Dopamine/Angiostensin Receptors in Genetic Hypertension

描述(由申请人提供)： 由于肾脏在血压的长期调节中起着重要的作用，也是钠稳态调节的主要器官，因此许多研究都集中在肾脏对氯化钠的异常处理在高血压发病机制中的作用。自分泌/旁分泌药物，多巴胺和血管紧张素II，以相反的方式调节肾功能。具体地说，多巴胺通过多巴胺D1和D3受体是利钠药，而血管紧张素II通过AT1受体是抗心钠剂。肾素血管紧张素系统(RAS)活性增加和多巴胺能系统功能丧失导致钠滞留和高血压。我们已经报道，由于G蛋白偶联受体激酶4型变异体GRK4A142V的过度表达而导致小鼠肾脏D1受体的损伤，导致高血压。类似的机制可能在人类高血压中起作用；GRK4基因位点(染色体4p16.3)与高血压相关，GRK4变异与高血压有关。GRK4变异体损害人肾近端小管上的D1受体功能。GRK4变异体在细胞系中的表达复制了在肾近端小管中发现的D1受体缺陷。抑制GRK4功能或表达可使表达GRK4基因变体的人肾近端小管细胞/细胞系的D11受体功能正常化。此外，肾脏选择性预防自发性高血压大鼠GRK4的表达可延缓高血压的发展。 PPG的总体目标是验证这样一个假设，即在遗传性高血压中，GRK4导致的D1和D3受体功能的降低不能对抗AT1受体功能，从而导致肾脏钠重吸收增加和高血压。为了实现我们的目标，我们组织了一个研究小组，他们在多巴胺和RAS的研究方面经验丰富，以阐明它们在健康和高血压中的基因/基因相互作用的性质。费尔德的项目将检验这样的假设，即变异的GRK4蛋白增加了结构性活性，使D1受体脱敏，但不会使AT1受体脱敏。Carey的项目将测试这样的假设，即当GRK4变体使肾脏中的D1受体不敏感时，会产生盐敏感性，当与RAS相关的变体也存在时，就会产生高血压。Jose的项目将检验这一假设，即肾脏近端小管钠转运部分受D1、D3和AT1受体之间的相互作用调节，并且由于GRK4变异而在高血压中发生异常相互作用。这些基因/基因的相互作用与这些受体在遗传性高血压的多基因病因中所起的关键作用是一致的。

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.