Alterations in Wnt pathway activity in mouse serum and kidne

ARTHRITIS&RHEUMATISM

Vol.63,No.2,February2011,pp513–522DOI10.1002/art.30116

©2011,AmericanCollegeofRheumatology

AlterationsinWntPathwayActivityinMouseSerumand

KidneysDuringLupusDevelopment

AndersAuneTveitaandOlePetterRekvig

Objective.ThecanonicalWnt/ -cateninpathway

wasrecentlyidentifiedasafactorinthepathogenesisofseveralrenaldiseases.TheaimofthisstudywastoevaluateWntsignalingactivityduringdiseasedevelop-mentinamurinemodeloflupusnephritis.

Methods.WntactivityandDkk-1expressionwereseriallyassayedintheserumandkidneysof(NZB NZW)F1miceduringprogressionoflupusnephritis.Theeffectsofserumobtainedfrommicewithlupusandserum-equivalentconcentrationsofDkk-1onmesangialcellswereassessedinvitro.

Results.Geneexpressionanalysesrevealedin-creasedcanonicalWntpathwayactivityinkidneysduringdevelopmentoflupusnephritis,paralleledbyanincreaseinrenalandserumlevelsoftheWntinhibitorDkk-1.Seraobtainedfromproteinuric-stage(NZB NZW)F1miceshowedstrongWnt-inhibitoryeffectsinvitro.Dkk-1concentrationscomparabletothoseob-servedinlupus-pronemiceinducedapoptosisintubularandmesangialcellsinvitro,whereasnosucheffectwasseenfortherangeofconcentrationsobservedinyoungprediseasedmiceandcontrolBALB/cmice.

Conclusion.ThesedatademonstratethatrenalWntsignalingactivityisincreasedinlupusandisaccompaniedbyanincreaseinrenalandserumlevelsofDkk-1.TheWntpathwayisinvolvedintheturnoverofextracellularmatrixconstituentsandrepresentsapo-tentialmediatorofthemorphologicchangesthatoccurwithintheglomerulusduringthedevelopmentofne-phritis.Furthermore,increasedlevelsofDkk-1serveas

SupportedbytheNorthernNorwayRegionalHealthAuthor-ityMedicalResearchProgram(grantsSFP-100-04andSFP-101-04).Dr.RekvigreceivedMilieusupportfromtheUniversityofTromsø.

AndersAuneTveita,MD,PhD,OlePetterRekvig,MD,

PhD:InstituteofMedicalBiology,UniversityofTromsø,Tromsø,Norway.

AddresscorrespondencetoAndersAuneTveita,MD,PhD,

MolecularPathologyResearchGroup,InstituteofMedicalBiology,UniversityofTromsø,N-9037Tromsø,Norway.E-mail:http://doc.guandang.neteita@uit.no.

SubmittedforpublicationMay8,2010;acceptedinrevised

formOctober21,2010.

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apotentialproapoptoticstimulusinvitroandpossiblyinvivoandcouldbeanimportantelementintheinitiationandprogressionofsystemicandend-organdiseasemanifestationsinsystemiclupuserythemato-sus.

TheWntsignalingpathwayisanintracellular

signalingcascadethatwasinitiallylinkedtoembryogen-esisandcancerdevelopment(1).UnderstandingoftherolesofWntsignalinginpostembryonicmammalsiscurrentlyincreasing,andduringthelastfewyears,interestinthissignalingnetworkhasincreasedduetothediscoveryofitsinvolvementinseveralimportantphysiologicandpathophysiologicconditions.Theclassic,so-calledcanonicalWntpathwayisactivatedthroughbindingofWntagonistproteinstomembersoftheFrizzledfamilyofreceptors.Thisinteractioninitiatesanintracytoplasmicsignaltransductioncascadethatpre-ventsglycogensynthasekinase3 (GSK3 )–mediateddegradationof -catenin,followedbytranslocationof -cateninintothenucleus,whereitassociateswiththeTcellfactor/lymphocyteenhancementfactor(TCF/LEF)familyoftranscriptionfactors.Thesetranscriptionfac-torsactivateavarietyoftargetgenesinvolvedincellulargrowthanddifferentiation.ThecanonicalWnt/ -cateninpathwayistightlyregulatedbyseveralsecretedantagonists,includingthesecretedFrizzled-relatedpro-teins,Wntinhibitoryfactor,andtheDickkopfproteinfamily.Ofthese,Dkk-1isaspecificinhibitorofcanon-icalWnt/ -cateninsignalingandhasbeenstudiedinthecontextofregulationoftheWntpathway(2).

Systemiclupuserythematosus(SLE)isanauto-immunediseasecharacterizedbythedevelopmentofautoreactivityagainstnuclearantigens,includingdouble-strandedDNA(dsDNA).In(NZB NZW)F1(NZB/NZW)mice,alupus-likediseasedevelopsspon-taneouslyandiscomplicatedbysevere,progressivenephritis.Theproductionofcirculatinganti-dsDNAautoantibodiesisaccompaniedbythedepositionofimmunecomplexeswithinextracellularmatrices,partic-

514ularlytheglomerularbasementmembrane.Thisprocessiscommonlyaccompaniedbytheapparentexpansionofextracellularmatrices.Theinitiatingmechanismsre-mainunknownbutarethoughttoinvolvesignalingpathwaystriggeredbythedepositedimmunecomplexes.

Inthecurrentstudy,weanalyzedwhethertheWntsignalingpathwaymaybeinvolvedinprogressionoflupusnephritis,basedonemergingreportsindicativeofaroleofthispathwayinrenalextracellularmatrixhomeostasis.IncreasedrenalWntsignalingwasrecentlyobservedinvariousmodelsofrenalfibrosis,includingunilateralureteralobstruction(3,4).Inthismodel,acti-vationoftheWnt/ -cateninpathwaycausedincreasedinterstitialexpressionofextracellularmatrixconstitu-ents,includingtypeIprocollagenandfibronectin(4).Moreover,inhibitionofWntsignalingbyoverexpressionofthesecretedWntantagonistDkk-1attenuatedinter-stitialcollagenmatrixaccumulationandtheseverityofrenalfibrosis(4).ThesedatapointtoWntsignalingasapotentialinterventiontargetinfibroticandpossiblyinflammatoryrenaldiseaseprocesses(5).Inaddition,increasedWntsignalinghasbeenshowntoinducetheexpressionofmatrixmetalloproteinases(MMPs)(6,7),whichmaybeofimportanceinextracellularmatrixremodelingandthelossofmembraneintegritythatoccurinlupusnephritis(8).

LessisknownabouttherolesofWntsignalinginglomerularcellsanddiseasesaffectingtheglomerularcompartment.Arecentstudyrevealedthatadriamycin-inducednephropathycausedWnt/ -cateninsignalinginpodocytesanddemonstratedacrucialroleof -cateninexpressionintheconsequentdevelopmentofprotein-uria(9).Increased -cateninexpressionwasalsodem-onstratedinbiopsyspecimensobtainedfrompatientswithdiabeticnephropathyandfocalsegmentalglomer-ulosclerosis(9).AlthoughthespectrumofeffectsofrenalWntsignalingremainsincompletelycharacterized,thesedataaresuggestiveofaroleofWnt/ -cateninsignalinginseveralglomerulopathies(9).Basedontheseresultsandaspartoftheongoingefforttocharacterizethemolecularchangesunderlyingthedevelopmentandprogressionoflupusnephritis,weevaluatedrenalWntsignalinginNZB/NZWmiceatdif …… 此处隐藏：34297字，全部文档内容请下载后查看。喜欢就下载吧 ……