DOC

Research on autosomal dominant polycystic kidney disease in China

By Jonathan Palmer,2014-01-25 09:01
13 views 0
Research on autosomal dominant polycystic kidney disease in China

    Research on autosomal dominant polycystic

    kidney disease in China

    ChineseMedicalJournal2006;119(22):191519241915

    Reviewarticle

    Researchonautosomaldominantpolycystickidney

    diseaseinChina

    DAIBingandMEIChanglin

    Keywords:autosomaldominantpolycystickidneydisease;pathogenesis;moleculardiagnosis;therapy

    objectiveToreviewthehistoryandrecentdevelopmentofresearchonautosomaldominantpolycystickidney

    disease(ADPKD)inChina.

    DatasourcesBothChineseandEnglishliteraturesweresearchedinMEDL

    CDROM(19792006)and

    theChineseBiomedicalLiteratureDisk(19792006).

    StudyselectionPublishedarticlesaboutADPKDfrommainlandofChinawereselected.Dataweremainly

    extractedfrom58articleswhicharelistedinthereferencesectionofthisreview. ResultsSomepreliminaryreponsoncystdecompressionsurgeriesandmutationanalysisrepresentthe

    contributiontotheADPKDresearchfromChinainthehistory.Aserialofbasicresearchandclinicalstudieson

    ADPKDinrecentyearsalsohavebeensummarized.AtechniqueplatformforADPKDresearchwasfirstly

    established.Thegenomics/proteomics/bioinformaticsapproachwasintroduced.whichprovidealotofvaluable

    informationforunderstandingthepathogenesis.Bydenaturehighperformanceliquidchrom

atography(DHPLC)

    techniquetheentirePKDlandPKD2genesequencescreeningsystemforChineseHanpopulationhasbeen

    successfullyestablished.BasedonthecharacteristicdataofChinesepatients,anintegratedtherapyprotocolwas

    putforwardandwonanadvantageoverthetraditionaitherapy.Somenovelexperimentalstudiesontherapyalso

    wereencouraging.

    ConclusionsRemarkableprogressofADPKDresearchinChinahavebeenmaderecently.Stillmanyworks.

    includingthegovernmentsupport,internationalcollaborationandactiveparticipationofmoreChinese

    nephrologists,shouldbeenhancedtoadvancethisprocessinthenearfuture. ChinMedJ2oO6:119(22):19151924

    utosomaldominantpolycystickidneydisease

    ^(ADPKD)isoneofthemostcommonhuman

    monogenichereditarydisorderswhichaffectsmore

    than1.5millionpeopleinChina.Itischaracterized

    bytheprogressivef0rmationandenlargementof

    multiplerenaIcystsandapproximately50%0f

    patientsdeveloprenaIinsufficiencyinthefifthand

    si)(thdecadesofIife.AccordingtotheDialysisand

    TransplantationRegisterDatafr0mShanghai.cystic

    kidneydiseaseranksthefourthinalIthecausesof

    endstagerenaIdisease(ESRD)andaccountsfor

    4.7%ofpatientsrequiringrenaIreplacementtherapy.

    ADPKDisalsoaIifethreateningsystemicdisease

    andrenaIinvolvementisoftenaccompaniedby

    extrarenaImanifestationssuchashepaticand

    pancreaticcysts,cardiacvalvulardefects,colonic

diverticulosisandintracranialaneurysms.'

    Twogenes,polycystickidneydiseaseI(PKD1)and polycystickidneydisease2(PKD2)associatedwith ADPKDhavebeen

    chromosomes16pl3.3

    respectivelymappedto

    and4q2122.PKD1

    mutationsaccountfor85%ofthecasesandmostof theremainderareduetochangesofPKD2.

