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.

血压（BP）Na+灵敏度的遗传原因尚不清楚。肾脏对 长期调节流体和电解质平衡和BP。那就是盐敏感性的发病机理 涉及肾脏NA+处理的扰动。盐敏感高血压与内含子变体有关 电源NaHCO3共转运蛋白基因（SLC4A5）。尽管没有Cl-的Na+负载可能不会引起压力 效果，nahco3可能在某些个体中引起高血压，但其压力效应小于NaCl。因此，在 大多数Na+敏感性高血压的病例，必须有Na+和Cl-保留率。基本高血压是 与低血清HCO3-相关，这意味着肾脏CL-和HCO3转运之间存在不平衡。肾 Na+/H+交换器类型3（NHE3），Cl-/HCO3-交换器和NAHCO3共转运蛋白对 肾脏多巴胺，由血管紧张素II阳性调节。这两个系统的破坏可能导致 高血压，肾脏CL-和HCO3转运失衡。 Na+的异常肾脏多巴胺调节 高血压中的运输可能是由五种多巴胺中任何一种的表达或功能降低引起的 受体。多巴胺受体的功能受损可能是其构成脱敏的继发的 在D1R和D3R的情况下，通过G蛋白偶联受体激酶4型（GRK4）。 GRK4变体（65L，142V，， 和486V）与高血压和/或盐敏感性有关。尤其是GRK4-65L也有关联 我们据报道具有与SLC4A5相关的盐敏感性高血压的队列中的盐灵敏度 变体。人GRK465L（HGRK465L）转基因小鼠单独或单独或IN对HGRK4-65L是盐敏感的 与SLC4A5内含子变体的关联，增加了SLC4A5的表达，可能涉及乙酰化 （例如，组蛋白脱乙酰基酶1，HDAC1），一种遗传学的实例，调节表观遗传学，然后又 调节基因转录（HGRK4，HDAC1，肝细胞核因子[HNF4A] 38A-C和SLC4A5）。 项目3将检验以下假设：在某些情况下，在盐敏感的高血压下，HGRK465L和内含子 SLC4A5的变体对表观遗传的异常遗传调节而增加了SLC4A5的表达 还会增加肾脏NHE3，NBCE2和CL-/HCO3-交换器活动的途径，调节 遗传学和表观遗传学在对盐敏感的BP的发展中起着至关重要的作用。