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

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 本课题组在原发性高血压患者的肾PTC中发现了D1受体/腺苷酸环化酶偶联缺陷。 我们已经发现由于GRK-4的激活变体，在人类原发性高血压中的肾PTC中GRK-4活性增加，该效应在转染的细胞模型中再现。 阻止GRK-4的翻译使高血压中D1受体与腺苷酸环化酶的偶联正常化。 GRK-4的基因变体引起D1受体的配体非依赖性丝氨酸磷酸化，导致其与G蛋白/效应物复合物解偶联。 假设肾PTC中D1受体的脱敏是DA的利钠作用受损的原因，其最终导致Na+潴留和高血压。 本方案的主要目的是证明，与0-2个SNP的受试者相比，具有3个或更多GRK-4 SNP的受试者中由非诺多泮D1样受体激活引起的尿钠排泄减弱。

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.