D1R and AT1R receptor interaction in human hypertension: clinical mechanisms

在美国，28%的成年人患有原发性高血压，并导致 早产儿的心脑血管和肾脏疾病。项目2的总体目标是 了解肾脏主要钠离子调节通路(多巴胺1、[DIR]、多巴胺)之间的相互作用 3[DSR]和血管紧张素1[ATIR]受体)，它们对高血压的调节至关重要。 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 独立地和协调地调节肾脏钠离子的排泄，这些途径中的缺陷可能导致 高血压。我们已经报道了高血压小鼠过表达人类G蛋白偶联 受体激酶4型变异体GRK4A142V与肾脏DLR表达降低和 功能和ATI R表达增加及功能类似的机制可能在人类身上起作用 原发性高血压。GRK4变异体在细胞系中的表达复制了人类中发现的DL R缺陷 高血压患者的肾近端小管细胞。抑制GRK4功能或表达使其正常化 人肾近端小管细胞/表达GRK4变异体的细胞系的DIR功能。此外，肾脏 选择性预防自发性高血压大鼠GRK4的表达 高血压的发展。高血压时DL-R去偶联损害抑制性旁分泌 多巴胺(DA)对肾脏近端小管和更远端肾单位段Na+转运的调节。由于DA通过DIRS和D3Rs拮抗血管紧张素II通过ATlRs引起的Na+重吸收增加，高血压时肾脏Na-I重吸收的增加可能是由于(DA)ATI R作用不对抗所致。项目2的总体假设是，在正常人中，ATI受体介导的抗心绞痛与D1Rs和D3Rs是相反的，并且这种保护机制在高血压患者中是缺乏的。三个具体目标将决定DIRS与D3Rs和ATlRs之间的相互作用及其在Na+排泄方面的后果：(1) 测试D3R激活导致钠尿的假设，部分(续下一页)

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)