D1R and AT1R receptor interaction in human hypertension: clinical mechanisms

D1R 和 AT1R 受体在人类高血压中的相互作用：临床机制

• 批准号: 7778673
• 负责人: ROBERT MUNSON CAREY
• 金额: $ 43.54万
• 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 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7778673
• 关键词: ANG gene; Adult; Affect; Angiotensin II; Angiotensin Receptor; Angiotensins; Animals; Attenuated; Biochemical; Blood Pressure; Body Fluids; Cardiovascular system; Cell Line; Cells; Clinical; Complex; Coupling; Defect; Development; Distal; Dopamine; Edema; Electrolyte Balance; Equilibrium; Essential Hypertension; Excretory function; Functional disorder; G protein coupled receptor kinase; GTP-Binding Proteins; Genetic; Goals; Human; Hypertension; Impairment; Inbred SHR Rats; Inbred WKY Rats; Kidney; Kidney Diseases; Lead; Limb structure; Mediating; Mus; Natriuresis; Nephrons; Organ; Pathway interactions; Patients; Phosphotransferases; Physiological; Play; Population; Proximal Kidney Tubules; Regulation; Regulatory Pathway; Renal tubule structure; Renin; Renin-Angiotensin System; Reporting; Research; Role; Sodium; System; Testing; Thick; United States; Variant; autocrine; blood pressure regulation; cerebrovascular; familial hypertension; human subject; normotensive; overexpression; paracrine; premature; pressure; receptor; receptor expression; receptor function; response; selective prevention; therapeutic target

Primary (essential) hypertension affects 28 % of the adult population in the United States and leads to premature cardiovascular, cerebrovascular and renal disease. The overall goal of Project #2 is to understand the interactions among the major renal Na+ regulatory pathways (dopamine 1, [DIR], dopamine 3 [DSR], and angiotensin type 1 [ATIR] receptors) which are critical to the regulation of blood pressure in humans. In experimental animals, the renal renin-angiotensin system and the renal dopaminergic system independently, and in concert, regulate renal Na-i- excretion, and defects in these pathways can lead to hypertension. We have reported that the hypertension in mice overexpressing the human G protein-coupled receptor kinase type 4 variant, GRK4 A142V is associated with decreased renal Dl R expression and function and increased ATI R expression and function A similar mechanism may be operating in human essential hypertension. Expression of GRK4 variants in cell lines replicates the Dl R defect noted in human renal proximal tubule cells from hypertensive subjects. Inhibition of GRK4 function or expression normalizes DIR function in human renal proximal tubule cells/cell lines expressing GRK4 variants. Moreover, renal selective prevention of the expression of GRK4 in spontaneously hypertensive rats attenuates the development of hypertension. The uncoupling of Dl R in hypertension impairs the inhibitory paracrine regulation by dopamine (DA) of renal Na+ transport in the proximal tubule and even more distal nephron segments. Because DA, via DiRs and D3Rs, normally antagonizes the increase in Na+ reabsorption caused by angiotensin II, via ATlRs, enhanced renal Na-i- reabsorption In hypertension may be due to an unopposed ATI R action (by DA). The overall hypothesis of Project #2 is that ATI R-mediated antinatriuresis is opposed by D1Rs and D3Rs, acting in concert in normal human subjects, and that this protective mechanism is deficient in patients with essential hypertension. Three specific aims will determine the interactions among DiRs and D3Rs and ATlRs and their consequences in terms of Na+ excretion: (1) to test the hypothesis that D3R activation induces natriuresis, in part, (continued on next page)

原发性（原发性）高血压影响美国28%的成年人口，并导致 早发心血管、脑血管和肾脏疾病。项目#2的总体目标是 了解主要的肾脏Na+调节途径（多巴胺1，[多巴胺]，多巴胺 3 [DSR]和血管紧张素1型[ATIR]受体），这些受体对调节糖尿病患者的血压至关重要。 人类在实验动物中，肾脏肾素-血管紧张素系统和肾脏多巴胺能系统 独立地且一致地调节肾Na+排泄，并且这些途径中的缺陷可导致 高血压我们已经报道过，高血压在小鼠过表达的人G蛋白偶联 受体激酶4型变体GRK 4 A142 V与肾D1 R表达降低相关， 功能和增加的ATI R表达和功能 原发性高血压GRK 4变体在细胞系中的表达复制了在人类中注意到的D1 R缺陷。 高血压患者的肾近端小管细胞。GRK 4功能或表达的抑制正常化 表达GRK 4变体的人肾近端小管细胞/细胞系中的GRK 4功能。此外，肾 选择性抑制自发性高血压大鼠GRK 4的表达， 高血压的发展。高血压病时Dl R解偶联损害抑制性旁分泌 多巴胺（DA）对近端小管甚至更远端肾单位段中肾脏Na+转运的调节。因为DA通过D1 R和D3 R通常拮抗由血管紧张素II通过AT 1 R引起的Na+重吸收的增加，所以高血压中肾Na+重吸收的增强可能是由于未对抗的AT 1 R作用（通过DA）。项目#2的总体假设是，ATR介导的抗白尿作用受到D1 R和D3 R的对抗，在正常人类受试者中协同作用，并且这种保护机制在原发性高血压患者中缺乏。三个具体目标将确定DiR和D3 R和ATlR之间的相互作用及其在Na+排泄方面的后果： 检验D3 R激活部分诱导尿钠排泄的假设（续下页）