4/17/2016 DangersWithin:DAMPResponsestoDamageandCellDeathinKidneyDisease

JAmSocNephrol.2011Mar22(3):416425. PMCID:PMC4493973
doi:10.1681/ASN.2010040430

DangersWithin:DAMPResponsestoDamageandCellDeathinKidneyDisease
DianeL.Rosin *andMarkD.Okusa

Departmentsof Medicineand
*
Pharmacologyand

the CenterforImmunity,InflammationandRegenerativeMedicine,UniversityofVirginia,Charlottesville,Virginia
Correspondingauthor.
Correspondence:Dr.DianeL.Rosin,DivisionofNephrology,Box800746,UniversityofVirginiaHealthSystem,Charlottesville,VA22908.,Phone:434
2436699Fax:4349245848Email:dr5e@virginia.edu

Copyright2011bytheAmericanSocietyofNephrology

ThisarticlehasbeencitedbyotherarticlesinPMC.

Abstract Goto:

Theresponsetoexogenouspathogensleadstoactivationofinnateimmunitythroughthereleaseofpathogen
associatedmolecularpatterns(PAMPs)andtheirbindingtopatternrecognitionreceptors.Aclassicexampleis
septicshockwhereTollreceptor4recognizesPAMPs.Althoughwellaccepted,thisconceptdoesnotexplainthe
activationofinnateimmunityandinflammationoccurswithtransplantation,autoimmunity,ortrauma.Increasingly
recognizedisthatendogenousmoleculesreleasedbydyingcells(damageassociatedmolecularpatternsDAMPs)
activatecellularreceptorsleadingtodownstreaminflammation.Thusendogenousdangersignalsandexogenous
PAMPselicitsimilarresponsesthroughseeminglysimilarmechanisms.Alsoemergingisourunderstandingthat
normalrepairprocessesbenefitfromdampeningtheimmuneresponsetotheseendogenousdangermolecules.Here
wefocusontheroleofDAMPsandtheirputativereceptorsinthepathogenesisofacuteandchronickidney
diseases.

Theinflammatoryresponsetoacuteorchronictissueinjuryengagestheimmunesystem.Whataretheinitial
activatorsofinjuryordisease?Howdoestheimmunesystemdiscriminatebetweenliveversusdeadcellsandknow
whethertorespond?Whatfactorsregulatetheinflammatoryresponsetoclearinjurywithoutcausingexcessive
tissuedamageandtheninitiaterepair?Wenowrecognizethatthewellknownactivationoftheimmunesystemin
responsetoforeignpathogensisrecapitulatedinanimmuneresponsetoendogenousmoleculesreleasedfrom
necrotic,andperhapsapoptotic,cellsaftertissueinjuryortraumarelatedtohypoxia,ischemia,mechanicalstress,or
pathogeninducedinflammation.
1 2
Matzinger originallyproposedthedangermodeltoclarifyexceptionstoJaneway'smodel oftheimmuneresponse
toforeignantigens,whichdidnotatthetimeexplainautoimmunityortheimmuneresponsetotransplantation.The
dangermodelsuggeststhatdamagedordyingcellsreleaseendogenousmoleculescalleddamage/dangerassociated
molecularpatterns(DAMPs)thatactivatetheimmunesysteminafashionanalogoustopathogenassociated
molecularpatterns(PAMPs),moleculesreleasedbypathogenicbacteriaorviruses.Theseendogenousorself
molecules(extracellularmatrixproteins(ECM),calciumbindingproteins,andstructuralproteins)typicallyfunction
3
innormalcellhomeostasisbutarealsorecognizedasdangersignalswhenreleasedintotheextracellularspace
4 46
exposinghydrophobicportionsofthemoleculesthatarenormallyhiddeninhealthylivingcells. Matzinger and
78
othershaveextendedthedangermodelasmorehasbeenlearnedabouttheroleofdangersignalsintissueinjury ,
9 10,11
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anddiseasessuchasarthritis andcancer andthebody'sneedformechanismsthatdampentheimmune
responseandinitiaterepair.HerewefocusontheroleofDAMPsandligandsofTollreceptors(TLRs)inrenal
12 15
disease andexpandrecentinteresttoabroaderviewofthecurrentlyidentifiedclassesofDAMPsandtheir
putativereceptors.