    AdditionaIgenesmaybeinvolvedbuthavenotbeen identified..Asac0nsequenceofdifferentgenetic backgrounds(mutationIoci,modifiergenes)and environmentaIfactors.thereisastrikingphenotypic DivisionofNephrology,KidneyInstituteofCPLA,Changzheng Hospital,SecondMilitaryMedicalUniversity,Shanghai20o003, ChinafDaiBandMeieL)

    Correspondenceto:Dr.M_EIChanglin,DivisionofNephrology,

    KidneyInsfituteofCPLA,ChangzhengHospital,SecondMilitary MedicalUniversity,Shanghai200003,China(Tel:862163521416

    Fax:862163521416.Email:chlmei@public1.sta.net.cn) ThisworkwassupportedbygrantsfromState"863"High11ech

    ProjectFund(No.2002AA2Z3130).theNafionalNaturalScience FoundationofChina(No.30170901:30271523;30330640: 30570867)andShanghaiScientificandTechnologicalCommittee (No.02JC14029;035407018.

1916ChinMedJ2006;119(22):19151924

    variabilityamongADPKDpatients..Butinthe

    cellularbiologicalIeveIthisdiseasesharessome commonfeatures:abnormaIcelIproliferationand

    apoptosis,polaritydisturbanceanddedifferentiation, enhancedtransepithelialfluidsecretion,extracellular matrixremodelingandinterstitiaIfibrosis. THEHISTORYOFADPKDRESEARCHINCHINA

    Chinesenephrologistsbegantopayattentionto ADPKDintheIate1970sofIastcenturyandthe earlypaperstheypublishedmainlyfocusedon describingtheclinicaIandradiologicaI

    manifestatiOns0fADPKDandtheoutcomesofcyst decompressionsurgeries.Intheearly1980s.He etaIandZhengetaIintwoseparateseriesof cases.reportedthatcystdecompressionsurgery couldresultinexcellentpainreliefandimprovement ofrenaIfunction.Thesewereamongtheearliest papersconfirmingtheefficacyofsurgicaI decompressionandhavebeencitedmanytimesby foreignnephrologists.In1995.LiuetaIfr0m PekingUniversityFirstHospitaIsummarizedthe renaIandextrarenaImanifestationsof205Chinese ADPKDpatients.1twasthefirstlarge.sampleclinical studyonADPKD,nChina.TPKD1andPKD2

    wereclonedintheIate1990s.manyChinese

    nephrologiststurnedtomutationanalysisby microsatellitelinkageanalysisandpolymerasechain reaction-singlestrandconformationpolymorphism (PCR-SSCP)techniques.In2002,DingetaI.bfrom SichuanUniversityreported3noveIPKD1mutations oftheHanChinese.ItwasthefirstADPKDpaper frOmthemainlandofChinapublishedinan

    internationaIiourna1.Thoughthesepapers

    mentionedaboveareofgreatsignificanceandcan beIookedatasIandmarksinthehistory,theycannot conceaIthehugegapsbetweenChinaandWestern countriesonADPKDresearch.Thetruthisthatfor manyyearsinChina.aIotofdoctorshavenot attachedsufficientimportancetoADPKDandfew centersconcentrateonthesubjectandIittlemoney wasinvestedonADPKDresearch.alIofwhichmake itveryhardtoorganizesystematicbasicresearchand high-qualityclinicaIstudies.

    ADPKDPROGRAMINOURLABORATORY

    OurlaboratoryinitiatedADPKDresearchin1995 andhasmadesomeprogress.

    EstablishmentoftechnicaIplatform

    Westartedbyestablishingatechniqueplatformfor ADPKDresearch.First.acyst-liningepithelialcelI linewasseparatedfr0mtherenalcystsofADPKD patientsandimmortalizedwithSV40viruses.The celllinehasbeenpassagedover30timeswithno apparentphenotypicchange.Thepositive

    expressionofcytokeratin,alkalinephosphataseand vimentinconfirmsitsepitheliaIorigin.Characteristic adhesionplaqueandmicrovilli-likecoatingof polarizedepitheliacanbeobservedbytransmission electronmicroscopy.Theimmortalizedcyst.1ining epitheliaIcelllineoffersusausefuI/nvitromodeIfor ADPKDresearch.

