title: Role of nuclear factor erythroid 2-related factor 2 in the oxidative stress-dependent hypertension associated with the depletion of DJ-1.
abstract: Renal dopamine 2 receptor dysfunction is associated with oxidative stress and high blood pressure (BP). We have reported that DJ-1, an oxidative stress response protein, is positively regulated by dopamine 2 receptor in the kidney. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) regulates the expression of several antioxidant genes. We tested the hypothesis that Nrf2 is involved in the renal DJ-1-mediated inhibition of reactive oxygen species production. We have reported that silencing dopamine 2 receptor in mouse renal proximal tubule cells decreases the expression of DJ-1. We now report that silencing DJ-1 or dopamine 2 receptor in mouse proximal tubule cells and mouse kidneys decreases Nrf2 expression and activity and increases reactive oxygen species production; BP is also increased in mice in which renal DJ-1 or dopamine 2 receptor is silenced. DJ-1(-/-) mice have decreased renal Nrf2 expression and activity and increased nitro-tyrosine levels and BP. Silencing Nrf2 in mouse proximal tubule cells does not alter the expression of DJ-1 or dopamine 2 receptor, indicating that Nrf2 is downstream of dopamine 2 receptor and DJ-1. An Nrf2 inducer, bardoxolone, normalizes the systolic BP and renal malondialdehyde levels in DJ-1(-/-) mice without affecting them in their wild-type littermates. Because Nrf2 ubiquitination is increased in DJ-1(-/-) mice, we conclude that the protective effect of DJ-1 on renal oxidative stress is mediated, in part, by preventing Nrf2 degradation. Moreover, renal dopamine 2 receptor and DJ-1 are necessary for normal Nrf2 activity to keep a normal redox balance and BP.
authors.affiliation: From the Department of Medicine, Division of Nephrology (S.C., Y.Y., P.K., L.D.A., J.F., J.J., V.A.V., I.A., P.A.J.) and Department of Physiology (P.A.J.), University of Maryland School of Medicine, Baltimore. scuevas@medicine.umaryland.edu.
authors.forename: Santiago
authors.initials: S
authors.lastname: Cuevas
authors.affiliation: From the Department of Medicine, Division of Nephrology (S.C., Y.Y., P.K., L.D.A., J.F., J.J., V.A.V., I.A., P.A.J.) and Department of Physiology (P.A.J.), University of Maryland School of Medicine, Baltimore.
authors.forename: Yu
authors.initials: Y
authors.lastname: Yang
authors.affiliation: From the Department of Medicine, Division of Nephrology (S.C., Y.Y., P.K., L.D.A., J.F., J.J., V.A.V., I.A., P.A.J.) and Department of Physiology (P.A.J.), University of Maryland School of Medicine, Baltimore.
authors.forename: Prasad
authors.initials: P
authors.lastname: Konkalmatt
authors.affiliation: From the Department of Medicine, Division of Nephrology (S.C., Y.Y., P.K., L.D.A., J.F., J.J., V.A.V., I.A., P.A.J.) and Department of Physiology (P.A.J.), University of Maryland School of Medicine, Baltimore.
authors.forename: Laureano D
authors.initials: LD
authors.lastname: Asico
authors.affiliation: From the Department of Medicine, Division of Nephrology (S.C., Y.Y., P.K., L.D.A., J.F., J.J., V.A.V., I.A., P.A.J.) and Department of Physiology (P.A.J.), University of Maryland School of Medicine, Baltimore.
authors.forename: Jun
authors.initials: J
authors.lastname: Feranil
authors.affiliation: From the Department of Medicine, Division of Nephrology (S.C., Y.Y., P.K., L.D.A., J.F., J.J., V.A.V., I.A., P.A.J.) and Department of Physiology (P.A.J.), University of Maryland School of Medicine, Baltimore.
authors.forename: John
authors.initials: J
authors.lastname: Jones
authors.affiliation: From the Department of Medicine, Division of Nephrology (S.C., Y.Y., P.K., L.D.A., J.F., J.J., V.A.V., I.A., P.A.J.) and Department of Physiology (P.A.J.), University of Maryland School of Medicine, Baltimore.
authors.forename: Van Anthony
authors.initials: VA
authors.lastname: Villar
authors.affiliation: From the Department of Medicine, Division of Nephrology (S.C., Y.Y., P.K., L.D.A., J.F., J.J., V.A.V., I.A., P.A.J.) and Department of Physiology (P.A.J.), University of Maryland School of Medicine, Baltimore.
authors.forename: Ines
authors.initials: I
authors.lastname: Armando
authors.affiliation: From the Department of Medicine, Division of Nephrology (S.C., Y.Y., P.K., L.D.A., J.F., J.J., V.A.V., I.A., P.A.J.) and Department of Physiology (P.A.J.), University of Maryland School of Medicine, Baltimore.
authors.forename: Pedro A
authors.initials: PA
authors.lastname: Jose
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006973:Hypertension / Q000235:genetics / Q000503:physiopathology*; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics*; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology*; D054464:Peroxiredoxins / Q000235:genetics*; D000071617:Protein Deglycase DJ-1; D011897:Random Allocation; D017382:Reactive Oxygen Species / Q000378:metabolism; D011954:Receptors, Dopamine / Q000378:metabolism; D012680:Sensitivity and Specificity
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; D015513:Oncogene Proteins; D017382:Reactive Oxygen Species; D011954:Receptors, Dopamine; D054464:Peroxiredoxins; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1
keywords: dopamine receptors; kidney; oxidative stress