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

多巴胺能和血管紧张素通过碳酸氢钠协同转运蛋白 (SLC4A5) 在人肾近端和远端小管细胞中调节钠代谢：GRK4 对盐敏感性的作用

• 批准号: 9283598
• 负责人: Robin A Felder
• 金额: $ 39.67万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9283598
• 关键词: APPBP2 gene; Affect; American; Angiotensin Receptor; Angiotensins; Anions; Apical; Bicarbonates; Binding Sites; Blood Pressure; Carbon Dioxide; Cells; Chloride-Bicarbonate Antiporters; Code; Coupled; Data; Diagnosis; Diffuse; Distal; Dopamine Receptor; Elements; Environmental Risk Factor; Epigenetic Process; Essential Hypertension; Etiology; G protein coupled receptor kinase; Gene Expression; Genes; Genetic; Genetic Code; Genetic Transcription; Goals; HNF4A gene; Homeostasis; Human; Individual; Intake; Introns; Ions; Kidney; Lead; Left; Letters; Limb structure; Messenger RNA; Metabolism; Modeling; Molecular; Na(+)-K(+)-Exchanging ATPase; Organ; Pathology; Phosphotransferases; Play; Population; Process; Proteins; Proximal Kidney Tubules; Pump; Receptor, Angiotensin, Type 1; Regulation; Regulatory Pathway; Renin-Angiotensin System; Reporting; Research Proposals; Role; Seminal; Single Nucleotide Polymorphism; Sodium; Sodium Bicarbonate; Sodium Chloride; Sodium-Bicarbonate Symporters; System; Testing; Thick; Translations; Type 2 Angiotensin II Receptor; Variant; Work; basolateral membrane; blood pressure regulation; brush border membrane; carbonate dehydratase; cohort; desensitization; epigenetic regulation; genetic variant; high risk; in vivo; mRNA Expression; normotensive; overexpression; putative anion transporter 1; receptor; risk variant; saluretic; sodium-hydrogen exchanger 3; symporter

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.

项目1摘要 这项研究建议的目的是扩展我们对肾素血管紧张素系统的研究 （RAS）和多巴胺能系统调节肾脏钠运输，并最终 参与盐敏感性的病因（一种影响51％的高血压和 26％的正常人）。具体来说，我们将检验总体假设 碳酸氢钠共转运蛋白NBCE2（由基因SLC4A5编码）和 NBCE1（由基因SLC4A4编码）通过调节涉及钠稳态 由RAS和多巴胺能系统以及其他关键钠转运蛋白（NHE3和 Na+，K+/ATPase）。此外，SLC4A5中的两个单核苷酸多态性（SNP）导致 通过SLC4A5 mRNA表达和 NBCE2活性。该项目的具体目的是：（1）检验盐的假设 敏感性是由于肾近端小管的异常多巴胺能和血管紧张素调节 由slc4a5中内含子变体和grk4（grk4-65l）的内含子变体引起的钠转运和 （2）通过研究特定目标1中的假设，通过研究表观遗传调节 SLC4A5中HNF4A结合位点的NBCE2（及相关离子转运蛋白）的表达 基因。