Association of intercellular adhesion molecule 1 (ICAM1) with diabetes and diabetic nephropathy.

1.7 MB·English

by  Gu, Harvest F.

REVIEWARTICLE
published:22January2013
doi:10.3389/fendo.2012.00179
Association of intercellular adhesion molecule 1 (ICAM1)
with diabetes and diabetic nephropathy
HarvestF.Gu1*,JunMa2,KarolinT.Gu3 andKerstinBrismar1
1M1:03RolfLuftCenterforDiabetesandEndocrinologyResearch,DepartmentofMolecularMedicineandSurgery,KarolinskaInstitutet,
KarolinskaUniversityHospital,Stockholm,Sweden
2DepartmentofAnesthesiology,AnzhenHospital,CapitalMedicalUniversity,Beijing,People’sRepublicofChina
3ViktorRydbergGymnasiumOdenplanSchool,Stockholm,Sweden
Editedby: Diabetes and diabetic nephropathy are complex diseases affected by genetic and
GabrielVirella,Universidadede environmental factors. Identification of the susceptibility genes and investigation of their
Lisboa,Portugal
rolesmayprovideusefulinformationforbetterunderstandingofthepathogenesisandfor
Reviewedby:
developing novel therapeutic approaches. Intercellular adhesion molecule 1 (ICAM1) is a
KayWaud,EasternVirginiaMedical
cell surface glycoprotein expressed on endothelial cells and leukocytes in the immune
School,USA
ShinichiOikawa,NipponMedical system. The ICAM1 gene is located on chromosome 19p13 within the linkage region
School,Japan of diabetes. In the recent years, accumulating reports have implicated that genetic
MelissaIreneMarch,BethIsrael
polymorphismsintheICAM1geneareassociatedwithdiabetesanddiabeticnephropathy.
DeaconessMedicalCenter,USA
SerumICAM1levelsindiabetespatientsandtheicam1geneexpressioninkidneytissues
*Correspondence:
ofdiabeticanimalsareincreasedcomparedtothecontrols.Therefore,ICAM1mayplaya
HarvestF.Gu,M1:03RolfLuft
CenterforDiabetesand roleinthedevelopmentofdiabetesanddiabeticnephropathy. Inthisreview, wepresent
EndocrinologyResearch,Department genomicstructure,variation,andregulationoftheICAM1gene,summarizedgeneticand
ofMolecularMedicineandSurgery,
biologicalstudiesofthisgeneindiabetesanddiabeticnephropathyanddiscussedaboutthe
KarolinskaInstitutet,Karolinska
potentialapplicationusingICAM1asabiomarkerandtargetforpredictionandtreatment
UniversityHospital,Stockholm
SE-17176,Sweden. ofdiabetesanddiabeticnephropathy.
e-mail:[email protected]
Keywords: intercellular adhesion molecule 1, diabetic nephropathy, end-stage renal disease, type 1 diabetes
mellitus,type2diabetesmellitus
INTRODUCTION Zimmet, 1998). Diabetes patients often develop macro- and/or
Diabetes mellitus is a group of metabolic diseases in which the micro-vascularcomplications.Diabeticnephropathy(DN)isone
patientshavehighbloodglucoselevels.Itsepidemichasbecome ofseriouscomplicationsandoccursin30–40%ofdiabeticpatients
a national and global crisis. Based upon the figures today, at (Heerspink and de Zeeuw, 2011; Marshall, 2012). This diabetic
least 366 million people at the worldwide have diabetes. By the complication is characterized by pathophysiological changes in
year 2030, this number is expected to be double (Bonow and glomerular hyperfiltration, renal hypertrophy, tubular function
Gheorghiade,2004; Wild etal.,2004; Cornell and Dorsey,2012; and then progress to proteinuria and reduction of glomerular
Lam and LeRoith, 2012). There are two major types of dia- filtrationrate(GFR).ThepatientswithDNexhibitpersistentpro-
betes. Type1diabetes(T1D),previouslycalledjuvenilediabetes teinuria, hypertension, declining renal function, and increased
orinsulin-dependentdiabetes, developsonthebasisof autoim- prematuremortalitylargelyasaresultof cardiovasculardisease.
