"Aperia","year":"2000","journal-title":"Annu. Rev. Physiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1097\/00041552-200303000-00010","article-title":"Dopamine and the kidney: A role in hypertension?","volume":"12","author":"Jose","year":"2003","journal-title":"Curr. Opin. Nephrol. Hypertens."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1097\/00041552-200201000-00013","article-title":"Role of dopamine receptors in the kidney in the regulation of blood pressure","volume":"11","author":"Jose","year":"2002","journal-title":"Curr. Opin. Nephrol. Hypertens."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1161\/01.HYP.0000222004.74872.17","article-title":"Amelioration of genetic hypertension by suppression of renal G protein-coupled receptor kinase type 4 expression","volume":"47","author":"Sanada","year":"2006","journal-title":"Hypertension"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3872","DOI":"10.1073\/pnas.062694599","article-title":"G protein-coupled receptor kinase 4 variants in human essential hypertension","volume":"99","author":"Felder","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1161\/HYPERTENSIONAHA.113.01766","article-title":"Role of GRK4 in the Regulation of Arterial AT1 Receptor in Hypertension","volume":"63","author":"Chen","year":"2014","journal-title":"Hypertension"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1203\/01.pdr.0000238250.64591.44","article-title":"The G protein-coupled receptor kinase 4 gene modulates stress-induced sodium excretion in black normotensive adolescents","volume":"60","author":"Zhu","year":"2006","journal-title":"Pediatr. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e9","DOI":"10.4081\/nr.2011.e9","article-title":"The A142V polymorphism of the G protein-coupled receptor kinase 4 gene predicts natriuretic response to saline challenge in young normotensive lean Black and White South African men","volume":"3","author":"Rayner","year":"2011","journal-title":"Nephrol. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Yatabe, Y., Yatabe, M.S., Yoneda, M., Felder, R.A., Jose, P.A., and Sanada, H. (2012). Hypertension-related gene polymorphisms of G-protein-coupled receptor kinase 4 are associated with NT-proBNP concentration in normotensive healthy adults. Int. J. Hypertens., 2012.","DOI":"10.1155\/2012\/806810"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1373\/clinchem.2005.059139","article-title":"Single-nucleotide polymorphisms for diagnosis of salt-sensitive hypertension","volume":"52","author":"Sanada","year":"2006","journal-title":"Clin. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1097\/00004872-200405000-00014","article-title":"Association of G-protein-coupled receptor kinase 4 haplotypes, but not HSD3B1 or PTP1B polymorphisms, with essential hypertension","volume":"22","author":"Speirs","year":"2004","journal-title":"J. Hypertens."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.amjhyper.2005.07.007","article-title":"The G protein-coupled receptor kinase 4 gene affects blood pressure in young normotensive twins","volume":"19","author":"Zhu","year":"2006","journal-title":"Am. J. Hypertens."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1038\/jhh.2011.33","article-title":"G-protein-coupled receptor kinase 4 (GRK-4) polymorphisms predict blood pressure response to dietary modification in black patients with mild to moderate hypertension","volume":"26","author":"Rayner","year":"2011","journal-title":"J. Hum. Hypertens."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1038\/ajh.2008.341","article-title":"G-Protein-coupled receptor kinase 4 polymorphisms and blood pressure response to metoprolol among african americans: Sex-specificity and interactions","volume":"22","author":"Bhatnagar","year":"2009","journal-title":"Am. J. Hypertens."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1161\/HYPERTENSIONAHA.112.198721","article-title":"G protein receptor kinase 4 polymorphisms: \u03b2-Blocker Pharmacogenetics and treatment-related outcomes in Hypertension","volume":"60","author":"Vandell","year":"2012","journal-title":"Hypertension"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/16\/3\/5741\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T20:43:24Z","timestamp":1760215404000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/16\/3\/5741"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,3,12]]},"references-count":24,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2015,3]]}},"alternative-id":["ijms16035741"],"URL":"https:\/\/doi.org\/10.3390\/ijms16035741","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,3,12]]}}}