DANGERASSOCIATEDMOLECULARPATTERNS:ENDOGENOUSDANGERSIGNALS Goto:

Aconsistentterminologyhasnotbeenadoptedfortheendogenousmoleculesthatconveyadangersignaltothe
immunesystem.SomeDAMPsthatstimulateanimmuneresponsehavebeencalledadjuvantmoleculesto
3
distinguishthemfromDAMPsthatproduceonlyacuteproinflammatoryeffects, sometimesreferredtoas
16 17 16 17
alarmins. , PAMPsandalarminshavebeengroupedtogetherassubcategoriesofalargefamilyofDAMPs, ,
9
whereasothersconsideralarminsandDAMPstoberelatedmoleculesthatareclearlydistinguishedfromPAMPs.
HereweusethetermDAMPStodescribeendogenousdangermoleculesasagroupthatisseparatefrompathogen
derivedPAMPs(Table1andFigure1)theirclassificationispredicatedondirectevidenceofinvolvementinthe
immuneresponsetoinjurywithaclearabsenceofconfoundingeffectsfrompotentialbacterialcontaminants,such
3 16
asLPS. ,

Table1.
DAMPsandreceptorsforDAMPs

Figure1.
Dangerandstrangermodels.Infectionsofpathogenicbacteriaorviruses
causereleaseofPAMPsthatbindtopatternrecognitionreceptors(PRRs),
suchasTLRs,onimmunecellsandstimulateaninnateimmuneresponse
thatisaccompaniedbyinflammation,...

HighmobilityGroupBox1Protein

PerhapsthemostwellcharacterizedDAMP,highmobilitygroupbox1(HMGB1)protein,isaubiquitously
expressednonhistoneDNAbindingproteinthatregulateschromosomalstability,stabilizesnucleosomes,and
18 22 23
regulatestranscription. AsanextracellularDAMPaftersecretionorpassiverelease, HMGB1isalatephase
24
proinflammatorymediatorinsepsis andinsterileinflammation,suchashepaticischemiareperfusioninjury
18 25 26
(IRI). , HMGB1ischemotacticforimmunecellsandstimulatesdendriticcell(DC)maturationandmigration.
27
HMGB1bindstothereceptorforadvancedglycationendproducts(RAGE) andstimulatesNFBinduced
28
transcriptionthroughinteractionswithTLR2,TLR4, andRAGE.

S100ProteinFamily

TheS100proteins,alargefamilyofcalciumbindingproteins,areimplicatedintheinflammationorfibrosis
29
associatedwithcancerordiseasesofthekidney,heart,joints,andlungs. Whenfunctioningextracellularlyas
30 31
DAMPsafterreleasefromphagocytes andothercellsinresponsetocellstress,S100proteinsbindtoRAGE
32 33
andotherreceptorsandproduceearlierproinflammatoryeffectslikeHMGB1. , S100A8andS100A9release
33
fromactivatedphagocytesactivatesTLR4andamplifieslethalendotoxininducedshock.

HeatshockProteins

Innormalhealthycells,heatshockproteins(HSPs)areintracellularproteinchaperonesthatguidenewly
synthesizedpolypeptidechainstopreventaggregationandmisfolding.Duringcellstress,inductionandsecretionof
HSPscausesproinflammatorycytokineandchemokinereleaseandactivationandmaturationofantigenpresenting
34 36
cells(APCs)toproducearobustinnateimmuneresponse. Indeed,HSPsextendtheirroleaschaperones
37 38
,
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intracellularlybybindingandpresentingantigenstocellsurfaceMHCclassImolecules. , Complexesof
extracellularHSPsandantigensaretakenupbyAPCsandpresentedtoMHCItoactivateTcellsthroughcross
36 37
presentation. ,

OtherLigandsofRAGE

Adiversegroupofligands(includingHMGB1,S100proteins,andHPSs)bindtoRAGE.Advancedglycationend
products(AGE)andrelatedmoleculesareglycationandoxidationproductsofproteinsandlipidsthatareformedin
hyperglycemicstatesbyoxidativestress,suchashypoxiaandischemia/reperfusion,andinanumberof
39 42
diseases.