    Second.wedevelopedmonoclonaIandpolyclonaI antibodiesagainsttheN-terminaI156aminoacidsof polycystin?1(flank-LRR.flankdomain),whichhave

    beenidentifiedbythePKDcenterofJohnHopkins Universityandusedintheirresearch.'Withthese antibodieswethendetectedthepolycystin-1 N-terminaIfragment(PC-1NF)concentrationin urine,serumandcysticfluidofADPKDpatientsand unaffectedcontrols.Urinaryandserumsamples fr0m117ADPKDpatients.15simplerenalcysts (SRC)patientsand110unaffectedcontrolswere collectedinourdivision.Cysticfluidsamplesfr0m40 ADPKDpatientsand11SRCpatientswereobrained bypercutaneouscysticfluidaspiration.After Westernblotanalysisofthesesamples.thePC.1NF concentrationinurine,serumandcysticfluidwere determinedbysandwichELlSA.ThefinaIresults wereveryinteresting.Ihereweresomesoluble formsofPC-1NFinurine,serumandcysticfluid. whichappearedasfourdifferentmolecularforms: 325kDa,200kDa,100kDa,andabout90kDa(Fig. 11.WhenalItheADPKDpatientswereclassifiedby differentCKDstagesaccordingtoK/DOQlguidelines wefoundthattheurinaryPC-1NFconcentrationof ADPKDpatientsincreasedwithagraduaIGFR deterioration.fr0mstageCKD1tostageCKD5the urinaryPC-1NFconcentrationofADPKDpatients wentupremarkablyfFig.2A).1nstageCKD2.stage CKD5stageADPKDpatients;theurinaryPC.1NF concentrationwassignificantlyhigherthanthatof normaIcontrolsandSRCpatients(Fig.2B).In comparisonwithslightlydecliningGFR,urinary PC-1NFconcentrationsweresignificantlyelevated

duringthewholestudyperiodin11ADPKDpatients

    (Fig.2C).TheincreaseofurinaryPC.1NF

    c0ncentratiOnappearedearlierthanthechangeof

CtliMedicMJournal2006:119f22).'19151924917

    }

    稿荫

    ?一鞠

    B

    Fig.1.WesternblotforPC.1NFjnserum.urine.andcysticfluidfromnormaIcontrols,ADPKDpatientsandSRCpatientsA:

    Lane1wasfull

    lengthpolycystin.1.Lanes25wereimmunoprecipitatedserumsamplesfromnormalcontrols,ADPKD

    patientswithPKD7mutationADPKDpatientswithP

    mutationandSRCpatients.Lane6wasferritin(usedfornegative

    control1.shownwith13ositive,normalADPKD1,ADPKD2,SRCandnegativerespectively.B:Lane1wasfUlI-length

    polycystin

    1Lanes25wereimmunoprecipitatedurinesamples[romnormalcontrols,ADPKDpatientswithPKDt

    mutation,ADPKDpatientswithPKD2mutationandSRCpatients.Lane6wasferritln,shownwithpositive.normal,ADPKD1

    ADPKD2.SRCandnegativerespectivelyCLane1wasfulI-lengthpolycystin-1,_anes2

    4werelmmunopreclpitated

    cysticf1uidsamplesfr0mADPKDpatientswithP

    mutation.ADPKDpatientswithPrrlutationandSRCpatients.

