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Transcription Factor Nrf2 Protects Renal Dopamine D1 Receptor Function During Oxidative Stress.

Authors: Banday, AA  Lokhandwala, MF 
Citation: Banday AA and Lokhandwala MF, Hypertension. 2013 Jul 22.
Pubmed: (View Article at PubMed) PMID:23876469
DOI: Full-text: DOI:10.1161/HYPERTENSIONAHA.113.01358

The renal dopaminergic system plays a significant role in controlling sodium excretion and blood pressure (BP). Overwhelming evidence shows that oxidative stress downregulates renal dopamine receptors (D1R), and antioxidant supplementation protects D1R function. However, the mechanisms for benefits of antioxidants in protecting D1R function are unknown. We investigated the role of nuclear factor E2-related factor 2 (Nrf2), a redox-sensitive transcription factor, in reducing oxidative stress, protecting renal D1R function and lowering BP in rats. Male Sprague-Dawley rats were treated with L-buthionine-sulfoximine (BSO) and sulforaphane for 4 weeks. Rats treated with BSO exhibited significant increase in oxidative stress and BP. BSO treatment reduced renal D1R expression and abolished SKF38393 (a D1R agonist)-induced Na/K-ATPase and Na/H-exchanger (NHE3) inhibition. Also, in these rats, SKF38393 failed to promote sodium excretion. BSO caused an increase in nuclear factor-kappaB expression, a modest nuclear translocation of Nrf2 and a moderate activation of phase II antioxidant enzymes. Treatment of rats with sulforaphane alone induced modest activation of Nrf2 and phase II antioxidant enzymes, although having no effect on BP, redox status, or D1R function. However, sulforaphane prevented oxidative stress, protected D1R function, and abrogated hypertension in BSO-treated rats. In these animals, sulforaphane, whereas attenuating nuclear factor-kappaB activation, caused a robust stimulation of Nrf2 and phase II antioxidant enzyme pathway. In conclusion, oxidative stress via nuclear factor-kappaB activation downregulated D1R function causing a decrease in sodium excretion, which contributed to an increase in BP. Sulforaphane via activation of Nrf2-phase II antioxidant enzyme pathway mitigated oxidative stress and nuclear factor-kappaB activation, preserved D1R function, and prevented hypertension.

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CRRD Object Information
CRRD ID: 7248553
Created: 2013-08-08
Species: All species
Last Modified: 2013-08-08
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.