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Mechanisms of Disease: the role of GRK4 in the etiology of essential hypertension and salt sensitivity

Nature Clinical Practice Nephrology volume 2, pages 637–650 (2006)Cite this article

Abstract

Hypertension and salt sensitivity of blood pressure are two conditions the etiologies of which are still elusive because of the complex influences of genes, environment, and behavior. Recent understanding of the molecular mechanisms that govern sodium homeostasis is shedding new light on how genes, their protein products, and interacting metabolic pathways contribute to disease. Sodium transport is increased in the proximal tubule and thick ascending limb of Henle of the kidney in human essential hypertension. This Review focuses on the counter-regulation between the dopaminergic and renin–angiotensin systems in the renal proximal tubule, which is the site of about 70% of total renal sodium reabsorption. The inhibitory effect of dopamine is most evident under conditions of moderate sodium excess, whereas the stimulatory effect of angiotensin II is most evident under conditions of sodium deficit. Dopamine and angiotensin II exert their actions via G protein-coupled receptors, which are in turn regulated by G protein-coupled receptor kinases (GRKs). Polymorphisms that lead to aberrant action of GRKs cause a number of conditions, including hypertension and salt sensitivity. Polymorphisms in one particular member of this family—GRK4—have been shown to cause hyperphosphorylation, desensitization and internalization of a member of the dopamine receptor family, the dopamine 1 receptor, while increasing the expression of a key receptor of the renin–angiotensin system, the angiotensin II type 1 receptor. Novel diagnostic and therapeutic approaches for identifying at-risk subjects, followed by selective treatment of hypertension and salt sensitivity, might center on restoring normal receptor function through blocking the effects of GRK4 polymorphisms.

Key Points

  • Dopamine (inhibitory) and angiotensin (stimulatory) counter-regulate sodium reabsorption in the proximal tubule

  • Dopamine and angiotensin exert their effects through G protein-coupled receptors, which are regulated by G protein-coupled receptor kinases (GRKs)

  • Uncoupling of the dopamine 1 receptor from its effector proteins (e.g. adenylyl cyclase) contributes to essential hypertension

  • Increased activity of GRK4 is correlated with high blood pressure

  • GRK4 gene variants have been detected in hypertensive and salt-sensitive humans

  • Antagonists of GRK4, which should restore coupling of the dopamine 1 receptor to its effector proteins, might prove to be useful antihypertensives

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Figure 1: The principal source of renal dopamine is circulating L-DOPA, which is freely filtered by the glomerulus.
Figure 2: Distribution of dopamine and angiotensin receptors in the nephron.
Figure 3: Schematic representation of G protein-coupled receptor kinase 4 with its three principal domains: the GPCR binding domain; the catalytic domain; and the membrane targeting domain.
Figure 4: Schematic diagrams of G protein-coupled receptor kinase 4 transgenes, with the receptor binding, catalytic and membrane targeting domains.

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Acknowledgements

We thank A Thompson for her assistance with preparing the manuscript. This work was supported by grant numbers PG-00127-2004.R1, HL23081, DK39308, HL68686, DK52612, and HL074940.

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Authors and Affiliations

  1. RA Felder is Professor of Pathology, Associate Director of Clinical Chemistry, and Director of the Medical Automation Research Center at the University of Virginia, Charlottesville, VA, USA

    Robin A Felder

  2. PA Jose is Director of Pediatric Nephrology Research, and Professor in the Departments of Pediatrics and Physiology & Biophysics, at Georgetown University, Washington, DC, USA

    Pedro A Jose

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Correspondence to Robin A Felder.

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The use of polymorphisms in GRK4 for the diagnosis and treatment of essential hypertension and salt sensitivity has resulted in a patent entitled 'G Protein-Related Kinase' (#6,660,474, 12.09.03) that has been assigned to Hypogen, Inc., Charlottesville, VA, a company in which the authors hold the majority share of the equity.

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Felder, R., Jose, P. Mechanisms of Disease: the role of GRK4 in the etiology of essential hypertension and salt sensitivity. Nat Rev Nephrol 2, 637–650 (2006). https://doi.org/10.1038/ncpneph0301

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