Dopamine, the kidney, and hypertension

Abstract

There is increasing evidence that the intrarenal dopaminergic system plays an important role in the regulation of blood pressure, and defects in dopamine signaling appear to be involved in the development of hypertension. Recent experimental models have definitively demonstrated that abnormalities in intrarenal dopamine production or receptor signaling can predispose to salt-sensitive hypertension and a dysregulated renin-angiotensin system. In addition, studies in both experimental animal models and in humans with salt-sensitive hypertension implicate abnormalities in dopamine receptor regulation due to receptor desensitization resulting from increased G-protein receptor kinase 4 (GRK4) activity. Functional polymorphisms that predispose to increased basal GRK4 activity both decrease dopamine receptor activity and increase angiotensin II type 1 (AT1) receptor activity and are associated with essential hypertension in a number of different human cohorts.

Fig. 1

Renal dopamine deficiency results in salt-sensitive hypertension. a Proximal tubule aromatic amino acid decarboxylase (AADC) was deleted in ptAADC−/− mice. b Salt-sensitive hypertension was observed in ptAADC−/− mice. *P<0.01 vs wild type on a normal-salt diet, †P<0.05 vs wild type on a high-salt diet, ‡P<0.005 vs ptAADC−/− on a normal-salt diet (n=9 in each group). (Adapted from Zhang et al. [31••])

Fig. 2

Dopamine directly inhibits renal sodium reabsorption and decreases activity of the renin-angiotensin system at multiple steps, helping to maintain normal blood pressure. GRK4 variants decrease dopamine receptor activity and increase AT1R activity, with a net effect of increased sodium reabsorption, which predisposes to hypertension. ACE angiotensin-converting enzyme, AT1 angiotensin II type 1, GRK4 G-protein receptor kinase 4