mune destruction of pancreatic β-cells, which results in insulin DNisthemostcommonsinglecauseof end-stagerenaldisease
deficiency. It mostly affects young people (<20 years old) but (ESRD).OnceovertDNoccurs,itprogressesslowlyorrapidlyto
occurs also in adults (Lightfoot etal., 2012). Type 2 diabetes the most advanced stage of chronic kidney disease which needs
(T2D) is the most common form of diabetes and accounts for dialysisortransplantationtreatment(Marshall,2004;Shieldsand
approximately 85–90% of all diabetic patients. In T2D, hyper- Maxwell,2010;Weiletal.,2010;ThomasandGroop,2011).The
glycemiaresultsfromacombinationofimpairedinsulinsecretion treatmentcostfordiabetespatientshasbeenincreasingstagger-
andinsulinresistance.Whenthepancreaticβ-cellsloosetheabil- ing in the recent decades and becomes a further burden of the
ity to compensate for insulin resistance in liver, skeletal muscle, healthcaresystem. DiabetesandDNaremulti-factorialdiseases,
andadiposetissues,hyperglycemiabecomesmanifest(Albertiand whichareinfluencedbybothgeneticandenvironmentalfactors
(Satkoetal.,2005;Pitkäniemietal.,2007;AshcroftandRorsman,
2012;Gonzalez-BulnesandOvilo,2012;Morahan,2012).There-
Abbreviations: ACR,urinaryalbumin/creatinineratio; AER,albuminexcretion
fore, identificationof thesusceptibilitygenesindevelopmentof
rate;CD54,clusterofdifferentiation54;DN,diabeticnephropathy;ESRD,end-stage
renaldisease;GFR,glomerularfiltrationrate;GoKinD,GeneticsofKidneysinDia- diabetesanddiabeticcomplicationsandinvestigationoftheirroles
betes;HDL,high-densitylipoprotein;HWE,Hardy–Weinbergequilibrium;ICAM1, areofimportancetoprovideusefulinformationforimprovement
intercellularadhesionmolecule1; LD,linkagedisequilibrium; LDL,low-density ofthepreventionandmedicationprograms.
lipoprotein; LFA, leukocyte adhesion protein; SNP, single-nucleotide polymor-
Intercellular adhesion molecule 1 (ICAM1, OMIM: 147840)
phism; T1DM,type1diabetesmellitus; T2DM,type2diabetesmellitus; UTR,
un-translationregion. is a cell surface glycoprotein and expressed in endothelial cells
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and leukocytes in the immune system. This endothelial- and andenvironments(Newmanetal.,1990).Interestingly,thereare
leukocyte-associatedtransmembraneproteinhasbeenknownfor severaltranscriptionbindingproteinsincludingNF-kappaB,NF-
itsimportanceinstabilizingcell–cellinteractionsandfacilitating kappaB1, STAT3, δCREB, STAT1, STAT1α, and STAT1β, which
leukocyte endothelial transmigration. Recently, the accumulat- mayup-regulatetheICAM1geneactivity(RoebuckandFinnegan,
ing reports from genetic studies in diabetic patients with and 1999).MicroRNA(miR-221)maydown-regulatethegeneexpres-
(cid:2)
without DN and from biological studies with diabetic animal sion in the region of 3-UTR of ICAM1 (Gong etal., 2011).
models have implicated that ICAM1 may play a role in the There are CpG islands for methylation in the promoter of the
pathogenesis of diabetes and DN. In this review, we will sum- ICAM1gene.Astudyintumorendothelialcellshasdemonstrated
marize the genetic and pathophysiological relevance of ICAM1 that the ICAM1 gene activity can be epigenetically silenced by
and discuss about the possible role of ICAM1 in the develop- promoter histone modifications (Hellebrekers etal., 2006). All
mentofdiabetesandDNaswellastheperspectivesoftheICAM1 regulatoryfactorsareofimportancetocontroltheICAM1activ-
research. itiesinimmune-relatedprocesses.Ourresearchhasbeenfocused
on investigating whether alterations in the ICAM1 gene struc-
GENOMICDNASTRUCTURE,mRNAANDPROTEINOFICAM1 tureandfunctionareassociatedwiththedevelopmentofdiabetes
The ICAM1 gene (GeneID: 3383) is located in chromosome andDN.