GenomicDoublestrandedDNA
43
MicrobialDNAisaligandforTLR9,butTLR9canalsorecognizeselfDNAfrominjuredmammaliancells.
ReleaseofDNAfromdyingmammaliancellsinitiatesaninnateimmuneresponsebyactivationofTLR9andthe
44 45
NALP3(cryopyrin)inflammasome,releaseofactivatedIL1andIL18, andinductionofDCmaturation. In
additiontogenomicDNA,injuryinducedreleaseofmitochondrialDNAcanalsocauseinflammationby
46 47
conservedpathogenicPAMPsequences. ,

Uric
UricAcid

Theaccumulationofuricacidintissueshaslongbeenknowntocausegout,butsolubleuricacidreleasedby
48
injuredcellsalsoactsasadangersignal. Theactivemoiety,monosodiumuratecrystals,formsintheextracellular
49 51
spacewhereitstimulatesanimmuneresponsebyactivatingtheNALP3inflammasome andbystimulatingDC
52
maturationandTcellresponses.

NeutrophilderivedAlarmins

Neutrophils,anearlyleukocytetoinfiltratetissueafterinjuryorinfection,undergodegranulationandrelease
53 54
immunemodulatoryproteinsandpolypeptides.Neutrophilderivedalarmins(suchasdefensins, cathelicidin,
55
andlactoferrin ),namedfortheirresponsetodangersignals,linkinnateandadaptiveimmunitybyrecruiting
17
leukocytesandinducingmaturationofAPCs,therebybridgingneutrophilandDCfunction.

ExtracellularDAMPS

Damagedordyingcellscanalsogeneratedangersignalsbycleavingmoleculesthatarestructuralcomponentsof
theECM.CleavedECMglycoproteins,suchasfibronectinandfibrinogen,andproteoglycans,suchashyaluronan,
biglycan,andversican,functionasDAMPsbysignalingthroughTLRs,theNLRP3inflammasome,andother
3 56 57
receptorssuchasCD44,promotingavigorousimmuneresponse , andcontributingtokidneydisease.

OtherDAMPs
58 59 60 64
OthercandidateDAMPsincludegalectins , ATPandadenosine thioredoxin,aubiquitousantioxidant
65 66 67
enzyme , theintranuclearcytokine,IL33 andTammHorsfallprotein(THPoruromodulin),aglycoprotein
expressedinthethickascendinglimbthatisexcretedintotheurineafterproteolyticcleavage.THPisthemost
68
abundantproteininurine,butitsfunctionremainsunclear ithasbeenimplicatedasabiomarkerofkidney
69 70
diseaseandallograftrejection , andmaybeadamagesignalinrenaltubularinjury.THPpromotescytokine
71 72
release andimmunecellactivation,includingDCmaturation, butmayalsohaveaprotectiveantiinflammatory
73
role.

RECEPTORS Goto:

DAMPsarerecognizedbypatternrecognitionreceptorssuchascertainTLRs,NODlikereceptors(NLRs,
74 75
includingtheNLRPinflammasomes),andRLRs(RIGIlikereceptors),therebyoverlappingwithPAMPs, , and
76
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76
byspecializedreceptorssuchasRAGE. CommonsignalingpathwayssharedbyDAMPsandPAMPsmayhave
47
anevolutionarybasis. InjuryinducedreleaseofbacterialrelatedDAMPsfrommitochondria,evolutionary
46
symbioticdescendentsofbacteria,causesinflammation. OtherDAMPsreceptorsincludeCD91,scavenger
3 11 16 74
receptors,CD2,integrins,chemokinereceptors,andCD44. , , ,

RAGEisamultiligandreceptorthatbindsAGE,someS100proteins,amyloidprotein,andHMGB1.Itamplifies
39
immuneresponses andisimplicatedindiseasessuchasdiabetes,Alzheimer'sdisease,cancer,andvarious
40 76 77 78
inflammatoryconditions. , , AsolubleformofRAGE(sRAGE)foundinhumanandmouseplasma mayact
asaliganddecoytobinddangermoleculesandchecktheimmuneresponse.CirculatingsRAGEandasplice
41 79
variant(endogenoussecretoryRAGE)maybeclinicalindicatorsorbiomarkersfortheseverityofdisease. ,

