title: Transcription factor Nrf2 protects renal dopamine D1 receptor function during oxidative stress.
abstract: 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-κB 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-κB activation, caused a robust stimulation of Nrf2 and phase II antioxidant enzyme pathway. In conclusion, oxidative stress via nuclear factor-κB 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-κB activation, preserved D1R function, and prevented hypertension.
authors.affiliation: Heart and Kidney Institute, College of Pharmacy, University of Houston, Houston, TX, USA. abanday@uh.edu
authors.forename: Anees Ahmad
authors.initials: AA
authors.lastname: Banday
authors.forename: Mustafa F
authors.initials: MF
authors.lastname: Lokhandwala
mesh_terms: D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000818:Animals; D018491:Dopamine Agonists / Q000494:pharmacology; D017879:Isothiocyanates; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009318:Natriuresis / Q000187:drug effects / Q000502:physiology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013454:Sulfoxides; D013861:Thiocyanates / Q000494:pharmacology
chemical_list: D018491:Dopamine Agonists; D017879:Isothiocyanates; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D017447:Receptors, Dopamine D1; C000613387:Slc9a3 protein, rat; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D013454:Sulfoxides; D013861:Thiocyanates; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D000254:Sodium-Potassium-Exchanging ATPase; C016766:sulforaphane
keywords: NHE3; Na/K-ATPase; hypertension; nuclear factor-κB; sulforaphane