D5 receptor antioxidant activity and hypertension

多巴胺产生和受体功能异常存在于人类原发性高血压和遗传性高血压啮齿动物模型中；一些多巴胺受体基因及其调节因子与高血压有关。D5受体是两种D1样受体（D1和D5）中的一种，破坏D5受体会导致小鼠高血压。在小鼠中，当D5受体被破坏时，多受体级联通过中枢和外周机制导致高血压。这种广泛的异常可能与活性氧（ROS）的产生增加有关。总的假设是，D5受体与其他多巴胺受体不同，它的作用是防止ROS的增加，与其他多巴胺受体不同，它的作用是防止由D5受体功能受损或高血压引起的ROS形成的增加。D5受体功能受损的后果可能是ROS的增加。特异性目的1将建立D5基因敲除小鼠和表达D5受体突变体的细胞中ROS增加的机制。我们将确定D5基因敲除小鼠和表达D5受体突变体的细胞中ROS的特异性增加。我们将确定其具体作用：(a)磷脂酶D （PLD）在ROS中的作用，因为由PLD产生的磷脂酸是NADPH活性的有效激活剂；(b)蛋白激酶a （PKA）活性降低，因此不能终止NADPH氧化酶活性，从而促进正在进行的ROS生成。初步数据表明，多态性D5受体不能增加cAMP的产生，但也会增加ROS。因此，D5受体不能产生cAMP/PKA，从而抑制NADPH氧化酶活性，可以增加ROS。特异性目的2将建立D5基因敲除小鼠和细胞氧化酶歧化酶缺乏抗氧化活性的机制。特异性目标3将检验多巴胺通过D1/D5受体对抗血管紧张素II致高血压作用的假设。这些研究将确定AT1和D1/D5受体在高血压发病机制中的相互作用。D5受体的单核苷酸多态性与刺激cAMP产生能力下降存在于人群中，因此对D5受体的研究可能有助于揭示人类原发性高血压的发病机制。

Abnormalities in dopamine production and receptor function are present in human essential hypertension and rodent models of genetic hypertension; some dopamine receptor genes and their regulators are in loci linked to hypertension. Disruption of the D5 receptor, one of the two D1-like receptors (D1 and D5), in mice produces hypertension. A multi- receptor cascade causes high blood pressure, via central and peripheral mechanisms, when the D5 receptor is disrupted in mice. This widespread abnormality may be related to the increased generation of reactive oxygen species (ROS). The overall hypothesis is that the D5 receptor, which is constitutively unlike the other dopamine receptors, acts to protect against an increase in ROS is constitutively activated unlike the other dopamine receptors, acts to protect against an increase in ROS formation engendered by impairment of D5 receptor function or by hypertension. A consequence of impaired function of the D5 receptor may be an increase in ROS. Specific aim 1 will establish the mechanism of increased ROS in D5 knockout mice and cells expressing D5 receptor mutants. We will determine the specific increased ROS in D5 knockout mice and cells expressing D5 receptor mutants. We will determine the specific role of: (a) phospholipase D (PLD) in ROS because phosphatidic acid, produced by PLD, is a potent activator of NADPH activity; (b) a reduced activity of protein kinase A (PKA), which thereby fails to terminate NADPH oxidase activity and hence promotes ongoing ROS production. Preliminary data indicates that a polymorphic D5 receptor that failed to increase cAMP production also increased ROS. Therefore, the failure of D5 receptors to generate cAMP/PKA, and thus, inhibition of NADPH oxidase activity, can increase ROS. Specific aim 2 will establish the mechanism of the deficient antioxidant activity in D5 knockout mice and cells oxidase dismutase. Specific aim 3 will test the hypothesis that dopamine, via D1/D5 receptors, serve to counter-act the hypertensinogenic effects of angiotensin II. These studies will determine the interactions between AT1 and D1/D5 receptors in the pathogenesis of hypertension. Single nucleotide polymorphisms of the D5 receptor with decreased ability to stimulate cAMP production are present in the human population, thus studies of D5 receptors may shed light into the pathogenesis of human essential hypertension.