D5 Receptor Antioxidant Activity and Hypertension

Georgetown University, Washington DC

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Abstract

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