(Verbatim from the application): There are abnormalities in dopamine (DA) production and receptor function in genetic hypertension: some DA receptor genes and their regulators are in loci linked to hypertension. Data generated during the previous funding period show that in mice disruption of the D dopamine receptor. one of the two D1 -like receptors, produces hypertension via a multireceptor cascade. The absence of the D5 receptor increases hypothalamic oxytocin (OT) secretion, sensitizes central V1 vasopressm receptors. activates central non-NMDA receptors and stimulates the sympathetic nervous system. D5 receptor disruption also leads to the generation of reactive oxygen species (ROS) that participate in the increase in BP. Renal tubular effects of D1 -like agonists are also impaired in D5 receptor mutant mice. Abnormalities in the D5 receptor may have functional significance in human essential hypertension because certain single nucleotide polymorphisms (SNPs) of the D5 receptor do not generate cAMP. SNPs of G protein-coupled receptor kinase 4y (GRK4y) and protein phosphatase 2A regulatory subunit, B56a, acting on the D1 receptor in the renal proximal tubule and medullary thick ascending limb cause a subset of genetic hypertension. Thus, D1 and D5 receptor dysfunction produces hypertension by renal and non-renal mechanisms. The overall objective of this proposal is to determine the mechanisms by which dysfunction of the D5 receptor increases system blood pressure. There are 4 specific aims: the first 2 deal with D5 receptor interactions with other G protein-coupled receptors while the last 2 deal with D5 receptor regulation of ROS production.
Specific aim 1 will test the hypothesis that disruption of both D1 and D5 receptors results in a greater impairment in the ability to excrete a sodium load and greater increase in BP than disruption of either DA receptor alone, Specific aim 2 will determine the precise roles of oxytocin and V1 receptors in generating the hypertension in the D5 knockout mice.
Specific aim 3 will determine the role of ROS in the pathogenesis of hypertension in D5 receptor mutant mice. The induction of heme oxvgenase- I (HO- 1) normalized BP in D5 receptor mutant mice. We will test the hypothesis that hypertension in D5 receptor mutant mice is caused, in part, by increased generation of ROS because of the mutant D5 receptor. per Se. and/or activation of OT/V1 receptors.
Specific aim 4 will test the hypothesis that desensitized D5 and D1 receptors and certain D5 receptor SNPs couple to Ga13 instead of Gsa resulting in increased generation of ROS and renal Sodium transport. These studies should shed light into the relative contributions of a genetic D5 receptor abnormality and other G protein-coupled receptors (OT and V1) in the pathogenesis of genetic hypertension.
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