Inflammasomes,largecytosoliccomplexesofNODlikereceptors,adaptorprotein,andcaspase1,linkpathogenic
andendogenousdangersignalstoactivationofcaspase1,andproteolyticprocessingandreleaseofthe
50 80 81 82
proinflammatorycytokines,IL1,andIL18. , , Inflammasomesareimportantingout, andtheirrolein
57
diseasehasbeenlinkedtoseveralDAMPs,includingtheECMmolecule,biglycan.

CHECKSANDBALANCES Goto:

Withsuchavastarrayofstrangeranddangersignalsandsomecrossoverintheirreceptors,howdoestheimmune
systemdistinguishPAMPsfromDAMPs?Furthermore,onceanimmuneresponseisinitiated,whatmechanisms
areengagedtopreventrampanttissuedamageandbegintherepairprocess?AlthoughPAMPsandDAMPsbindto
someofthesamereceptors,interactionwithdifferentcoreceptorsmayaccountntforadivergenceforadivergence
83 84 85
indownstreameffects allowingfordiscriminationbetweenPAMPsandDAMPs , andselectivesuppressionof
85 87
DAMPsignaling(Figure2).

Figure2.
ProposedmechanismsfordiscriminatingDAMPSfromPAMPsandlimiting
theimmuneresponse.Severalgroupshaverecentlyproposedmechanisms
thatshareacommonthemeinvolvingcoreceptorsthatpairwithreceptorsfor
DAMPsandPAMPstoallowcellstodistinguish...

SomemechanismscontroldamageinducingimmuneresponsesthroughDAMPsinactivation.AntiHMGB1
88 40
antibodies andsRAGEreduceHMGB1bioavailability. Extracellularredoxconditionsmayregulatethe
immuneresponsebybalancingearlystagereducingenvironmentpromotingproinflammatoryconditionswithlate
stageoxidationinducedDAMPsinactivationdisruptionofthisbalancemaycontributetochronic
19 89 90
inflammation. , , BCL2proteins,afamilyofproorantiapoptoticmoieties,maybetissueprotectivewhen
91
releasedextracellularlyinIRI.
92
Someendogenousmoleculescontributetotheresolutionofinflammationandinitiationofrenalrepair. Weibel
PaladebodiesareorganellesofendothelialcellsthatcontainbioactivesubstancessuchasvonWillebrandfactor,IL
93
8,Pselectin,angiopoietin2,andeotaxin thatparticipateinhemostasisandinflammation.Uricacidreleaseafter
94 95
IRmobilizesstemcells,protectskidneysfrominjury, , andthroughexocytosisofWeibelPaladebodiesand
96
releaseoftheirconstituentmoleculesmaypromotepostischemicrepair. SomeDAMPs,includingHMGB1and
someECMproteins,suchashyaluronanandheparinsulfate,initiateimmuneresponsesbutarealsonecessaryfor
19
recoveryandhealing.

DAMPSANDKIDNEYDISEASE Goto:

Despitesignificantadvancesinunderstandingtheimportantcontributionofinflammationandimmunemechanisms
tothepathogenesisofavarietyofkidneydiseases,fewspecificorefficacioustherapiesexist.Understandingthe
roleofcandidateDAMPsreleasedfromsomatickidneyorimmunecellscouldrevealnoveldrugtargetsfor
inhibitingtheinflammatoryresponseorpromotingrepairprocessesinacuteandchronickidneydisease(CKD).
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DAMPscontributetomultiplediseases.TLRsareimportantinIRIandvariousformsofglomerulonephritis
12 15
includinglupusnephritis. Advancedglycationendproducts,DAMPsthatbindtoRAGEratherthanTLRs,
areincreasedinrenalfailureandareinvolvedintheprogressionofCKDindiabeticandnondiabetickidney
97 98
disease. ,

