Mechanisms of disease: the role of GRK4 in the etiology of essential hypertension and salt sensitivity.
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.
Felder
Robin A
RA
Department of Pathology, Post Office Box 800403, University of Virginia Health Sciences Center, Charlottesville, VA 22908, USA. rfelder@virginia.edu
Jose
Pedro A
PA
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D004298:Dopamine / Q000378:metabolism; D054771:G-Protein-Coupled Receptor Kinase 4; D006801:Humans; D006973:Hypertension / Q000209:etiology* / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D011110:Polymorphism, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012084:Renin-Angiotensin System; D012965:Sodium Chloride / Q000494:pharmacology*
D012965:Sodium Chloride; D017346:Protein Serine-Threonine Kinases; D054771:G-Protein-Coupled Receptor Kinase 4; C517855:GRK4 protein, human; D004298:Dopamine