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1、RESEARCHARTICLEMETABOLICDISORDERS2015©TheAuthors,somerightsreserved;exclusivelicenseeAmericanAssociationforRoleofToll-likereceptorsindiabeticrenaltheAdvancementofScience.DistributedunderaCreativeCommonsAttributionlesionsinaminiaturepigmodelNonCommercialLicense4.0(CCBY-NC).10.1126/sciadv.1400
2、1831211†1†YuanyuanFeng,*ShulinYang,*YuxiangMa,Xue-YuanBai,XiangmeiChenThemechanismsofdiabeticrenalinjuryremainunclear.Recentstudieshaveshownthatimmunologicalandinflammatoryelementsplayimportantrolesintheinitiationanddevelopmentofdiabeticnephropathy(DN).Toll-likereceptors(TLRs)compriseasuperf
3、amilyofinnateimmunesystemreceptors.TherolesandmechanismsofTLRsinthepathogenesisofdiabeticrenallesionsaremostlyunknown.Comparedwithrodents,miniaturepigsaremoresimilartohumanswithrespecttometabolism,kidneystructure,andimmunesystem,andthereforerepresentanideallarge-animalmodelforDNmechanisticst
4、udies.Adiabetesmodelwasestablishedbyfeedingminiaturepigswithhigh-sugarandhigh-fatdiets.Functionalandpathologicalmarkers,expressionandactiva-tionofendogenousTLRligands[HSP70(heatshockprotein70)andHMGB1],TLR1toTLR11andtheirdownstreamsignalingpathwaymolecules(MyD88,IRAK-1,andIRF-3),nuclearfacto
5、rkB(NF-kB)signalingpathwaymolecules(IKKb,IkBa,andNF-kBp65),inflammatorycytokines[IL-6(interleukin-6),MIP-2,MCP-1,CCL5,andVCAM-1(vascularDownloadedfromcelladhesionmolecule–1)],andinfiltrationofinflammatorycellsweresystematicallyevaluated.TheexpressionofHSP70wassignificantlyincreasedindiabetic
6、pigkidneys.TheexpressionofMyD88-dependentTLR2,TLR4,TLR5,TLR7,TLR8,andTLR11andtheirdownstreamsignalingmoleculesMyD88andphospho–IRAK-1(activatedIRAK-1),aswellasthatofMyD88-independentTLR3andTLR4andtheirdownstreamsignalingmoleculephospho–IRF-3(acti-vatedIRF-3),wassignificantlyup-regulated.Theex
7、pressionandactivationofNF-kBpathwaymoleculesphospho-IKKb,phospho-IkBa,NF-kBp65,andphospho-NF-kBp65weresignificantlyincreased.LevelsofIL-6,MIP-2,MCP-1,http://advances.sciencemag.org/CCL5,VCAM-1,andmacrophagemarkerCD68weresignificantlyincreasedindiab
