SCI文献全文

950

DOI10.1002/prca.200780145

ProteomicsClin.Appl.2008,2,950–955

REVIEW

Analysisofmolecularformsofalbumininurine

GlenL.HortinandDenisSviridov

DepartmentofLaboratoryMedicine,WarrenMagnusonClinicalCenter,NationalInstitutesofHealth,MD,USA

Albuminisnotonlyoneofthemostabundanturinaryproteincomponentsandoneofthemostwidelyusedclinicalmarkersforkidneydisease,italsoisasignificantsourceofmolecularcom-plexityoftheurinaryproteomeandpeptidome.Urinecontainsmultiplefragmentsandmodifiedformsofalbumin.Analysisofmolecularformsofalbumininurineisoffundamentalimpor-tanceforunderstandingclinicalassaysforalbuminquantification,specimenstability,andpro-teomicandpeptidomicanalysisofurine.

Keywords:

Albuminuria/Kidneydisease/Urinaryalbumin/Urinarypeptidomics/Urinaryprote-omics

Received:November30,2007

Revised:January23,2008Accepted:January24,2008

1Introduction

Albuminisoneofthemostwidelyusedurinarymarkersinclinicalpractice,owingtorecognitionthatincreasedurinaryexcretionofalbuminisasensitivemarkerforkidneydis-easeindiabetics[1].Recently,albuminexcretionhasbeenrecognizedasanevenmoregeneralriskfactorforcardio-vasculardiseaseandmortality[2].Albuminisoneofthemostabundantproteinsinurinefromhealthysubjects,withdailyexcretionofabout10mgofthetotaldailyproteinexcretionoflessthan100mg[1–5].Atusualurinaryvolumeoutputsof1–2L/days,theconcentrationofalbumininurinethereforeisabout5000-foldlowerthaninplasma.Thekidneyachievesthisefficientremovalofalbuminthroughatwo-stageprocess.Thefirststageissize-selectiveultrafiltrationinglomeruli,andthesecondstageisreceptor-mediateduptakeofproteinsintherenaltubules[4–6].Breakdownsineitherstepleadstoincreasedalbuminexcretion.Controversyhasemergedrecentlyaboutthequantitativecontributionsofglomerularfiltrationandtu-bularuptake[7,8];resolutionofthisissueisrelevanttoalbuminentryintourineandgenerationoffragmentedandmodifiedformsofalbumin.

Fromthestandpointofproteomicanalysisofurineasdescribedinrecentreviews[6,9,10],albuminisofimpor-tanceinseveralrespects:(i)itisahighlyabundantcompo-nentthatmaskslowabundancecomponents;strategiesforalbumindepletionimprovedetectionoflowabundancecomponents[9–11].(ii)Albuminisausefulmarkerforclin-icalclassificationofurinespecimens[1–5].(iii)Itcanserveasadenominatorinratiosversusotherurinaryproteincompo-nents.TheratiooflargerproteincomponentssuchasIgG,a2-macroglobulin,orIgMversusalbuminhasbeentermedtheselectivityindex,ameasureoffunctionoftheglomerularbarrier[4,12].(iv)Albuminisasourceofmultiplefragmentsandmodifiedformsthatcontributemanyabundantcompo-nentstotheurinaryproteomeandpeptidome,andsomeofthesemolecularvariantsofalbuminmaybeusefulphysio-logicalorpathologicalmarkersasdescribedinsubsequentsections.

2Albuminstructure

Correspondence:Dr.GlenL.Hortin,DepartmentofLaboratoryMedicine,NIH,Building10,Room2C-407,Bethesda,MD20892-1508,USA

E-mail:ghortin@mail.cc.nih.govFax:11-301-402-1885

Albuminisasingle-chainmolecule585residuesinlengthandacalculatedmassof66,438Da[3].Itdoesnotundergoanybiosyntheticmodifications,suchasglycosylationorphosphorylation,buttheunpairedcysteineresidueatposi-tion34occurspartiallyinareducedformandpartiallyindisulfide-bondedformslinkedtocysteine,glutathione,orhomocysteine[3,13,14].Theunpairedcysteinealsocanundergooxidationtosulfenic,sulfinic,orsulfonicacid[13,