Role of renal DJ-1 in the pathogenesis of hypertension associated with increased reactive oxygen species production.
The D(2) dopamine receptor (D(2)R) is important in the pathogenesis of essential hypertension. We have already reported that systemic deletion of the D(2)R gene in mice results in reactive oxygen species (ROS)-dependent hypertension, suggesting that the D(2)R has antioxidant effects. However, the mechanism of this effect is unknown. DJ-1 is a protein that has antioxidant properties. D(2)R and DJ-1 are expressed in the mouse kidney and colocalize and coimunoprecipitate in mouse renal proximal tubule cells. We hypothesized that D(2)Rs regulate renal ROS production in the kidney through regulation of DJ-1 expression or function. Heterozygous D(2)(+/-) mice have increased blood pressure, urinary 8-isoprostanes, and renal Nox 4 expression, but decreased renal DJ-1 expression. Silencing D(2)R expression in mouse renal proximal tubule cells increases ROS production and decreases the expression of DJ-1. Conversely, treatment of these cells with a D(2)R agonist increases DJ-1 expression and decreases Nox 4 expression and NADPH oxidase activity, effects that are partially blocked by a D(2)R antagonist. Silencing DJ-1 expression in mouse renal proximal tubule cells increases ROS production and Nox 4 expression. Selective renal DJ-1 silencing by the subcapsular infusion of DJ-1 siRNA in mice increases blood pressure, renal Nox4 expression, and NADPH oxidase activity. These results suggest that the inhibitory effects of D(2)R on renal ROS production are at least, in part, mediated by a positive regulation of DJ-1 expression/function and that DJ-1 may have a role in the prevention of hypertension associated with increased ROS production.
Center for Molecular Physiology Research, Children's National Medical Center, 111 Michigan Avenue NW, Washington, DC 20010, USA. scgonzal@cnmc.org
Santiago
S
Cuevas
Yanrong
Y
Zhang
Yu
Y
Yang
Crisanto
C
Escano
Laureano
L
Asico
John E
JE
Jones
Ines
I
Armando
Pedro A
PA
Jose
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D006973:Hypertension / Q000209:etiology* / Q000378:metabolism* / Q000503:physiopathology; D007668:Kidney / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D054464:Peroxiredoxins; D000071617:Protein Deglycase DJ-1; D034741:RNA, Small Interfering / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
D015513:Oncogene Proteins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D017448:Receptors, Dopamine D2; D054464:Peroxiredoxins; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1