Nrf2 transcription factor inhibition aggravates oxidative stress induced D1R dysfunction and hypertension in mice

Abstract

The renal dopamine 1 receptor (D1R) dysfunction is strongly associated with oxidative stress and high blood pressure (BP). Nuclear factor E2‐related factor 2 (Nrf2), a redox‐sensitive transcriptional factor is a key regulator in antioxidant response element (ARE)‐mediated induction of phase II antioxidant enzymes. The present study was conducted to investigate the role of Nrf2/ARE signaling pathway in renal D1R function and BP in mice. C57BL/6J mice were treated with a pro‐oxidant buthionine sulfoximine (BSO) (10 mmol/L in drinking water) and ML385, a Nrf2 inhibitor that binds to Nrf2 and inhibits its downstream target gene expression (10 mg/kg body weight/day, intraperitoneally through osmotic pumps) for 8 weeks. BSO administration to wild type mice resulted in marked increased in oxidative stress and mean arterial pressure (MAP) which was accompanied by decreased renal D1R expression and glomerular filtration rate (GFR). Also, SKF38393 (D1R agonist) infusion failed to promote sodium excretion indicating D1R dysfunction in BSO treated animals. ML385 treatment per se had no significant change in MAP, D1R, heme oxygenase‐1 (HO‐1) and NADPH quinone oxidoreductase1 (NQO‐1) expression, GFR and sodium excretion. However, co‐treatment of ML385 and BSO exhibited robust increase in MAP, aggravated oxidative damage and significantly decreased GFR. ML385 treatment to BSO administered animals further impaired the D1R function that resulted in decrease in sodium excretion. Moreover, ML385 and BSO co‐treatment showed decreased D1R and phase II antioxidant enzyme (HO‐1 and NQO‐1) expression in comparison to BSO alone animals. In conclusion, the results suggest Nrf2 inhibition exacerbated oxidative stress induced D1R dysfunction and hypertension possibly by attenuating the phase II antioxidant defense response.Support or Funding InformationThis work is funded by National Institutes of Health (National Heart, Lung, and Blood Institute) Grant HL‐139808.