Abnormalities in renal dopamine signaling and hypertension: the role of GRK4

Abstract

Purpose of review: This review will highlight the recent findings concerning the role of the intrarenal dopaminergic system in hypertension, especially the role of alterations in G-protein receptor kinase 4 (GRK4) activity.

Recent findings: Recent studies highlight the importance of the intrarenal dopaminergic system in blood pressure regulation and how defects in dopamine signaling are involved in the development of hypertension. There are recent experimental models that definitively demonstrate that abnormalities in intrarenal dopamine production or receptor signaling can predispose to salt-sensitive hypertension and a dysregulated renin-angiotensin system. Furthermore, studies in experimental animal models and in humans with salt-sensitive hypertension implicate abnormalities in dopamine receptor regulation because of receptor desensitization resulting from increased GRK4 activity. Functional polymorphisms that predispose to increased basal GRK4 activity both decrease dopamine receptor activity and increase angiotensin II AT1 receptor activity and are associated with essential hypertension in a number of different human cohorts.

Summary: The ongoing elucidation of this important regulatory pathway further emphasizes the importance of the kidney in maintenance of blood pressure control and may help to delineate the underlying mechanisms predisposing individuals or populations to increased risk for development of hypertension.

Effects of GRK4 variants to mediate hypertension. Coupling of wild type GRK4 to dopamine receptors stimulates their activity and inhibits salt reabsorption, while wild type GRK4 inhibits AT1 receptor activity. Conversely, GRK4 variants increase AT1R activity and decrease dopamine receptor activity, with a net effect of increased sodium reabsorption, which predisposes to hypertension.