GRK4 and development of salt sensitivity (R01HL092196)

描述（由申请人提供）：人类盐敏感性的遗传原因尚不清楚。肾脏对整体液体和电解质平衡以及血压（BP）的长期调节至关重要。因此，盐敏感性的发病机制必须涉及当钠负荷增加时不能减少钠转运和增加钠排泄。人类G蛋白偶联受体激酶4型（hGRK）基因的变体调节有限数量的G蛋白偶联受体，与几个种族的原发性高血压相关。hGRK 4g 486 V变体在小鼠中的表达取决于遗传背景而引起盐敏感性。初步数据表明，孤儿受体GPR 83可以抵消hGRK 4g 486 V的盐敏感性产生效应，其表达取决于遗传背景，并且可以解释盐敏感性的种族相关差异。 该项目将测试整体新假设，即hGRK 4g 486 V赋予的盐敏感性是由于孤儿受体GPR 83的表达/功能下降，导致利尿钠（多巴胺D1受体，D1 R）和抗利尿钠（血管紧张素1型受体，AT 1 R）系统失衡，从而增加血压。具体目标1将检验以下假设：GPR 83功能对于在钠过量条件下维持正常血压是必需的，并且GPR 83功能缺乏或降低将对耐盐背景中的小鼠产生最小影响。本特异性目的1也将阐明GRK 4和D1 R对GPR 83表达调控的作用。具体目标2将检验GPR 83的保护作用是由AT 1 R的负调节和D1 R功能的正调节介导的假设。这个特定的目标将阐明参与这些功能调节的细胞机制。具体目标3将检验GPR 83功能被hGRK 4g 486 V损害以及损害GPR 83功能的能力取决于“盐敏感性”和“盐抗性”基因的比例的假设。在具有主要盐敏感性背景的小鼠中，即使钠摄入量不增加，肾脏GPR 83也是维持正常血压所必需的。这些研究将能够首次确定“盐敏感性”和“盐抗性”基因的相互作用在原发性高血压发病机制中的作用。一个新的抗盐基因的鉴定，GPR 83可能导致靶向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.