D5 Receptor Antioxidant Activity and Hypertension

多巴胺受体的D1样亚家族（由D1 R和D5 R组成）在多巴胺受体的调节中是重要的。 肾离子转运和血压（BP）。破坏小鼠的D1 R或D5 R基因会增加血压。 D1 R和D5 R在分子、细胞、器官和组织上抵消AT 1 R的促高血压作用， 整个动物水平，部分通过调节活性氧（ROS）的产生。D5 R抑制 促氧化酶和刺激抗氧化酶。D5 R的这些影响发生在短期内 从长远来看，后者通过调节这些蛋白质的降解来实现。短期调控 ROS的产生还不清楚，特别是在肾小管细胞中。D5 R的这种短期调节 通过改变NAD（P）H氧化酶亚基和G蛋白的靶向发生（例如，Rac 1、Ga 12、Ga 13）进入 细胞膜微区（小窝相关脂筏和非脂筏）。三个具体目标将测试 总体假设是短期D5 R介导的ROS产生和NAD（P）H减少 氧化酶活性通过干扰特异性NAD（P）H氧化酶和G蛋白的移位而发生 亚基转化为小窝相关的脂筏和非脂筏，转化为BP的长期调节。 具体目标1是一系列细胞和小管研究，旨在检验D5 R调节细胞凋亡的假设。 通过干扰细胞内NAD（P）H氧化酶亚基的组装而短期降低ROS 膜。具体目标2是一系列分子研究，旨在验证D5 R 通过与AT 1 R异源二聚化并干扰AT 1 R介导的ROS产生增加， AT 1 R和G（a12）/G（a13）连接和/或AT 1 R与NAD（P）H氧化酶亚基的相互作用。具体目标3直接 测试细胞和分子研究与BP调节的相关性。使用交叉肾移植 策略，我们将探讨D5 R-/-小鼠的高血压是由肾功能增加引起的假设。 ROS的产生。研究D5 R干扰ROS产生的机制，特别是 通过AT 1 R诱导，可以更好地理解和设计可以绕过特定G蛋白的药物 偶联受体，但仍确保特异性和限制性作用。这些可能导致发展 治疗高血压的新药。

The D1-like subfamily of dopamine receptors (comprised of D1R and D5R) is important in the regulation of renal ion transport and blood pressure (BP). Disruption either the D1R or D5R gene in mice increases BP. The D1R and D5R counteract the pro-hypertensive actions of AT1R at the molecular, cellular, organ, and whole animal level, in part, via regulation of reactive oxygen species (ROS) production. The D5R inhibits pro-oxidant enzymes and stimulates anti-oxidant enzymes. These effects of the D5R occur in the short-term and in the long-term, the latter by regulating the degradation of these proteins. The short-term regulation of ROSproduction is not well understood, especially in renal tubule cells. This short-term regulation by D5R occurs via alterations in targeting of NAD(P)H oxidase subunits and G proteins (e.g., Rac 1, Ga12, Ga13) into cell membrane microdomains (caveolae-related lipid rafts and non-lipid rafts). Three specific aims will test the overall hypothesis that the short-term D5R-mediated decrease in ROS production and NAD(P)H oxidase activity occurs by interference with the translocation of specific NAD(P)H oxidase and G protein subunits intocaveolae-associated lipid rafts and non-lipid rafts, translating into long-term regulation of BP. Specific aim 1 is a series of cell and tubule studies designed to test the hypothesis that D5R regulates the short-term decrease in ROS by interfering with the assembly of NAD(P)H oxidase subunits in cell membranes. Specific aim 2 is a series of molecular studies designed to test the hypothesis that D5R impairs the AT1R-mediated increase in ROS production by heterodimerizing with AT1R and interfering with AT1R and G(a12)/G(a13) linkage and/or AT1R interaction with NAD(P)H oxidase subunits. Specific aim 3 directly tests the relevance of the cellular and molecular studies to BP regulation. Using a cross renal transplantation strategy, we will probe the hypothesis that the hypertension in D5R -/- mice is caused by increased renal production of ROS. Studying the mechanisms by which D5R interferes with ROS production, especially that induced by AT1R, may lead to a better understanding and design of drugs that can bypass specific G protein coupled receptors, yet still ensure specific and restricted action. These could lead to the development of novel drugs to treat hypertension.