CLINICAL TRIAL: EFFECT OF GENE VARIANTS ON DOPAMINE RECEPTOR NATRIURETIC RESPONS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 我们的研究小组在原发性高血压患者的肾脏PTCs中发现了一种D1受体/腺苷环化酶偶联缺陷。我们发现，由于激活GRK-4的变异体，人类高血压患者肾脏PTCs中GRK-4活性增加，这种效应在转基因细胞模型中重现。阻止GRK-4的翻译使高血压患者的D1受体与腺苷环化酶的偶联正常化。GRK-4的基因变异导致D1受体的非配体依赖性丝氨酸磷酸化，导致其与G蛋白/效应器复合体解偶联。肾脏PTC中D1受体的脱敏被认为是DA的钠利尿作用受损的原因，最终导致钠滞留和高血压。该方案的主要目的是证明在携带3个或更多GRK-4 SNPs的受试者中，与携带0-2个SNPs的受试者相比，非诺多巴激活D1样受体所产生的利钠作用减弱。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our research group has discovered a D1 receptor/adenylyl cyclase coupling defect in renal PTCs from subjects with essential hypertension. We have found increased GRK-4 activity in renal PTCs in human essential hypertension due to activating variants of GRK-4, an effect that was reproduced in a transfected cell model. Preventing the translation of GRK-4 normalized the coupling of the D1 receptor to adenylyl cyclase in hypertension. Gene variants of GRK-4 cause a ligand-independent serine-phosphorylation of the D1 receptor, resulting in its uncoupling from the G-protein/effector complex. The desensitization of the D1 receptor in the renal PTC is hypothesized to be the cause of the compromised natriuretic effect of DA that eventually leads to Na+ retention and hypertension. The primary objective of this protocol is to demonstrate that natriuresis engendered by D1-like receptor activation with fenoldopam is blunted in subjects with 3 or more SNPs of GRK-4 compared with responses in subjects with 0-2 SNPs.