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. We have reported that DJ-1, an oxidative stress response protein, is positively regulated by dopamine 2 receptor in the kidney. The transcription factor 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; blood pressure 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 an dopamine 2 receptor d blood pressure. 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. A Nrf2 inducer, bardoxolone, normalizes the systolic blood pressure 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 blood pressure.

Downregulation of Nuclear Factor Erythroid 2–Related Factor and Associated Antioxidant Genes Contributes to Redox-Sensitive Vascular Dysfunction in Hypertension

“…In mice with renal dopamine 2 receptor deficiency, elevated blood pressure and reduced renal Nrf2 expression were normalized by bardoxolone. 29 In SHRSP-fed fermented barley, which increases hepatic Nrf2 expression …”

Cardioprotective effects of Cu(II)ATSM in human vascular smooth muscle cells and cardiomyocytes mediated by Nrf2 and DJ-1

“…Notably, renal depletion of DJ-1 in mice decreases Nrf2 expression and activity, leading to increased oxidative stress and elevated systolic blood pressure 42 . Knockdown of renal Nrf2 in mice increases systolic blood pressure without effecting DJ-1 expression, suggesting that Nrf2 activation is downstream of DJ-1 and is thus required for the maintenance of redox balance.…”

ND-13, a DJ-1-Derived Peptide, Attenuates the Renal Expression of Fibrotic and Inflammatory Markers Associated with Unilateral Ureter Obstruction

“…Nrf2 attenuates the NFκB-inflammatory pathway and suppresses proinflammatory cell signaling [ 18 , 19 ]. We previously reported that the kidney-selective silencing of DJ-1 in mice leads to impairment of the antioxidant response mediated by the dopamine receptor 2 and increases in blood pressure associated with decreased Nrf2 expression and activity in the kidney [ 16 , 20 ]. In addition, mice with DJ-1 selectively silenced in the kidney, and mice with germline deletion of DJ-1 ( DJ-1 −/− mice), develop high blood pressure, renal damage and decreased kidney expression and activity of Nrf2 [ 20 ], suggesting that DJ-1 inhibits the production of renal reactive oxygen species (ROS), at least in part, via the activation of Nrf2-controlled antioxidant genes.…”