Dopamine and G protein-coupled receptor kinase 4 in the kidney: role in blood pressure regulation

Abstract

Complex interactions between genes and environment result in a sodium-induced elevation in blood pressure (salt sensitivity) and/or hypertension that lead to significant morbidity and mortality affecting up to 25% of the middle-aged adult population worldwide. Determining the etiology of genetic and/or environmentally-induced high blood pressure has been difficult because of the many interacting systems involved. Two main pathways have been implicated as principal determinants of blood pressure since they are located in the kidney (the key organ responsible for blood pressure regulation), and have profound effects on sodium balance: the dopaminergic and renin-angiotensin systems. These systems counteract or modulate each other, in concert with a host of intracellular second messenger pathways to regulate sodium and water balance. In particular, the G protein-coupled receptor kinase type 4 (GRK4) appears to play a key role in regulating dopaminergic-mediated natriuresis. Constitutively activated GRK4 gene variants (R65L, A142V, and A486V), by themselves or by their interaction with other genes involved in blood pressure regulation, are associated with essential hypertension and/or salt-sensitive hypertension in several ethnic groups. GRK4γ 142Vtransgenic mice are hypertensive on normal salt intake while GRK4γ 486V transgenic mice develop hypertension only with an increase in salt intake. GRK4 gene variants have been shown to hyperphosphorylate, desensitize, and internalize two members of the dopamine receptor family, the D(1) (D(1)R) and D(3) (D(3)R) dopamine receptors, but also increase the expression of a key receptor of the renin-angiotensin system, the angiotensin type 1 receptor (AT(1)R). Knowledge of the numerous blood pressure regulatory pathways involving angiotensin and dopamine may provide new therapeutic approaches to the pharmacological regulation of sodium excretion and ultimately blood pressure control.

Figure 1

GRK4 and renal dopamine and angiotensin type 1 receptor interaction During conditions of moderately increased NaCl intake, the renal D₁R is stimulated by dopamine produced in the kidney. The D₁R or D₃R, whose coupling to G protein subunits is regulated by G protein-coupled receptor kinase type 4 (GRK4), inhibits sodium reabsorption in several nephron segments. This results in an increase in sodium excretion and maintenance of normal blood pressure. GRK4 wild-type (GRK4 WT) also negatively regulates AT₁R transcription. The decrease in AT₁R expression, caused by GRK4 WT, facilitates the inhibitory effect of D₁R on renal sodium transport. In essential hypertension, constitutively active variants of GRK4 not only uncouple D₁R and D₃R from G protein subunits, but also increase AT₁R transcription in the kidney. These effects impair the ability of the kidney to excrete the excess sodium load, resulting in sodium retention, and ultimately hypertension. Green = normal coupling of D₁R and D₃R to G protein subunits, Red = uncoupling of D₁R and D₃R from G protein subunits Green arrows = stimulatory, Red arrows = inhibitory