19p13.2 and spans 15,775 base pairs (bp) along the short arm
of this chromosome (10,381,517–10,397,291 bp from pter). Its LINKAGEOFTHEICAM1GENETODIABETESANDDIABETIC
aliasesincludeclusterof differentiation54(CD54)andcellsur- NEPHROPATHY
face glycoprotein P3.58 (BB2). Figure 1 demonstrates genomic Diabetes and DN are multi-factorial diseases, which are influ-
structure,regulation,andvariationoftheICAM1gene.Thereare enced by both genetic and environmental factors. To search for
sevenexonsandsixintronsintheICAM1gene.Arelativelylarge thesusceptibilitygenesforthediseases,genome-widescanlinkage
(cid:2)
un-translationregion(UTRs)residesrespectivelyatboth5 and analysishasbeenused.Thisisafamily-basedapproachtoinves-
(cid:2)
3-sequencesofthegene,whilethetranslationstartpointislocated tigateif thegeneticmarkerssuchasmicrosatellitesorSNPsthat
inexon1.Fromthe2–6exon,thereisonenon-synonymoussingle- spanthewholegenomeandco-segregatewithdiseasephenotypes.
nucleotidepolymorphism(SNP)each,bywhichtheaminoacid Microsatellitesaresimplerepeatsof1–6bpingenomeand(CA)n
changes of ICAM1 protein are caused. ICAM1 is a transmem- is the most common form. A total of ∼30,000 microsatellites
branceglycoproteinmoleculeoftheimmunoglobulinsuperfamily presenthighlevelsofinter-andintra-specificpolymorphismsand
andcharacterizedbyfivedistinctimmunoglobulin-likedomains, distributeinwholegenome(ofteninintergenicDNAregionsand
atransmembrancedomainandacytoplasmictail(vandeStolpe rarelyinthesequencesof thegenes). SNPsarethesubstitutions
andvanderSaag,1996).ICAM1proteinis505aminoacidsinthe of nucleotides in genomic DNA. In general speaking, bi-allelic
length,themoleculeweightsbetween80and114kDadepending SNPsarethemostcommontype.Tri-alleliconesandsmallinser-
upon the levels of glycosylation, which varies among cell types tions/deletionsarealsoincluded. C/TisthemostcommonSNP
FIGURE1|GenomicDNAstructure,variation,andregulationofthe epigeneticallysilencebyhistonemodificationsaswellastranscriptionbinding
ICAM1gene.TheICAM1geneisconsistedofsevenexonsandsixintrons. sitesfortheproteins,includingNF-kappaB,NF-kappaB1,STAT3,δCREB,
Thereareseveralnon-synonymousSNPs,whichresideoneeachinexons STAT1,STAT1α,andSTAT1β.Inaddition,microRNA(miR-221)intheregionof
2–6.Inthegenepromoter,thereareCpGislandsformethylationand 3(cid:2)-UTRmaydown-regulatetheICAM1geneexpression.