AcuteKidneyInjury

Acutekidneyinjury(AKI)resultsmostcommonlyfromIR,andalthoughtherearemanycauses,acommon
99
pathwayleadingtoproximaltubuleinjuryisactivationofinnateandadaptiveimmunityleadingtoinflammation.
InjuryelicitsreleaseofproinflammatoryDAMPs,whichmaybesignalsthatengendertheinflammatoryresponse
100
toIRIbybindingtoreceptorssuchasTLRsandRAGE. ThebestcharacterizedDAMPsinAKIareHSPsand
HMGB1.Althoughtheirroleinmediatingrenalinjuryinacuteischemiceventsiswelldocumented,somestudies
donotestablishthattheyfunctionasDAMPstostimulatetheimmunesystem.Nevertheless,weincludethemas
viableDAMPscandidatesonthebasisoftheirroleasDAMPsinotherpathologies.Inischemickidneysorhypoxic
101
renalepithelialcells,stimulationoftheTLR2mediatedERKpathwayisregulatedbytheHSP,gp96.
102
Geldanamycin,aninhibitorofHsp90andgp96,protectsmousekidneysfromIRI. Hsp70andHsp27areup
103 104 105
regulatedinratkidneysafterIRI however,tissueprotective andproinflammatory rolesforHsp27have
alsobeenreportedinkidneysafterIRI.Ethylpyruvate,aninhibitorofHMGB1release,protectskidneysfromIRI
106
andreducestheincreaseinTNFinratkidneyssubjectedtoIRI. TLR4andMyD88deficientmiceshowed
protectionfromkidneyIRIHMGB1,hyaluronan,andbiglycanexpressionincreasedinthesenullmice,suggesting
107
thattheseDAMPsmaybeligandsfortheobservedroleofTLR4inIRI.

Highconcentrationsofuricacidaccumulateinischemictissuesandprecipitatetoformmonosodiumuratecrystals
thatelicitanimmuneresponse.However,asingletreatmentwithuricacidortheenzymeuricasetoproducean
acuteriseinbloodlevelsofuricacidmobilizedendothelialprogenitorcellsandprotectedkidneysfromIRIthis
95
effectwasabsentwithhyperuricemia.

Kidneyinjurymolecule1(Kim1/Tim1),oneofagrowinglistofbiomarkersofAKIandCKD,isamultifunction
108
receptorproteinexpressedinproximaltubulesthatisreleasedintotheurineofpatientswithkidneydisease. In
109
additiontoimpartingphagocyticpropertiestotubuleepithelialcells, Kim1/Tim1mayinhibitdevelopmentof
108
autoimmuneresponsesandpromoteresolutionofinflammationafterkidneyinjury, thereforesuggestingitsrole
asapossibleDAMPmoleculeorreceptor.

DiabeticNephropathyandNondiabeticGlomerularDiseases

ThereisexpansiveliteratureontheinvolvementofAGEandRAGEinpodocytes,diabetes,anddiabetic
42 76 97 110 117
nephropathy. , , , Itispresumedbutnotalwaysdemonstratedthatthesemoleculesareimportantas
42 115 118 120
DAMPsbecauseoftheinvolvementofinflammationandtheimmunesystemindiabetes. , , RAGE,
functioningasanendothelialadhesionreceptor,isimplicatedinanovelpathwayforleukocyterecruitmentin
inflammatorydisordersanddiabeticmice,andthisprocessisenhancedbyS100,aproinflammatoryRAGE
121
ligand. ExperimentsusingRAGEnulloroverexpressingmice,neutralizingRAGEantibodies,orsRAGE
76 112 122
implicateRAGEinthepathophysiologyofdiabeticnephropathyandchronicinflammation. , , Indb/dbmice,
increasedRAGEandS100expressioninpodocytesassociatesbothwithrenalpathologyandwithincreased
112
infiltrationofmononuclearphagocytestoglomerulitheseeffectsareblockedbyantiRAGEantibody. Serum
RAGElevels,kidneydamage,andinflammatorymediatorsindiabeticanimalsandhumansareinverselyrelatedto
123 124 123
levelsofAGEreceptor1, , suggestinganantiinflammatoryprotectiveroleforAGEreceptor1indiabetes.
97 117
AGE,RAGE, , andotherDAMPsarealsostronglyimplicatedinthepathogenesisofnondiabeticglomerular
diseases.PodocyteinjuryandadriamycininducedglomerulosclerosisareaccompaniedbyproductionofRAGE
125
ligandsRAGEdeficientorsRAGEtreatedmiceareprotectedfromglomerularinjury. IncreasedAGEand
RAGElevels,macrophageinfiltration,fibrosis,andinflammationarefoundinthekidneysofmicethatdevelop
glomerulardiseasefromanatherogenichighfatdietthislipidinducedrenalinjuryisregulatedinpartbygalectin
126
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126
3.

