D5 dopamine receptor regulation of reactive oxygen species production, NADPH oxidase, and blood pressure.
Activation of D1-like receptors (D1 and/or D5) induces antioxidant responses; however, the mechanism(s) involved in their antioxidant actions are not known. We hypothesized that stimulation of the D5 receptor inhibits NADPH oxidase activity, and thus the production of reactive oxygen species (ROS). We investigated this issue in D5 receptor-deficient (D5-/-) and wild-type (D5+/+) mice. NADPH oxidase protein expression (gp91(phox), p47(phox), and Nox 4) and activity in kidney and brain, as well as plasma thiobarbituric acid-reactive substances (TBARS) were higher in D5-/- than in D5+/+ mice. Furthermore, apocynin, an NADPH oxidase inhibitor, normalized blood pressure, renal NADPH oxidase activity, and plasma TBARS in D5-/- mice. In HEK-293 cells that heterologously expressed human D5 receptor, its agonist fenoldopam decreased NADPH oxidase activity, expression of one of its subunits (gp91(phox)), and ROS production. The inhibitory effect of the D5 receptor activation on NADPH oxidase activity was independent of cAMP/PKA but was partially dependent on phospholipase D2. The ability of D5 receptor stimulation to decrease ROS production may explain, in part, the antihypertensive action of D5 receptor activation.
Yang
Zhiwei
Z
Department of Pediatrics and Physiology, Georgetown University Medical Center, 3800 Reservoir Rd., NW, Washington, DC 20007, USA.
Asico
Laureano D
LD
Yu
Peiying
P
Wang
Zheng
Z
Jones
John E
JE
Escano
Crisanto S
CS
Wang
Xiaoyan
X
Quinn
Mark T
MT
Sibley
David R
DR
Romero
Guillermo G
GG
Felder
Robin A
RA
Jose
Pedro A
PA
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D001794:Blood Pressure / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D018818:Fenoldopam / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D050641:Receptors, Dopamine D5 / Q000235:genetics / Q000378:metabolism*; D012965:Sodium Chloride
D001552:Benzazepines; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D017382:Reactive Oxygen Species; D050641:Receptors, Dopamine D5; D012965:Sodium Chloride; D019255:NADPH Oxidases; D018818:Fenoldopam