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in the human genome. SNPs reside in the coding region of the ASSOCIATIONOFTHEICAM1GENETICPOLYMORPHISMS
genes are called cSNPs, which include non-synonymous SNPs WITHDIABETESANDDIABETICNEPHROPATHY
(withaminoacidchanges)andsynonymousSNPs(withoutamino Severalresearchgroupsincludingourshavereportedthegenetic
acidchanges).MostofSNPsarelocatedinnon-codingregionsof association studies of the ICAM1 gene in T1DM and DN. Guja
the genes, including promoter, intron, and UTRs. SNPs in the etal.(1999)reportedthatthetransmissionoftheGalleleofSNP
promoterregionmayaltertranscriptionbindingsiteandthereby K469E(A/G)isincreasedinRomanianT1DMfamilies.Oneyear
affectthetranscriptionalactivityofthegene.Moreover,anumber later, Nishimura etal. (2000) replicated that this K469E poly-
ofSNPsarefoundininter-genicsequences.Uptodate,morethan morphism is associated with adult-onset T1DM in a Japanese
40millionSNPsarerecordedinthepublicSNPdatabases,which population. However, the association of K469E polymorphism
arefreelyavailableforresearchuse.Usingthegeneticmarkers,the intheICAM1genewithT1DMwasnotfoundinDanish,Finnish,
linkageanalysisallowsustoidentifythegenomethatistransmit- and British Caucasian (Nejentsev etal., 2000). Furthermore,
tedwithinfamiliesalongwiththediseasephenotypesof interest Nejentsev etal. (2003) demonstrated that another synonymous
atagenome-widescale. Basedonfindingastatisticalsignal,the SNP G241R in the ICAM1 gene was associated with T1DM.All
probability of co-segregation of a disease with a chromosomal these previous studies were designed for analysis of one or two
locusisgiven(Gulcher,2012).Inthisapproachofgenome-wide SNP(s). In order to ascertain whether the ICAM1 genetic poly-
scan, highlypolymorphicgeneticmarkersdistributedacrossthe morphisms are associated with T1DM and DN, we conducted
genomearegenotypedinlargefamilypedigreesorinaffectedand thecomprehensivegeneticassociationstudies.ThestudiedSNPs
discordantsiblingpairs. includingK469EandG241Rwereselectedbasedupontheinfor-
Byusingtheapproachofgenome-widescanandlinkageanal- mation of their position in the ICAM1 gene and their linkage
yses, several chromosomal regions including 19p13 have been disequilibrium (LD) values in the HapMap. Our data from sin-
predictedtolinkwithdiabetesandDN.Meinetal.(1998)havepre- glemarkerassociationanalysesindicatedthatK469Eandanother
viouslyconductedgenomewidescananalysisin93affectedsibpair intronic polymorphism (rs281432) were significantly associated
familiesand263multiplexfamiliesfromtheUKandindicatedthat withT1DMinSwedishCaucasians(Maetal.,2006).Interestingly,
lociinchromosome19p13arelinkedtoT1DM.Lateron,thelink- these two SNPs are located in intron 2 and exon 6, respectively.
ageofT1DMtochromosome19p13isreplicatedbythestudywith According to the data of pair-wise LD values for SNPs in the
2658affectedsib-pairsinUSA(Concannonetal.,2009).Interest- ICAM1gene,arelativelystrongLD(/D(cid:2)/≥0.7)existedtoextend
(cid:2)
ingly, lipid-related traits such total cholesterol, triglycerides and overtheregionbetweenthesetwoSNPs.Duetothelarge5-and
(cid:2)
low-densitylipoprotein(LDL)concentrationsinT2DMarelinked 3-UTRsinexons1and7,theLDblockcoversalmostthewhole
to chromosome 19p13 and this finding has been replicated in codingregionof thegene. Furthermultiplexmarkerassociation
Caucasians,African-AmericanandHispanicfamilies(Imperatore analysis was done and the common haplotype C-A constructed
etal.,2000; Adeyemo etal.,2005; Malhotra andWolford,2005). byCallelefromK469EandAallelefromrs281432wasfoundto
