D5 Receptor Antioxidant Activity and Hypertension

D1R和D5R组成的多巴胺受体亚家族在调节细胞周期中起重要作用。 肾离子转运和血压(BP)。破坏小鼠的D1R或D5R基因都会增加血压。 D1R和D5R在分子、细胞、器官和 整个动物水平，部分是通过调节活性氧(ROS)的产生来实现的。D5R抑制 促进氧化物酶和刺激抗氧化物酶。D5R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。短期监管的问题 尤其是在肾小管上皮细胞中，其产生的机制还不是很清楚。D5R的这一短期监管 通过靶向NAD(P)H氧化酶亚基和G蛋白(例如，Rac 1、GA12、Ga13)的改变而发生 细胞膜微域(小窝相关脂筏和非脂筏)。三个具体目标将受到考验 总体假设短期D5R介导的ROS产生和NAD(P)H的减少 氧化酶活性是通过干扰特定的NAD(P)H氧化酶和G蛋白的移位而发生的 亚基分为小窝相关的脂筏和非脂筏，转化为对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D5R调节 干扰细胞内NAD(P)H氧化酶亚基组装的ROS短期下降 膜。特殊目标2是一系列分子研究，旨在检验D5R 通过与AT1R异二聚化和干扰AT1R来削弱AT1R介导的ROS产生的增加 AT1R和G(A12)/G(A13)与NAD(P)H氧化酶亚基连接和/或AT1R相互作用。直接针对特定目标3 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，我们将探索D5R-/-小鼠高血压是由肾脏增加引起的假设 ROS的生产。研究D5R干扰ROS产生的机制，特别是D5R干扰ROS产生的机制 由AT1R诱导，可能导致对可以绕过特定G蛋白的药物的更好的理解和设计 偶联受体，但仍确保特定和受限的作用。这些都可能导致发展 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.