GRK4 and development of salt sensitivity

描述（由申请人提供）：高钠摄入量与血压无关，与心血管风险增加有关。然而，盐敏感性的遗传原因尚不清楚。将基因与复杂疾病（如高血压和盐敏感性）联系起来的决定性证据是一种表型与另一种表型的交换。G蛋白偶联受体激酶4 （GRK4）是唯一被认为是高血压病因的基因，满足这一标准，即GRK4基因变异在小鼠中产生盐敏感性和高血压。GRK43 142V转基因小鼠表现为耐盐性高血压，而GRK43 486V转基因小鼠表现为盐敏感性高血压。根据遗传背景的不同，GRK43野生型的过表达可将盐敏感小鼠（C57BL/6J）转化为盐抗性小鼠，而GRK43 486V的过表达可将盐抗性小鼠（SJL/J）转化为盐敏感小鼠。总体目的是验证人类GRK43野生型赋予耐盐性，而人类GRK43 486V引起盐敏感性高血压的假设。目的1将验证人类GRK43野生型通过促进钠排泄引起耐盐性的假设。这种表型变化部分是由于人类GRK43野生型gpcr的差异调节（例如，D1R和AT1R）参与控制肾脏NaCl运输和血压。Aim 2将验证人类GRK43 486V部分通过损害肾脏D1R功能和增强AT1R表达导致盐敏感性高血压的假设。我们将研究敲除GRK4并在小鼠体内用人GRK43野生型基因和变异（486V）靶向基因替代GRK4对肾脏钠排泄和血压的调节作用。这些研究将有助于解读盐敏感性的机制及其对血压的影响。适度减少儿童、青少年和成人的盐摄入量可以立即降低血压，并具有长期效益。然而，饮食中的钠限制可能不是对所有人都有益。生活方式可以降低血压，降低心血管风险，但动力是个问题。这些研究的结果可能对制定诊断试验、药物治疗（药物基因组学）和改变生活方式具有重要意义。公共卫生相关性：一种名为GRK4的基因变异预测血压会随着盐摄入量的增加而升高，准确率为70-90%。利尿剂对具有该基因变体的个体降低血压更有效。这些研究的结果将有助于制定诊断测试，以及药物治疗（药物基因组学）和改变生活方式。

DESCRIPTION (provided by applicant): High sodium intake, independent of blood pressure, is associated with increased cardiovascular risk. However, the genetic cause(s) of salt sensitivity is not known. The definitive evidence to link genes to complex diseases, such as hypertension and salt sensitivity is the swapping of one phenotype for another. G protein-coupled receptor kinase 4 (GRK4) is the only gene postulated as causal of hypertension that fulfills this criterion, i.e., GRK4 gene variants produce salt sensitivity and hypertension in mice. GRK43 142V transgenic mice develop salt-resistant hypertension while GRK43 486V transgenic mice develop salt-sensitive hypertension. Depending upon the genetic background, overexpression of GRK43 wild type converts a salt- sensitive mouse (C57BL/6J) to a salt-resistant mouse while overexpression of GRK43 486V converts a salt- resistant mouse (SJL/J) to salt-sensitive mouse. The overall objective is to test the hypothesis that human GRK43 wild type imparts salt resistance while human GRK43 486V causes salt-sensitive hypertension. Aim 1 will test the hypothesis that human GRK43 wild type causes salt resistance by facilitating sodium excretion. This change in phenotype is due, in part, to human GRK43 wild type differential regulation of GPCRs (e.g., D1R and AT1R) involved in the control of renal NaCl transport and blood pressure. Aim 2 will test the hypothesis that human GRK43 486V causes salt-sensitive hypertension, in part, by impairing renal D1R function and enhancing AT1R expression. The effect of knockout of GRK4 and targeted gene replacement with human GRK43 wild type gene and variants (486V) in mice on the regulation of renal sodium excretion and blood pressure will be studied. These studies will enable the deciphering of the mechanism of salt sensitivity and its impact on blood pressure. A modest reduction in salt intake in children, adolescents, and adults results in an immediate decrease in blood pressure, with long term benefits. However, dietary sodium restriction may not be beneficial to all. Lifestyle changes lower blood pressure and reduces cardiovascular risk but motivation is a problem. Results from these studies may be important in formulating diagnostic tests, drug therapy (pharmacogenomics) and lifestyle modification. PUBLIC HEALTH RELEVANCE: Variants of a gene called GRK4 predict with 70-90% accuracy that blood pressure will rise with increased salt intake. Diuretics are more effective in lowering blood pressure in individuals with variants of this gene. Results from these studies will be beneficial in the formulation of diagnostic tests, as well as drug therapy (pharmacogenomics) and lifestyle modification.