Role of Nuclear Factor Erythroid 2-Related Factor 2 in the Oxidative Stress-Dependent Hypertension Associated with the Depletion of DJ-1

Authors

Santiago Cuevas, University of Maryland School of Medicine
Yu Yang, University of Maryland School of Medicine
Prasad Konkalmatt, University of Maryland School of Medicine
Laureano D. Asico, University of Maryland School of Medicine
Jun Feranil, University of Maryland School of Medicine
John Jones, University of Maryland School of Medicine
Van Anthony Villar, University of Maryland School of Medicine
Ines Armando, University of Maryland School of Medicine
Pedro A. Jose, University of Maryland School of Medicine

Document Type

Journal Article

Publication Date

1-1-2015

Journal

Hypertension

Volume

65

Issue

6

DOI

10.1161/HYPERTENSIONAHA.114.04525

Keywords

dopamine receptors; kidney; oxidative stress

Abstract

© 2015 American Heart Association, Inc. 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.

APA Citation

Cuevas, S., Yang, Y., Konkalmatt, P., Asico, L., Feranil, J., Jones, J., Villar, V., Armando, I., & Jose, P. (2015). Role of Nuclear Factor Erythroid 2-Related Factor 2 in the Oxidative Stress-Dependent Hypertension Associated with the Depletion of DJ-1. Hypertension, 65 (6). http://dx.doi.org/10.1161/HYPERTENSIONAHA.114.04525