Several interesting candidate genes, including insulin receptor, beassociatedwithT1D(Maetal.,2006).Lateron,wefoundthat
resistin and ICAM1, are involved in the region of chromosome K469EpolymorphismintheICAM1isassociatedwithDNinT1D
19p13.ThelinkageofLDLconcentrationstochromosome19p13 patientsofAmericansofEuropeandescentandselectedfromthe
has been replicated in the study with 612 individuals from 28 GeneticofKidneyDiseasesinDiabetes(GoKinD)study(Mueller
Amish families in USA (Pollin etal., 2004). Furthermore, Leon etal., 2006). However, no association of G241R in the ICAM1
etal. (2007) have performed a genome-wide scan study in 1251 gene with T1DM and DN in Swedish and GoKinD populations
African Americans (AA) and 1129 European Americans (EA) wasfound(Maetal.,2008).InpatientswithT2D,theK469Epoly-
hypertensivesiblingsfromtheHypertensionGeneticEpidemiol- morphismintheICAM1genewasfoundtoassociatewithplasma
ogyNetworkstudyandindicatedthatlociinchromosome19pare fibrinogenlevelsanddiabeticretinopathy(Kamiuchietal.,2002;
linkedwithalbumintocreatinineratio(ACR)whenbothAAand Yokoyamaetal.,2005;Liuetal.,2006;Petrovicetal.,2008;Vinita
EA subjects are combined in the analyses. Particularly, Kathire- etal.,2012).Uptodate,thereis,however,noreportregardingthe
sanetal.(2008)haveanalyzedthegenome-widescandatafrom associationofICAM1geneticpolymorphismwithDNinT2D.
threestudiesincluding8816T2Dsubjectsandfoundsixnewloci Interestingly, we have observed that genotype distribution of
associatedwithLDL,cholesterol,HDL,andtriglycerides.Oneof K469E polymorphism in the ICAM1 gene presents a high het-
the loci is located in chromosome 19p13. Previously, Arya etal. erozygous index (∼50%; Ma etal., 2006). Figure 2 represents
(2006) have conducted a genome-wide scan and linkage study thegenotypedistributionoftheICAM1E469Kpolymorphismin
and suggested that loci in both chromosomal arms of 19p13.2 Swedishnon-diabeticcontrolsubjects,T1Dpatientswithoutand
and 19q13.4 may be linked to birth weight in T2D families of with DN. From non-diabetic control subjects, to T1D patients
both Mexican Americans and EA. By the analyses of the com- withoutDNandthepatientswithDN,thefrequenciesofthecar-
binedmetabolicsyndromeandechocardiographicfactors,Kraja rierswithheterozygousgenotypeareincreased,whilethecarriers
etal. (2008) have found the linkage of blood pressure in T2D with469Ehomozygousgenotypedecreased.Inordertoavoidthe
patientsofAAandEAwiththeregionchromosome19p13.Tak- possibilitythathighheterozygousindexmaybecausedbygeno-
ing together with the information from above briefly described typingerrors,weconfirmedthegenotypingexperimentswithtwo
genome-wide scan studies, it is clear that there are the loci in differenttechniquessuchasdynamicallele-specifichybridization
chromosome 19p may confer the susceptibility risk to diabetes (DASH)andpyrosequencing(Ronaghietal.,1998;Howelletal.,
andDN. 1999). In the human genome, there are segmental duplications
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FIGURE2|GenotypedistributionoftheICAM1K469E anddarkforE469E.Obviously,theheterozygousindexishigh
polymorphism.ThegenotypedistributionoftheICAM1K469E comparedtothepercentageofhomozygousandincreasedfrom
polymorphismisrepresentedfromageneticassociationstudyinSwedish thegroupofnon-diabeticcontrolsubjects,totype1diabetes(T1D)
population(Maetal.,2006).ThreegenotypesoftheICAM1K469E patientswithoutdiabeticnephropathyandthepatientswithdiabetic
polymorphismareshowninaslightgraycolorforK469K,grayforK469E, nephropathy.
