Dopamine/Angiostensin Receptors in Genetic Hypertension

遗传性高血压中的多巴胺/血管紧张素受体

• 批准号: 6704382
• 负责人: Robin A Felder
• 金额: $ 198.71万
• 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 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6704382
• 关键词: G protein coupled receptor kinase; angiotensin receptor; clinical research; dopamine receptor; familial hypertension; gene interaction; pathologic process

DESCRIPTION (provided by applicant): Because the kidney is important in the long term regulation of blood pressure and is the major organ involved in the regulation of sodium homeostasis, many studies have focused on abnormal renal handling of sodium chloride in the pathogenesis of essential hypertension. The autocrine/paracrine agents, dopamine and angiotensin II, work in an opposing manner to regulate renal function. Specifically, dopamine, via dopamine D1 and D3 receptors, is natriuretic while angiotensin II, via AT1 receptors, is antinatriuretic. Increased activity of the renin angiotensin system (RAS) and loss of function in the dopaminergic system lead to sodium retention and hypertension. We have reported that impairment of the renal D1 receptor in mice caused by overexpressing the G protein-coupled receptor kinase type 4 variant, GRK4 A142V, leads to high blood pressure. A similar mechanism may be operating in human essential hypertension; the GRK4 gene locus (chromosome 4p16.3) is linked to and GRK4 variants are associated with hypertension. GRK4 variants impair D1 receptor function in human renal proximal tubules. Expression of GRK4 variants in cell lines replicates the D1 receptor defect noted in renal proximal tubules. Inhibition of GRK4 function or expression normalizes D11 receptor function in and human renal proximal tubule cells/cell lines expressing GRK4 gene variants. Moreover, renal selective prevention of the expression of GRK4 in spontaneously hypertensive rats attenuates the development of hypertension. The overall goal of this PPG is to test the hypothesis that in genetic hypertension the reduction of D1 and D3 receptor function, caused by GRK4, cannot oppose AT1 receptor function leading to increased renal sodium reabsorption and high blood pressure. To accomplish our goal, we have organized a team of investigators, experienced in studies of dopamine and RAS, to elucidate the nature of their gene/gene interactions in health and in hypertension. Project by Felder will test the hypothesis that variant GRK4 proteins have increased constitutive activities that desensitize the D1 receptor but not the AT1 receptor. Project by Carey will test the hypothesis that salt sensitivity is produced when GRK4 variants desensitize the D1 receptor in the kidney, and that hypertension is produced when variants related to the RAS are also present. Project by Jose will test the hypothesis that renal proximal tubule sodium transport is regulated, in part, by an interaction among D1, D3, and AT1 receptors and that an aberrant interaction occurs in hypertension because of GRK4 variants. These gene/gene interactions are in keeping with the critical roles these receptors play in the polygenic causation of genetic hypertension.

描述（由申请人提供）： 由于肾脏在长期调节血压方面很重要，并且是钠稳态调节的主要器官，因此许多研究集中在基本高血压发病机理中的肾脏异常。 多巴胺和血管紧张素II的自分泌/旁分泌剂以相反的方式调节肾功能。 具体而言，多巴胺通过多巴胺D1和D3受体是亚催化剂，而血管紧张素II（通过AT1受体）是抗钠尿素。 肾素血管紧张素系统（RAS）的活性增加和多巴胺能系统中功能丧失会导致钠保留和高血压。 我们报告说，由于过表达G蛋白偶联受体激酶4型变体GRK4 A142V引起的小鼠肾脏D1受体的损害会导致高血压。 类似的机制可能在人类基本高血压中运行。 GRK4基因基因座（4p16.3染色体）与Hypertension相关，GRK4变体与高血压相关。 GRK4变体会损害人肾近端小管中的D1受体功能。 GRK4在细胞系中的表达复制了肾近端小管中指出的D1受体缺陷。 GRK4功能或表达的抑制使D11受体功能在表达GRK4基因变异的D11受体功能和人肾近端小管细胞/细胞系中。 此外，肾脏选择性预防GRK4在自发性高血压大鼠中的表达减弱了高血压的发展。 该PPG的总体目标是检验以下假设：在遗传性高血压中，由GRK4引起的D1和D3受体功能的降低不能反对AT1受体功能，从而导致肾钠吸收增加和高血压。 为了实现我们的目标，我们组织了一组研究人员，在多巴胺和RAS研究方面经历了研究，以阐明其在健康和高血压中的基因/基因相互作用的性质。 Felder的项目将检验以下假设：变体GRK4蛋白具有增加脱敏D1受体而不是AT1受体脱敏的活性。 凯里（Carey）的项目将检验以下假设：当GRK4变体脱敏D1受体中的D1受体时会产生盐敏感性，并且当同时存在与RAS相关的变体时产生高血压。 Jose的项目将检验以下假设：肾近端小管钠转运受到D1，D3和AT1受体之间的相互作用的部分调节，并且由于GRK4变体而在高血压中发生异常相互作用。 这些基因/基因相互作用与这些受体在遗传性高血压的多基因因果关系中起的关键作用保持一致。