Animal models of salt sensitivity: roles of GRK4 and sodium transporters on salt sensitivity

盐敏感性动物模型：GRK4 和钠转运蛋白对盐敏感性的作用

• 批准号: 9283600
• 负责人: Pedro A. Jose
• 金额: $ 74.68万
• 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/9283600
• 关键词: Acetylation; Acids; Adenylate Cyclase; African American; American; Angiotensin II; Animal Model; Bicarbonates; Binding; Biological; Blood Plasma Volume; Blood Pressure; Cardiac Myocytes; Chronic; Coupled; Coupling; DRD2 gene; Data; Development; Dopamine; Dopamine D1 Receptor; Dopamine Receptor; Electrolyte Balance; Ensure; Epigenetic Process; Equilibrium; Essential Hypertension; Fluid Balance; G protein coupled receptor kinase; G-Protein-Coupled Receptors; Genes; Genetic; Genetic Transcription; HDAC1 gene; HNF4A gene; Histone Deacetylase; Human; Hypertension; Impairment; Inbred SHR Rats; Individual; Insulin Resistance; Intake; Kidney; Lead; Mediating; Medical; Membrane Transport Proteins; Methods; Molecular; Mus; Natriuretic Factors; Pathogenesis; Pathway interactions; Phosphotransferases; Physiological; Plasma; Play; Protein Isoforms; Proteins; Proximal Kidney Tubules; Receptor, Angiotensin, Type 1; Regulation; Renal function; Renin-Angiotensin-Aldosterone System; Reporting; Role; Secondary to; Serum; Sodium; Sodium Chloride; System; Taxes; Testing; Transgenic Mice; Tubular formation; United States; Variant; Vascular resistance; cohort; cost; desensitization; epigenetic regulation; genetic variant; hepatocyte nuclear factor; prevent; receptor; response; salt sensitive; salt sensitive hypertension; saluretic; sorting nexins

The genetic causes of Na+ sensitivity of blood pressure (BP) are not well known. The kidney is critical to the long-term regulation of fluid and electrolyte balance and BP. Thus, the pathogenesis of salt sensitivity must involve a perturbation of renal Na+ handling. Salt-sensitive hypertension is associated with intronic variants of the electrogenic NaHCO3 cotransporter gene (SLC4A5). Although Na+ load without Cl- may not elicit a pressor effect, NaHCO3 can cause hypertension in some individuals but its pressor effect is less than NaCl. Hence, in most cases of Na+-sensitive hypertension, there must be Na+ and Cl- retention. Essential hypertension is associated with low serum HCO3-, implying an imbalance between renal Cl- and HCO3- transport. The renal Na+/H+ exchanger type 3 (NHE3), Cl-/HCO3- exchanger, and NaHCO3 cotransporter are negatively regulated by renal dopamine and positively regulated by angiotensin II. A disruption of these two systems may result in hypertension with an imbalance of renal Cl- and HCO3- transport. Aberrant renal dopamine regulation of Na+ transport in hypertension can be caused by decreased expression or function of any of the five dopamine receptors. The impaired function of dopamine receptors may be secondary to their constitutive desensitization by G protein-coupled receptor kinase type 4 (GRK4), in the case of D1R and D3R. GRK4 variants (65L, 142V, and 486V) are associated with hypertension and/or salt sensitivity. GRK4-65L, in particular, is also associated with salt sensitivity in the cohort that we reported to have salt-sensitive hypertension associated with SLC4A5 variants. Human GRK465L (hGRK465L) transgenic mice are salt-sensitive and hGRK4-65L, alone or in association with SLC4A5 intronic variants, increases the expression of SLC4A5, that may involve acetylation (e.g., histone deacetylase 1, HDAC1), an instance of genetics regulating epigenetics which, in turn, then regulates gene transcription (hGRK4, HDAC1, hepatocyte nuclear factor  [HNF4A]38a-c, and SLC4A5). Project 3 will test the hypothesis that in some cases of salt-sensitive hypertension, hGRK465L and intronic variants of SLC4A5 increase SLC4A5 expression in response to aberrant genetic regulation of epigenetic pathways that also increase renal NHE3, NBCe2, and Cl-/HCO3- exchanger activities, The inter-regulation of genetics and epigenetics plays a crucial role in the development of salt-sensitive BP.

Na+对血压（BP）敏感性的遗传原因尚不清楚。肾脏对…至关重要