title: D5 dopamine receptor decreases NADPH oxidase, reactive oxygen species and blood pressure via heme oxygenase-1.
abstract: D5 dopamine receptor (D5R) knock-out mice (D5(-/-)) have a higher blood pressure (BP) and higher reactive oxygen species (ROS) production than their D5R wild-type littermates (D5(+/+)). We tested the hypothesis that the high BP and increased ROS production in D5(-/-) mice may be caused by decreased heme oxygenase-1 (HO-1) expression and activity. We found that renal HO-1 protein expression and HO enzyme activity were decreased (65 and 50%, respectively) in D5(-/-) relative to D5(+/+) mice. A 24 h of administration of hemin, an HO-1 inducer, increased HO-1 expression and HO activity (6.8- and 1.9-fold, respectively) and normalized the increased ROS production and BP in D5(-/-) mice. Expression of HO-1 protein and HO activity were increased (2.3- and 1.5-fold, respectively) in HEK cells that heterologously expressed human wild-type D5R (HEK-hD5R), but not the empty vector-transfected HEK-293 cells. Fenoldopam (Fen), a D5R agonist, increased HO activity (3 h), HO-1 protein expression, HO-1 and D5R colocalization and co-immunoprecipitation in HEK-hD5R cells. Cellular NADPH oxidase activity was decreased by 35% in HEK-hD5R that was abrogated with silencing of the heme oxygenase 1 gene (HMOX1). HMOX1 siRNA also impaired the ability of Fen to decrease NADPH oxidase activity in HEK-hD5R cells. In summary, the D5R positively regulates HO-1 through direct protein/protein interaction in the short-term and by increasing HO-1 protein expression in the long-term. The impaired D5R regulation of HO-1 and ROS production contributes to the pathogenesis of hypertension in D5(-/-) mice.
authors: Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors: Quansheng
authors: Q
authors: Lu
authors: Yu
authors: Y
authors: Yang
authors: Van Anthony
authors: VA
authors: Villar
authors: Laureano
authors: L
authors: Asico
authors: John E
authors: JE
authors: Jones
authors: Peiying
authors: P
authors: Yu
authors: Hewang
authors: H
authors: Li
authors: Edward J
authors: EJ
authors: Weinman
authors: Gilbert M
authors: GM
authors: Eisner
authors: Pedro A
authors: PA
authors: Jose
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D018491:Dopamine Agonists / Q000494:pharmacology; D018818:Fenoldopam / Q000494:pharmacology; D057809:HEK293 Cells; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D006973:Hypertension / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D050641:Receptors, Dopamine D5 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D018491:Dopamine Agonists; D017382:Reactive Oxygen Species; D050641:Receptors, Dopamine D5; D051547:Heme Oxygenase-1; D019255:NADPH Oxidases; D018818:Fenoldopam