TLR4isupregulatedinmousemodelsofcryoglobulinemicmembranoproliferativeglomerulonephritisand
localizestopodocytesofnephriticglomerulistimulationofpodocyteswitheitherTLR4ligandsorfibrinogen
resultsinsimilarpatternsofenhancedchemokineexpression,suggestingthatTLR4functionsasaDAMPsreceptor
127
forendogenousligandsandmaymediateglomerularinjurybystimulatinginnateimmunity. Innephrotoxic
nephritis,amodelofrapidlyprogressiveglomerulonephritis,Hsp60isreleasedfromkidneysandexcretedinurine,
128
andadministrationofHsp60exacerbatesdiseaseinaTcelldependentmanner.

ExpressionofS100proteinsincreasesinkidneysinantiThy1antibodyinducedglomerulonephritis,aratmodelof
129
mesangialproliferativeglomerulonephritis. PatientswithglomerulonephritishaveHMGB1inserum,interstitial
130
mononuclearcells,andglomeruli. TwoS100proteins,myeloidrelatedproteinsMRP8andMRP14,aredetected
inmacrophagesinrenalbiopsiesfrompatientswithglomerulonephritisthepresenceoftheseproteinsandtheir
heterodimericcomplexesinmacrophagesinfiltratingglomerulicorrelateswiththeseverityoftheacute
inflammatoryprocess,andchronicinflammationassociateswithMRP8/MRP14infiltrateswithoutcomplex
131
formationintherenalinterstitium.

Fibrosis
132 133 134
ExpressionofHsp27,phosphoHsp27, RAGE, andcalreticulin isupregulatedinananimalmodelof
tubulointerstitialfibrosis(unilateralureteralobstruction[UUO])andTGFinducedepithelialtomesenchymal
transitioninproximaltubularepithelialcellsinvitro.TheECMprotein,biglycan,increasesintubuleepithelialcells
135
4daysafterUUOandlaterininfiltratingandinterstitialcells. BiglycanisaproinflammatoryDAMPinUUO
inducedkidneyinjuryactivationoftheNLRP3inflammasomeandincreasesinlevelsofproinflammatoryIL1
57
afterUUOarereducedinbiglycannullmice. Reactiveoxygenspecies,oxidativestress,S100A4,andHsp47are
136
involvedinfibrosisafterIRI,buttheirroleinimmunefunctionhasnotbeeninvestigated.

LupusNephropathyandAutoimmuneDisease

HMGB1hasbeenlinkedtothepathogenesisofavarietyofproinflammatoryandautoimmunediseases,including
137 138 139
systemiclupuserythematosus(SLE). CirculatingHMGB1levelsincreaseinSLEpatientsandinmice, ,
140
andHMGB1maybeinvolvedinantibodyinducedkidneydamageinSLE. InlupusproneMRLFas(lpr)mice,
p38MAPKactivationinducedinfiltrationandmaturationofDCsandsecretionofHMGB1fromDCshavebeen
141
implicatedinautoimmunekidneydisease. InflammatoryandimmuneresponsesinSLE,andparticularlyinlupus
138 142
nephritis,canbeinducedbyHMGB1nucleosomecomplexes, , butnecroticnucleosomesalsocontaindouble
strandedDNA,whichhaslongbeenrecognizedasakeymediatoroflupusnephritis.Chromatinfragmentscan
participateinthepathogenesisofkidneydiseaseinSLEbystimulatingtheinnateimmunesystemandbyengaging
theadaptiveimmuneresponsetoproduceantichromatinandantidoublestrandedDNAantibodiesleadingto
glomerulardepositsofimmunecomplexes,whicharethehallmarkandlikelythecriticalinitiatingeventsinlupus
143
nephritis.

