Dimethylfumarate Attenuates Renal Fibrosis via NF-E2-Related Factor 2-Mediated Inhibition of Transforming Growth Factor-βSmad Signaling 英文参考文献.docVIP

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Dimethylfumarate Attenuates Renal Fibrosis via NF-E2-Related Factor 2-Mediated Inhibition of Transforming Growth Factor-βSmad Signaling 英文参考文献.doc

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Dimethylfumarate Attenuates Renal Fibrosis via NF-E2-Related Factor 2-Mediated Inhibition of Transforming Growth Factor-βSmad Signaling 英文参考文献

DimethylfumarateAttenuatesRenalFibrosisviaNF-E2- RelatedFactor2-MediatedInhibitionofTransforming GrowthFactor-b/SmadSignaling ChangJooOh1,Joon-YoungKim1,2,Young-KeunChoi1,Han-JongKim1,3,Ji-YunJeong1,Kwi-HyunBae1, Keun-GyuPark1,In-KyuLee1* 1DepartmentsofInternalMedicine,ResearchInstituteofAgingandMetabolism,WCUProgram,KyungpookNationalUniversitySchoolofMedicine,Daegu,Republicof Korea,2GISTCollege,GwangjuInstituteofScienceandTechnology,Gwangju,RepublicofKorea,3ResearchInstituteofClinicalMedicine,ChonnamNationalUniversity HwasunHospital,Hwasun,RepublicofKorea Abstract TGF-b plays a key role in the development of renal fibrosis. Suppressing the TGF-b signaling pathway is a possible therapeuticapproachforpreventingthisdisease,andreportshavesuggestedthatNrf2protectsagainstrenalfibrosisby inhibiting TGF-b signaling. This study examines whether dimethylfumarate (DMF), which stimulates Nrf2, prevents renal fibrosisviatheNrf2-mediatedsuppressionofTGF-bsignaling.ResultsshowedthatDMFincreasednuclearlevelsofNrf2,and bothDMFandadenovirus-mediatedoverexpressionofNrf2(Ad-Nrf2)decreasedPAI-1,alpha-smoothmuscleactin(a-SMA), fibronectinandtype1collagenexpressioninTGF-b-treatedratmesangialcells(RMCs)andrenalfibroblastcells(NRK-49F). Additionally,DMFandAd-Nrf2repressedTGF-b-stimulatedSmad3activitybyinhibitingSmad3phosphorylation,whichwas restoredbysiRNA-mediatedknockdownofNrf2expression.However,downregulationoftheantioxidantresponseelement (ARE)-drivenNrf2targetgenessuchasNQO1,HO-1andglutathioneS-transferase(GST)didnotreversetheinhibitoryeffect of DMF on TGF-b-induced upregulation of profibrotic genes or extracellular matrix proteins, suggesting an ARE- independent anti-fibrotic activity of DMF. Finally, DMF suppressed unilateral ureteral obstruction (UUO)-induced renal fibrosis and a-SMA, fibronectin and type 1 collagen expression in the obstructed kidneys from UUO mice, along with increasedanddecreasedexpressionofNrf2andphospho-Smad3,respectively.Insummary,DMFattenuatedrenalfibrosis