The D1-like subfamily of dopamine receptors (comprised of D1R and D5R) is important in the regulation ofrenal 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, andwhole animal level, in part, via regulation of reactive oxygen species (ROS) production. The D5R inhibitspro-oxidant enzymes and stimulates anti-oxidant enzymes. These effects of the D5R occur in the short-termand in the long-term, the latter by regulating the degradation of these proteins. The short-term regulation ofROSproduction is not well understood, especially in renal tubule cells. This short-term regulation by D5Roccurs via alterations in targeting of NAD(P)H oxidase subunits and G proteins (e.g., Rac 1, Ga12, Ga13) intocell membrane microdomains (caveolae-related lipid rafts and non-lipid rafts).
Three specific aims will testthe overall hypothesis that the short-term D5R-mediated decrease in ROS production and NAD(P)Hoxidase activity occurs by interference with the translocation of specific NAD(P)H oxidase and G proteinsubunits 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 theshort-term decrease in ROS by interfering with the assembly of NAD(P)H oxidase subunits in cellmembranes.
Specific aim 2 is a series of molecular studies designed to test the hypothesis that D5Rimpairs the AT1R-mediated increase in ROS production by heterodimerizing with AT1R and interfering withAT1R and G(a12)/G(a13) linkage and/or AT1R interaction with NAD(P)H oxidase subunits.
Specific aim 3 directlytests the relevance of the cellular and molecular studies to BP regulation. Using a cross renal transplantationstrategy, we will probe the hypothesis that the hypertension in D5R -/- mice is caused by increased renalproduction of ROS. Studying the mechanisms by which D5R interferes with ROS production, especially thatinduced by AT1R, may lead to a better understanding and design of drugs that can bypass specific G proteincoupled receptors, yet still ensure specific and restricted action. These could lead to the development ofnovel drugs to treat hypertension.
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