D3, D1, AT1 Receptor Interaction--Genetic Hypertension

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The overall goal of Project by Jose is to determine D3, D1, and AT1 receptor interaction in the kidney. The D3 dopamine receptor can regulate renal sodium transport and blood pressure independent of the D1 receptor because disruption of the D3 receptor in mice increases blood pressure and impairs their ability to excrete an acute saline load. However, the D3 receptor can also synergistically interact with the D1 receptor to increase sodium excretion. In rodent models of genetic hypertension (Dahl salt sensitive and spontaneously hypertensive rat, SHR), the natriuretic effect of D3 receptors is impaired and the interaction between the D1 and D3 receptor is lost. The impairment of the renal D1 receptor function in genetic hypertension is caused by increased activity of G protein-coupled receptor kinase, type 4 (GRK4). GRK4 gene locus is linked to and GRK4 variants are associated with human essential hypertension. Heterologous expression of these variants in Chinese hamster ovary and HEK cells impairs D1 receptor function and mice overexpressing the GRK4 variant A142V develop hypertension and have an impaired natriuretic response to D1 receptor agonist stimulation. Moreover, inhibition of GRK4 activity in renal proximal tubule cells (or cell lines) from human hypertensives restores D1 receptor function and selective renal inhibition of GRK4 expression attenuates the increase in blood pressure in SHRs. Whether the impaired renal D3 receptor function in genetic hypertension is secondary to increased GRK4 activity, which impairs both the D1 and D3 receptor, is not known. However, D3-/- mice have impaired D1 receptor function, and increased renal renin content and AT1 receptor. Thus, a decreased D1 receptor and an increased AT1 receptor function in D3-/- mice may contribute to their impaired ability to excrete a saline load and hypertension. The overall hypothesis of Project by Jose is that renal proximal tubule sodium transport is regulated, in part, by an interaction among D1, D3 and AT1 receptors, acutely, by receptor/receptor interaction, and chronically, by regulation of receptor expression. Moreover, in genetic hypertension, impaired D3 (and D1) receptor function due to increased GRK4 activity, allows unimpeded AT1 receptor action. Specific aim I will test the hypothesis that D3 receptor deficiency in mice both impairs D1 receptor function and allows unimpeded AT1 receptor function. Specific aim 2 will test the hypothesis that increased GRK4 activity, due to constitutively active variants, impairs D3 receptor function in genetic hypertension. The results of these studies, using molecular biological and pharmacological tools, may shed light into the possibility that ability of GRK4 to regulate several genes may make GRK4 dysfunction a major cause of genetic hypertension.