GRK4 & Development of Salt Sensitivity

描述（由申请人提供）：人类对盐敏感的遗传原因尚不清楚。肾脏对整体体液和电解质平衡以及血压的长期调节至关重要。因此，盐敏感的发病机制必然与钠负荷增加时不能减少钠转运和增加钠排泄有关。人类G蛋白偶联受体激酶4型（hGRK）基因的变异调节有限数量的G蛋白偶联受体，与几个民族的原发性高血压有关。hGRK4g486V变异在小鼠中的表达会根据遗传背景导致盐敏感性。初步数据表明，孤儿受体GPR83可能抵消hgrk4486v的盐敏感性产生作用，hgrk4486v的表达依赖于遗传背景，可能解释了盐敏感性的种族差异。该项目将测试hgrk4486v赋予盐敏感性的整体新假设，即由于孤儿受体GPR83的表达/功能降低，导致利钠（多巴胺D1受体，D1R）和抗钠尿（血管紧张素1型受体，AT1R）系统失衡，从而增加血压。特异性目标1将验证GPR83功能对于在钠过量条件下维持正常血压是必要的，而GPR83功能缺乏或降低对耐盐背景下小鼠的影响最小。本文还将阐明GRK4和D1R对GPR83表达调控的作用。特异性目的2将验证GPR83的保护作用是通过AT1R的负调控和D1R功能的正调控来介导的。本专题将阐明参与这些功能调控的细胞机制。Specific Aim 3将检验hGRK4g486V对GPR83功能损害的假设，以及GPR83功能损害的能力取决于“盐敏感”和“耐盐”基因的比例。在盐敏感的小鼠中，即使钠摄入量没有增加，肾脏GPR83也是维持正常血压所必需的。这些研究将能够首次确定“盐敏感”和“耐盐”基因相互作用在原发性高血压发病机制中的作用。新的耐盐基因GPR83的鉴定可能会导致针对其表达和功能的药物的开发。

DESCRIPTION (provided by applicant): The genetic causes of salt sensitivity in humans are not well known. The kidney is critical to the overall fluid and electrolyte balance and long-term regulation of blood pressure (BP). Therefore, the pathogenesis of salt sensitivity must involve an inability to decrease sodium transport and increase sodium excretion when the sodium load is increased. Variants of the human G protein-coupled receptor kinase type 4 (hGRK) genes that regulates a limited number of G protein-coupled receptors, are associated with essential hypertension in several ethnic groups. Expression of the hGRK4g486V variant in mice causes salt sensitivity depending on the genetic background. Preliminary data suggest that the orphan receptor GPR83 may counteract the salt- sensitive producing effect of hGRK4g 486V, the expression of which is dependent on the genetic background and may explain ethnic-related differences in salt sensitivity. This project will test the overall novel hypothesis that salt sensitivity imparted by hGRK4g 486V is due to decreased expression/function of the orphan receptor GPR83 that results in an imbalance in natriuretic (dopamine D1 receptor, D1R) and antinatriuretic (angiotensin type 1 receptor, AT1R) systems which increases BP. Specific Aim 1 will test the hypothesis that GPR83 function is necessary to maintain a normal blood pressure under conditions of sodium excess and that lack or decreased GPR83 function will have the least effect on mice in a salt-resistant background. This Specific Aim 1 will also clarify the effects of GRK4 and D1R on the regulation of GPR83 expression. Specific Aim 2 will test the hypothesis that the protective effects of GPR83 are mediated by negative regulation of AT1R and positive regulation of D1R functions. This Specific Aim will clarify the cellular mechanisms involved in the regulation of these functions. Specific Aim 3 will test the hypothesis that GPR83 function is impaired by hGRK4g486V and that the ability to impair GPR83 function is dependent on the proportion of "salt sensitivity" and "salt resistance" genes. In mice with a predominant salt-sensitive background renal GPR83 is necessary to maintain normal blood pressure even when sodium intake is not increased. These studies will be able to determine, for the first time, the role of the interaction of "salt sensitivity" and "salt resistance" genes in the pathogenesis o essential hypertension. The identification of a novel salt resistance gene, i.e., GPR83, may lead to the development of drugs that target its expression and function.