(duplicons) with >90% sequence similarity between the copies, and van der Saag,1996), but is targeted to two integrins of the
which may cause specific allelic and genotypic diversities, such β2subunitfamily,i.e.,leukocyteadhesionprotein-1(LFA-1)and
as high heterozygous index in complex diseases (Venter etal., Mac-1 (integrin, alpha M; Janeway, 2001). Thus, based upon
2001;ShawandLupski,2004).ToascertainwhetherK469ESNP the interaction with these two molecules, ICAM1 has a role for
is involved in a duplicon, we further performed a cloning and two important immune-related functions: T lymphocytes acti-
sequencinganalysisandfoundthatnoduplicationresidesinthe vation and leukocyte–endothelial cell interaction. The role of
generegion(Maetal.,2006).K469Eisanon-synonymousSNPin ICAM1inthedevelopmentofdiabetesandDNhasnotbeenfully
exon6oftheICAM1gene,whichcausestheaminoacidchanges explored.Recentstudies,however,haveprovidedtheinformation
of the ICAM1 protein. We have submitted ICAM1 amino acid topredictthatICAM1isinvolvedinthepathogenesisofdiabetes
sequences with K469 and 469E alleles respectively into SWISS- andDN(Sahakyanetal.,2010a,b).
MODEL (Peitsch, 1995; Arnold etal., 2006) to understand the Diabeticnephropathyisaprogressdisease,whichiscategorized
changes of ICAM1 protein. There are 532 amino acids in the intostagesbaseduponurinaryalbuminexcretion(UAE)values.
proteinsequenceofICAM1,K469iswild-typeandhas100%iden- Theearlyphase,whichcanbereversed,ismicroalbuminuria.The
tifiedhomology.ComparedtotheDIMERimageofwildICAM1 reductionofrenalfunctionbeginswithproteinuria.Clinicalinves-
protein, however, the structure of ICAM with mutant 469E is tigation has demonstrated that soluble ICAM1 levels in stored
significantlychanged.Althoughthemodelinganalysisimplicates blood samples from T1D patients are higher compared to non-
thattheK469EpolymorphismintheICAM1genemayhavefunc- diabeticcontrolsubjects.HighICAM1levelsinT1Dpatientsare
tionaleffect,furtherinvestigationwithtransfectionof469Eallele associatedwitharelativeriskof1.67(95CI0.96–2.92,P=0.03)
into cells such human embryonic kidney (HEK) 293A or with of developingincidentsustainedmicroalbuminuriaafteradjust-
icam1 knock-out mouse model is necessary in order to further mentforbaselineage,sex,durationofdiabetes,andrandomized
understandthepathogenicmechanism. treatmentassignment(Linetal.,2008).Furthermore,Astrupetal.
(2008)havereportedthatsolubleICAM1levelsareassociatedwith
POSSIBLEROLEOFICAM1INDEVELOPMENTOFDIABETES all-causedmortalityandcardiovascularmorbidityinT1Dpatients
ANDDIABETICNEPHROPATHY withDN.ThesimilarfindingshavebeenobservedinT2Dpatients.
Ingeneralspeaking, ICAM1proteinsactasligandsandthepri- Soluble ICAM1 levels are significantly correlated with albumin-
maryreceptorsforICAM1areintegrins,whichmediatecell–cell uria in T2D patients (Rubio-Guerra etal., 2007). T2D patients
interactions and allow signal transduction. Specifically, ICAM1, with diabetic micro-angiopathic complications have higher sol-
unlikemostintegrin-bindingproteins,doesnotcontainanRGD uble ICAM1 levels in comparison with diabetic group without
(Arg-Gly-Asp)motiftopromoteintegrinbinding(vandeStolpe micro-angiopathic complications and healthy control subjects
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(MastejandAdamiec,2008).Thefindingsfromclinicalinvestiga- A biomarker can be used as an indicator of a particular disease
tionshavebeensupportedbystudieswithdiabeticanimalmodels statesuchasdiabetesandDN(CaveneyandCohen,2011).Cur-
such as the db/db mice and streptozotocin-induced rats. Com- rently,thebiomarkerusedforpredictionanddiagnosisofDNis
pared to non-diabetic rats, serum and urinary ICAM1 levels in UAE. This biomarker, however, is less valuable for early predic-
streptozotocin-inducedratsarefoundtobeincreased,whichare tion and diagnosis of DN. Therefore, researchers have searched
parallelwiththeelevationofUAE(Qianetal.,2008).Furthermore, for novel biomarkers of DN in order to improve the diagnosis
evidencehasindicatedthatICAM1isoverexpressedinglomeruli approachandpreventionprogram(Hellemonsetal.,2012).Aswe
diabeticrats(Watanabeetal.,2011)andintubularepithelialcells described above, genetic and biological studies have implicated
of kidney in T2D db/db mice (Kosugi etal., 2009). Therefore, thatICAM1playsaroleinthedevelopmentofdiabetesandDN.
