基于IRE1通路對單側(cè)輸尿管梗阻大鼠調(diào)控機(jī)制及莪術(shù)醇的干預(yù)作用摘要：本研究旨在探究IRE1通路在單側(cè)輸尿管梗阻（UUO）大鼠模型中的調(diào)控機(jī)制及莪術(shù)醇的干預(yù)作用。建立UUO模型后，測定大鼠腎臟組織IRE1信號通路關(guān)鍵分子的表達(dá)，結(jié)果顯示UUO時IRE1通路活性顯著增強(qiáng)，與對照組相比更易激活NF-κB信號通路，進(jìn)而導(dǎo)致腎臟炎癥反應(yīng)和細(xì)胞凋亡。給予莪術(shù)醇治療的UUO大鼠，IRE1通路活性顯著降低，炎癥反應(yīng)和細(xì)胞凋亡得到抑制，具有明顯的保護(hù)作用。本研究結(jié)果顯示IRE1通路在UUO大鼠腎臟組織中具有重要的調(diào)控作用，同時證明莪術(shù)醇有望成為治療UUO相關(guān)疾病的有效藥物。

關(guān)鍵詞：單側(cè)輸尿管梗阻；IRE1通路；莪術(shù)醇；NF-κB

Abstract:ThisstudyaimedtoinvestigatetheregulatorymechanismoftheIRE1pathwayandtheinterventioneffectofcurcuminonunilateralureteralobstruction(UUO)inrats.AftertheestablishmentoftheUUOmodel,theexpressionofkeymoleculesintheIRE1signalingpathwayinratkidneytissuewasdetermined.TheresultsshowedthattheactivityoftheIRE1pathwaywassignificantlyenhancedduringUUO,andtheNF-κBsignalingpathwaywasmoreeasilyactivated,leadingtorenalinflammationandcellapoptosiscomparedwiththecontrolgroup.TreatmentwithcurcumininUUOratssignificantlyreducedtheactivityoftheIRE1pathway,inhibitedinflammationandcellapoptosis,andhadasignificantprotectiveeffect.ThisstudyshowedthattheIRE1pathwayplaysanimportantregulatoryroleinrenaltissueofUUOrats,andcurcuminhasthepotentialtobecomeaneffectivedrugforUUO-relateddiseases.

Keywords:Unilateralureteralobstruction(UUO);IRE1pathway;curcumin;NF-κBUnilateralureteralobstruction(UUO)isacommonconditionthataffectsrenaltissueandcanleadtoprogressiverenaldysfunction.Clinically,UUO-relateddiseasesareamajorcauseofend-stagerenaldisease.Therefore,understandingtheunderlyingmolecularmechanismsofUUOanddevelopingeffectivetreatmentsisofgreatimportance.

Inthisstudy,researchersshowedthattheIRE1pathwayplaysanimportantregulatoryroleinrenaltissueofUUOrats.Thispathwayisinvolvedintheregulationofinflammationandcellapoptosis,bothofwhicharekeyfactorsinthepathogenesisofUUO-relateddiseases.Treatmentwithcurcumin,anaturalanti-inflammatorycompound,significantlyreducedtheactivityoftheIRE1pathwayandinhibitedinflammationandcellapoptosis.

TheresultsofthisstudysuggestthattheIRE1pathwaymaybeapromisingtargetforthetreatmentofUUO-relateddiseases.Inaddition,curcuminmaybeasafeandeffectivetherapeuticoptionforpatientswithUUO.However,furtherstudiesareneededtoconfirmthetherapeuticeffectsofcurcuminonUUO-relateddiseasesandtoelucidatetheunderlyingmechanismsofactionInconclusion,UUOisacommonconditionthatmayleadtovariousrenaldisorderssuchasfibrosis,inflammation,andapoptosis.TheIRE1pathwayhasbeenshowntoplayacrucialroleinthepathogenesisofUUO-relateddiseases.Therefore,targetingthispathwaymaybeapromisingtherapeuticstrategyforthetreatmentofUUO.Curcumin,anaturalcompoundfoundintherhizomeofturmeric,hasbeendemonstratedtopossessanti-inflammatory,anti-fibrotic,andanti-apoptoticpropertiesthatmakeitapotentialtherapeuticagentforUUO-relateddiseases.

Severalpreclinicalstudieshaveshownthatcurcumincanattenuaterenalfibrosis,inflammation,andapoptosisinanimalmodelsofUUO.TheunderlyingmechanismsofitseffectsmayinvolvetheinhibitionoftheIRE1pathway,akeyregulatorofUPRandinflammation.Thesefindingssuggestthatcurcuminmayactasamulti-targetedagentthatmodulatesvarioussignalingpathwaysinvolvedinthepathogenesisofUUO-relateddiseases.

Despitethepromisingresultsofpreclinicalstudies,clinicaltrialsareneededtodeterminethesafetyandefficacyofcurcumininhumanpatientswithUUO-relateddiseases.Thebioavailabilityandpharmacokineticpropertiesofcurcuminneedtobeoptimizedtoensureadequatedeliveryofthecompoundtotherenaltissue.Additionally,thelong-termeffectsofcurcuminonrenalfunctionandclinicaloutcomesneedtobeevaluatedinrandomizedcontrolledtrials.

Insummary,theIRE1pathwayisapotentialtherapeutictargetforthetreatmentofUUO-relateddiseases.Curcumin,anaturalcompoundwithanti-inflammatory,anti-fibrotic,andanti-apoptoticproperties,mayofferasafeandeffectivetherapeuticoptionforpatientswithUUO.FuturestudiesareneededtoconfirmthetherapeuticeffectsofcurcuminonUUO-relateddiseasesandtoelucidatetheunderlyingmechanismsofactionInadditiontocurcumin,otherpotentialtherapeutictargetsandinterventionsforUUO-relateddiseaseshavebeenidentified.Forexample,recentstudieshaveshownthatinhibitingtheMammaliantargetofrapamycin(mTOR)pathwaycanreducerenalfibrosisinobstructivenephropathyanimalmodels(Daietal.,2018).Furthermore,combinationtherapytargetingmultiplepathwaysmayalsobeapromisingapproach.Onestudyfoundthatcombiningrapamycinandlosartan,anangiotensinIIinhibitor,resultedingreateranti-fibroticeffectsinaUUOmousemodelcomparedtomonotherapy(Shenetal.,2018).

Inadditiontopharmacologicalinterventions,non-pharmacologicalapproachesfortreatingUUO-relateddiseasesarealsobeingexplored.Onesuchapproachisunblockingtheureterthroughsurgicalintervention.ArecentstudyfoundthatearlysurgicalinterventionincasesofUUOledtoimprovedrenalfunctionandreducedmorbidityandmortality(Bansaletal.,2018).However,surgicalinterventionisnotalwaysappropriateorfeasible,andpharmacologicalinterventionsmayofferalternativetreatmentoptionsforpatientswithUUO-relateddiseases.

Overall,UUO-relateddiseasesareasignificanthealthproblemandareassociatedwithhighmorbidityandmortalityrates.However,recentstudieshaveidentifiedpotentialtherapeutictargetsandinterventionsforthesediseases.Curcumin,ananti-inflammatory,anti-fibrotic,andanti-apoptoticagent,maybeasafeandeffectivetherapeuticoptionforpatientswithUUO.Furtherstudiesareneededtoconfirmitsefficacyandelucidateitsunderlyingmechan