ERK12 and p38 MAPKs Are Complementarily Involved in Estradiol 17？-d-Glucuronide-Induced Cholestasis Crosstalk with cPKC and PI3K 英文参考文献.docVIP

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ERK12 and p38 MAPKs Are Complementarily Involved in Estradiol 17？-d-Glucuronide-Induced Cholestasis Crosstalk with cPKC and PI3K 英文参考文献.doc

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ERK12 and p38 MAPKs Are Complementarily Involved in Estradiol 17？-d-Glucuronide-Induced Cholestasis Crosstalk with cPKC and PI3K 英文参考文献

ERK1/2andp38MAPKsAreComplementarilyInvolvedin Estradiol17?-D-Glucuronide-InducedCholestasis: CrosstalkwithcPKCandPI3K AndreaC.Boaglio,Andre′sE.Zucchetti,FlaviaD.Toledo,IsmaelR.Barosso,EnriqueJ.Sa′nchezPozzi, FernandoA.Crocenzi*,MarceloG.Roma* InstituteofExperimentalPhysiology,NationalScientificandTechnicalResearchCouncil/NationalUniversityofRosario,Rosario,Argentina Abstract Objective:Theendogenous,cholestaticmetaboliteestradiol17?-D-glucuronide(E217G)inducesendocyticinternalizationof thecanaliculartransportersrelevanttobileformation,BsepandMrp2.WeevaluatedherewhetherMAPKsareinvolvedin thiseffect. Design: ERK1/2, JNK1/2, and p38 MAPK activation was assessed by the increase in their phosphorylation status. Hepatocanalicularfunctionwasevaluatedinisolatedrathepatocytecouplets(IRHCs)byquantifyingtheapicalsecretionof fluorescentBsepandMrp2substrates,andinisolated,perfusedratlivers(IPRLs),usingtaurocholateand2,4-dinitrophenyl-S- glutathione,respectively.ProteinkinaseparticipationinE217G-inducedsecretoryfailurewasassessedbyco-administering selectiveinhibitors.InternalizationofBsep/Mrp2wasassessedbyconfocalmicroscopyandimageanalysis. Results:E217GactivatedallkindsofMAPKs.ThePI3KinhibitorwortmanninpreventedERK1/2activation,whereasthecPKC inhibitorGo¨6976preventedp38activation,suggestingthatERK1/2andp38aredownstreamofPI3KandcPKC,respectively. Thep38inhibitorSB203580andtheERK1/2inhibitorPD98059,butnottheJNK1/2inhibitorSP600125,partiallyprevented E217G-inducedchangesintransporteractivityandlocalizationinIRHCs.p38andERK1/2co-inhibitionresultedinadditive protection, suggesting complementary involvement of these MAPKs. In IPRLs, E217G induced endocytosis of canalicular transportersandarapidandsustaineddecreaseinbileflowandbiliaryexcretionofBsep/Mrp2substrates.p38inhibition preventedthisinitialdecay,andtheinternalizationofBsep/Mrp2.Contrarily,ERK1/2inhibitionacceleratedtherecoveryof biliarysecretionandthecanalicularreinsertionofBsep/Mrp2. Conclusions: cPKC/p38 MAPK and PI3K/ERK1/