Dopaminergic and angiotensin regulation of sodium metabolism via the sodium bicarbonate co-transporter (SLC4A5) in the human renal proximal and distal tubule cells: Role of GRK4 on salt sensitivity

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ABSTRACT FOR PROJECT 1 The goal of this research proposal is to extend our studies of how the renin angiotensin system (RAS) and dopaminergic systems regulate renal sodium transport and ultimately their involvement in the etiology of salt sensitivity (a pathology affecting 51% of hypertensive and 26% of normotensive individuals). Specifically, we will test the overall hypothesis that the electrogenic sodium bicarbonate cotransporters NBCe2 (coded by the gene SLC4A5) and NBCe1 (coded by the gene SLC4A4) are involved with sodium homeostasis through regulation by the RAS and dopaminergic systems and other critical sodium transporters (NHE3 and Na+,K+/ATPase). Furthermore, two single nucleotide polymorphisms (SNPs) in SLC4A5 lead to the dysregulation of sodium reabsorption through increases in SLC4A5 mRNA expression and NBCe2 activity. The specific aims for this project are: (1) To test the hypothesis that salt sensitivity is due to aberrant dopaminergic and angiotensin regulation of renal proximal tubule sodium transport caused by intronic variants in SLC4A5 and a variant of GRK4 (GRK4-65L) and (2) To test the hypothesis in specific aim 1 by investigating the epigenetic regulation of the expression of NBCe2 (and related ion transporters) by an HNF4A binding site in the SLC4A5 gene.