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

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 我们的研究小组在原发性高血压受试者的肾 PTC 中发现了 D1 受体/腺苷酸环化酶偶联缺陷。 我们发现，由于 GRK-4 的激活变体，人类原发性高血压的肾 PTC 中 GRK-4 活性增加，这种效应在转染细胞模型中得到了重现。 阻止 GRK-4 的翻译可以使高血压中 D1 受体与腺苷酸环化酶的偶联正常化。 GRK-4 的基因变异导致 D1 受体发生配体依赖性丝氨酸磷酸化，导致其与 G 蛋白/效应复合物解偶联。 据推测，肾脏 PTC 中 D1 受体的脱敏是 DA 利尿钠作用受损的原因，最终导致钠潴留和高血压。 该方案的主要目的是证明，与具有 0-2 个 SNP 的受试者的反应相比，具有 3 个或更多 GRK-4 SNP 的受试者中由非诺多泮激活 D1 样受体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.