Renal dopamine D2 receptor (D2R) dysfunction is associated with increased oxidative stress and high blood pressure. We have reported that DJ-1 is regulated by D2R in the kidney. Nrf2 is a transcription factor that regulates the expression of several antioxidant genes. We hypothesize that Nrf2 is involved in the DJ-1-mediated regulation of reactive oxygen species (ROS) production in the kidney. DJ-1 and Nrf2 co-inmunoprecipitate in mouse kidney. Selective renal silencing of D2R in mice by the renal subcapsular infusion of D2R siRNA (~50%) decreases Nrf2 expression (63.4%±3.4, n=7, P<0.05), and silencing of D2R expression in mouse proximal tubule cells (mRPTCs) decrease Nrf2 promoter activity (53±2%, n=5, P<0.05). Silencing DJ-1 expression in mRPTCs, via siRNA, decreases the expression of DJ-1 (75±4.5%, n=4, P<0.05), Nrf2 (63.2±6%, n=3, P<0.05), NQO1 (71±1%, n=3, P<0.05), and GST Yc-2 (42±1%, n=4, P<0.05) and Nrf2 promoter activity (58±1%, n=5, P<0.05). Selective renal silencing of DJ-1 in mice by renal subcapsular infusion of DJ-1 siRNA decreases expression of DJ-1 (31±2.6%, n=3, P<0.05), Nrf2 (57±7.9%,n=3, P<0.05), NQO1 (46±9.3%, n=3, P<0.05) and GST Yc2 (28±2.2%, n=3, P<0.05) and increases blood pressure (BP). DJ-1-/- mice also have increased systolic BP (30.7±1%, P<0.01, n=5 under anesthesia) and renal expression of nitro-tyrosine (76.8±13.5%, P<0.05, n=5), and decreases the expression of Nrf2 (46.8±6.8%, n=5, P<0.05) and NQO1 (19.4±2.7%, n=5, P<0.05). Silencing Nrf2 expression mRPTCs via siRNA decreases the expression of Nrf2 (34±1.8%, n=4, P<0.05), NQO1 (29.1±0.5%, n=4, P<0.05), and increases Nox2 (137±23.7%, n=4, P<0.05), but the expression of Nox4 and DJ-1 are not affected. Quinpirole a D2R agonist, does not modify the expression of Nrf2, NQO1, GST Yc-2, and Nrf2 promoter activity in MPCTS. However, in the presence of H2O2, quinpirole increases Nrf2 promoter activity (220±58.4%, n=5, P<0.05) and an effect that is blocked by pretreatment with D2R antagonist L741,626. Therefore, the inhibitory effect of DJ-1 on renal ROS production is, in part, mediated by positive regulation of Nrf2. Moreover, D2R and DJ-1 are necessary for normal Nrf2 activity to keep a normal redox balance in the kidney.