Transplantation

ThecontributionofDAMPstoIRIislikelyalsopertinentinkidneytransplantation,becausedonorkidneysare
susceptibletodelayedgraftfunctionresultingfromischemiafollowedbyreperfusion.ReleaseofDAMPs,suchas
HMGB1,ATP,uricacid,andIL1,fromallograftsmayinduceproinflammatoryeffectsandadaptiveimmune
144
responses. TLRsmediatetheeffectsofsometheseendogenousmoleculesintransplantbysignalingthroughtype
145
1interferons. Inhumankidneytransplants,increasedexpressionofTLR4andHMGB1isfoundindeceased
donorkidneys,andkidneysfrompatientswithaTLR4lossoffunctionmutationhavelowerlevelsofinflammatory
146
markersandimprovedgraftfunctionposttransplant. Moreover,TLRsandtheirendogenousligandsmaybe
importantinchronicallograftdysfunction.ExpressionofDAMPs,includingbiglycan,HSPs,fibrinogen,and
147
HMGB1,increasesintheacuteandchronicphasesafterkidneytransplantation. Kidneytransplantstomice
lackingTLR2,TLR4,ortheadaptorproteins,MyD88andTRIF,showimprovedgraftfunctionandmorphology
147
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147
anddecreasedleukocyteinfiltrationandexpressionoffibroticmarkers,cytokines,andchemokines.

HigherlevelsofS100A8andS100A9inrenalbiopsiestakenintheacutephaseaftertransplantarepredictiveof
favorablegraftoutcome(patientsthatlaterhadstablegraftfunctioncomparedwiththoseprogressingtochronic
148
allograftnephropathy) theseS100proteinsaretypicallyproinflammatory,buttheirbeneficialroleinwound
repairmaypredominateintransplantationandrejection.GlycosylationofTammHorsfallglycoproteinisaltered,
anditsvariousimmunomodulatoryfunctionsarediminishedinrenaltransplantpatientsatleastinpartbecauseof
149
alteredNFBp52nucleartranslocation.

NondiabeticChronicKidneyDisease

ManyoftheDAMPsmoleculesassociatedwithAKIarealsoimportantinCKD.IncreasedHMGB1levels
150
correlatewithproinflammatorymarkersanddecliningkidneyfunctioninCKD. Endothelialdysfunctionin
CKD,whichassociateswithelevatedserumlevelsofAGE,maybeduetoAGEinducedsuppressionof
151 152
endothelialNOS. RAGEisproinflammatoryinhemodialysispatients sRAGEandendogenoussecretory
153 154
RAGElevelsinverselycorrelatewithrenalfunctionandinflammatorystateinhemodialysispatients. ,
ElevatedTLR2expressioninpatientswithCKDandinmicewithobstructivenephropathyassociateswith
inflammationandincreasedexpressionofbiglycanandHMGB1,butTLR2maynotbenecessaryforchronic
155 72
kidneyinjury. BycontrastTammHorsfallproteinactivatesinnateandadaptiveimmunitythroughTLR4 and
71
mayplayaninflammatoryroleinprogressionofCKD. LevelsofHSPs,antiHSPantibodies,andinflammatory
156
markersarehigherinchildrenandyoungadultswithCKD.

CONCLUSIONS Goto:

Processesthatcontributetothepathogenesisofacuteandchronickidneydiseaseinvolvetheactivationofinnate
andadaptiveimmunity.Releaseofendogenousmoleculesfromdyingcellsleadstoactivationofinnateimmunity
anddownstreaminflammation.Bybridgingtoadaptiveimmunity,DAMPsalsocontributetoprogressiveinjuryor
toattenuationofinjury.Asourunderstandingofthesemoleculesandpathwaysevolves,informationonprecise
therapeutictargetswilllikelyleadtoimprovedoutcomes.

DISCLOSURES Goto:

ThisworkwassupportedinpartbygrantsfromtheNationalInstitutesofHealth(R01DK062324and
R01DK056223)andGenzyme(GRIP).

Footnotes Goto:

Publishedonlineaheadofprint.Publicationdateavailableatwww.jasn.org.

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