    Lane5wasferritin.shownwithpositive.ADPKD1,ADPKD2,SRCandnegative.respectivelyDistlnctbandswerepresent

    at325kDa200kDaandapproxlmately90kDainalIserum.urineandcysticfluldsampiesassh

owninA,BandC.1n

    additiontotheabovethreebandsanotherbandabout100kDaappearedinthecysticfluldsampi

    eInthepositivecentrel

    sample.distinctbandswerepresentat520kDaand370kDaFerritInwasnotdetecledIntheneg

    ativecentrellane

    serumcreatinine,GFRandproteinuria.However. therewerenodifferenceinserumPC1NF

    concentrationamongADPKDSRCpatientsand controls.SoweconcludedthaturinarvPC-1NF mightbeanovelbiomarkerforADPKDandthe PC1NFconcentrationanditsvaryingtendencymay behelpfulinmonitoringtheprogressionofADPKD. Finally,twoanimalmodelsofADPKD.theHam SPRDratandthepkd2..'mousewereimported intoChinafromMayoClinicandYaleUniversity. Theyprovideusinvivomodelsforstudyingthe pathogenesisandtherapyofADPKD.

    Molecularpathogenesis

    ToelucidatethemolecularmechanIsmandidentify targetsfortherapeuticinterventionofADPKDwe appliedthegenomics/proteomics/bioinformatics approachloourresearchFirst.thedifferenceof geneexpressionbetweennormaIkidneytissuesand polycystickidneytissueswascomparedbycDNA microarray.Totally,357geneswerefoundtobe differentiallyexpressed.especiallyincludingmany genesencodinggrowthfactorsandextracellular matrixproteins(Table.

    Funher.comparativeanalysesbetweenthe

    proteomesofcystliningepithelialcellsandnormaI tubularepithelialcells.theunneorserumfr0mADPKD patientsandfrOmnormaIcontrolsweremadewith isotope-codedaffin_tvtag(ICAT)andtwodimensionaI IiquidchromatographVtandemmassspectrometry Table1.Differentialgenesinpolycystickidneytissues comparedwithnormaIkidneytissues

    (

    

    ?

    

'

    

    m

    OL

    .

    Mp~INF(n#l……,

    ./

    

    j/

    .

    ,1T

    Bi?

    if)

    i}

    5

    3n

FiggRelationshipbetweenUnnaryPC1NFandGFR

    ATheADPKOpatientswerec~assifiedbvdifferentCKD

    stagesaccordInglothecriteriapubllshedfnlheK/DO0I

    auIdeGFRIsreflectedCcfvaueandCcrvaluels

    4P-caIculatedPvtheCockcroftandGaultformulaUrinary

    ?1'c.INI'PC1NFconcentrationofADPKDpatientsncreasedwith

    apradualGFRdeterrerationTberelationsh0Pbetween

    fhe1wovariableIsIustratedbycurves

    GFR=1/(00139+18106E-05~urinaryPC-1)(f=07188)

    BWithPC-1NFbelow500pg/mgfrelationsh'P

    betweenurnaryPC?1NFconcentrationlnADPKD

    patientsSRCpatientsCGNpatientsandnort3aIcontrols

    lhGwascomparedAurinaryPC-1NFconcentration

    0fnolmorethan1775pg/mgfvedicaIdo~ed?

    ne$representing95%confidencelntervaIofPC-1NFconcenlrationIr3norma controls)wasusedasano~maIscopeforurInaryeG-1NRTheufInaryPC-1NFconcentrationirlnormacontrolsSRC

    patientsaridCGNpatie~tsallwithinmisTanoeWIthinthescopeotGFR9Oml/mintherewasnosignilicanI

    differenceinurinaryPC1NFconcenlraflonamongADPKDpatientsSRCpat1entsCGNpattenbandnOrmacontrols

    WhilefortheADPKDpatRntsnstageGKD2CKD5}heMrnaryPC-1NFconcentrationwassignifican[1yhigherthanin

    SRCpahents,CGNpatentsornormaJconIrolsCmecourseannlysisofMrlrlaryPC.1NFandGFRinADPKDpatients

    1qlechangeofparameterWaSreflectedasthepercentageofchangefrombaseIneevelsThedatawerefrom11ADPKD

    patientsandtheva1MealeachtimeDO{n1wastheaverageofIheobservedpatienbThePC?1NFconcentrationlncreased

Report this document

For any questions or suggestions please email
cust-service@docsford.com