The overall goal of Project by Carey is to understand the interaction between the major renal sodium regulatory pathways (D1 and AT1 receptors) which are critical to the regulation of blood pressure in man. The renal renin-angiotensin and dopaminergic systems independently and in concert regulate the majority of renal sodium excretion, and defects in these pathways can lead to hypertension. We have reported that impairment of the renal D1 receptor in mice caused by overexpressing the G protein-coupled receptor kinase type 4 variant, GRK4 A142V, leads to high blood pressure. A similar mechanism may be operating in human essential hypertension; the GRK4 gene locus (chromosome 4p16.3) is linked to and GRK4 variants are associated with hypertension. GRK4 variants impair D1 receptor function in human renal proximal tubules. Expression of GRK4 variants in cell lines replicates the D1 receptor defect noted in renal proximal tubules. Inhibition of GRK4 function or expression normalizes D1 receptor function in and human renal proximal tubule cells/cell lines expressing GRK4 gene variants. Moreover, renal selective prevention of the expression of GRK4 in spontaneously hypertensive rats attenuates the development of hypertension. The uncoupling of D1 receptors in genetic hypertension impairs the inhibitory paracrine regulation by dopamine of renal Na+ transport in the proximal tubule and the thick ascending limb of Henle. Because dopamine, via D1 receptors, normally antagonizes the increase in sodium reabsorption caused by angiotensin II, via AT1 receptors, enhanced renal Na+ reabsorption in hypertension may be due to an unopposed AT1 receptor action (by dopamine). The overall hypothesis of Project by Carey is that salt sensitivity is produced when GRK4 variants desensitize the D1 receptor in the kidney and that hypertension is produced when genetic variants of the renin-angiotensin system (RAS) also are present.
Three specific aims will determine mechanisms of GRK4 variants on D1 and AT1 receptors and their consequences in terms of sodium excretion and blood pressure: (1) to test the hypothesis that salt sensitivity of blood pressure is associated with GRK4 variants; (2) to test the hypothesis that decreased D1-like receptor-induced natriuretic responses are related to the presence of GRK4 variants: and (3) to test the hypothesis that increased antinatriuresis in hypertension is related to increased AT1 receptor-mediated sodium reabsorption, unopposed by dopamine, when both GRK4 variants and gene variants of the RAS are present. Studies will be performed in normotensive and hypertensive human subjects genotyped for variants of GRK4 as well as variants of genes of the RAS. On the basis of our studies on the role of GRK4 variants in D1 receptor signaling, we suggest that a single gene that regulates many other genes may be a major contributor to the pathophysiology of essential hypertension.
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