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

项目1的摘要 这项研究提案的目标是扩展我们对肾素血管紧张素系统如何 (RAS)和多巴胺能系统调节肾脏的钠转运，最终调节它们的 参与盐敏感性的病因学(这是一种影响51%的高血压和 26%的血压正常的人)。具体地说，我们将测试总体假设 产生电的碳酸氢钠共转运体NBCe2(由SLC4A5基因编码)和 NBCe1(由SLC4A4基因编码)通过调节参与钠稳态 由RAS和多巴胺能系统以及其他关键的钠转运蛋白(NHE3和 Na+、K+/ATPase)。此外，SLC4A5中的两个单核苷酸多态(SNPs)导致 通过增加SLC4A5 mRNA的表达和增加钠重吸收的失调 NBCe2活性。这个项目的具体目标是：(1)检验盐的假设 敏感性是由于肾近端小管的多巴胺能和血管紧张素调节异常所致 SLC4A5内含子变异和GRK4(GRK4-65L)变异引起的钠转运 (2)通过研究表观遗传调控来检验特定目标1的假说。 SLC4A5中HNF4a结合位点表达NBCe2(及相关离子转运体) 吉恩。

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.