Soluble Erythropoietin Receptor Contributes to Erythropoietin Resistance in End-Stage Renal Disease 英文参考文献.docVIP

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Soluble Erythropoietin Receptor Contributes to Erythropoietin Resistance in End-Stage Renal Disease 英文参考文献.doc

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Soluble Erythropoietin Receptor Contributes to Erythropoietin Resistance in End-Stage Renal Disease 英文参考文献

SolubleErythropoietinReceptorContributesto ErythropoietinResistanceinEnd-StageRenalDisease EliyahuV.Khankin1.,WalterP.Mutter1.,HectorTamez1,Hai-TaoYuan1,S.AnanthKarumanchi1,3* ,Ravi Thadhani2 1Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America, 2Department of Medicine,MassachusettsGeneralHospitalandHarvardMedicalSchool,Boston,Massachusetts,UnitedStatesofAmerica,3HowardHughesMedicalInstitute,BethIsrael DeaconessMedicalCenterandHarvardMedicalSchool,Boston,Massachusetts,UnitedStatesofAmerica Abstract Background:Erythropoietinisagrowthfactorcommonlyusedtomanageanemiainpatientswithchronickidneydisease.A significantclinicalchallengeisrelativeresistancetoerythropoietin,whichleadstouseofsuccessivelyhighererythropoietin doses,failuretoachievetargethemoglobinlevels,andincreasedriskofadverseoutcomes.Erythropoietinactsthroughthe erythropoietinreceptor(EpoR)presentinerythroblasts.AlternativemRNAsplicingproducesasolubleformofEpoR(sEpoR) foundinhumanblood,howeveritsroleinanemiaisnotknown. MethodsandFindings:Usingarchivedserumsamplesobtainedfromsubjectswithendstagekidneydiseaseweshowthat sEpoRisdetectableasa27kDaproteinintheserumofdialysispatients,andthathigherserumsEpoRlevelscorrelatewith increased erythropoietin requirements. Soluble EpoR inhibits erythropoietin mediated signal transducer and activator of transcription5(Stat5)phosphorylationincelllinesexpressingEpoR.Importantly,wedemonstratethatserumfrompatients withelevatedsEpoRlevelsblocksthisphosphorylationinexvivostudies.Finally,weshowthatsEpoRisincreasedinthe supernatantofahumanerythroleukaemiacelllinewhenstimulatedbyinflammatorymediatorssuchasinterleukin-6and tumornecrosisfactoralphaimplyingalinkbetweeninflammationanderythropoietinresistance. Conclusions:TheseobservationssuggestthatsEpoRlevelsmaycontributetoerythropoietinresistanceinendstagerenal disease,andthatsEpoRproductionmaybemediatedbypro-inflammatorycytokines. Citation:KhankinEV,M