ICAM1mayplayaroleinthedevelopmentof diabetesDNand First,theICAM1geneislocatedinalinkageregionwithdiabetes
possiblemechanismisshowninFigure3.Inadiabeticcondition and DN. Second, the K469E polymorphism in the ICAM1 gene
withhyperglycemia,theICAM1genetranscriptioninthenuclei is associated with diabetes and DN. Third, serum ICAM1 levels
is increased and the ICAM1 gene expression on the surface of aregraduallyincreasedfromlowlevelsinnormalalbuminuriato
endothelium cells is up-regulated. ICAM1 binding activity with highlevelsinmicro-albuminuriaandtoevenhigherlevelsinpro-
LFA-1isincreasedandmorelymphocytesfrombloodaretrans- teinuria.Therefore,weconcludedthatICAM1isassociatedwith
ferredintocellsinglomeruliandperitubularcapillariesofnephron diabetesandDN.Thismoleculeismostlikelyausefulbiomarker
inkidney. Consequently,injureof kidneyglomeruliandtubular forpredictionofendothelialdysfunctionindiabetesandDN.Fur-
occursandtheproteinsareexcretedtourine.Inthisfigure,how- therevaluationofICAM1asabiomarkerinalargecohortofT1D
ever,twoquestionsstillremain.First,howisICAM1geneactivity andT2DpatientswithandwithoutDNneedstobedone.
stimulatedbyhighbloodglucoselevels?Second,howdoesICAM1
elevationcausekidneytubularandglomeruliinjury? ICAM1ASATARGETFORDRUGDEVELOPMENT
ICAM1 is a molecule involved in many pathways including
ICAM1ASABIOMARKERSFORPREDICTIONOFDIABETIC anti-inflammation. Although the picture of ICAM1 involve-
NEPHROPATHY ment and interaction is complex, experiments have indicated
Biomarkersaresubstancesandstructuresthatcanbemeasuredin that inhibition of the ICAM1 gene expression may improve the
biologicalsamplessuchasurine,blood,saliva,DNA,andprotein. progressofdiabetesandDN.Glucagon-likepeptide-1(GLP-1)has
FIGURE3|PossibleroleofICAM1inthedevelopmentofdiabetic (LFA-1)isincreasedandmorelymphocytesfrombloodaretransferred
nephropathy.Underadiabeticconditionwithhyperglycemia,the intocellsofglomeruliandperitubularcapillariesofnephroninkidney.
ICAM1genetranscriptioninthenucleiisincreasedandtheICAM1 Consequently,serumICAM1levelsareincreased.Injuryinkidney
geneexpressiononthesurfaceofendotheliumcellsisup-regulated. glomeruliandtubularisoccurredandtheproteinsarereleasedto
ICAM1proteinbindingactivitywithleukocyteadhesionprotein-1 urine.
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various extra-pancreatic actions, in addition to its enhance- SUMMARYANDPERSPECTIVES
ment of insulin secretion from pancreatic islets. Kodera etal. WehavedescribedgeneticandbiologicalstudiesofICAM1india-
(2011)havedemonstratedthatGLP-1receptoragonist,exendin-4, betesandDN.DataimplicatethatICAM1canbeusedabiomarker
decreasestheICAM1geneexpressionandamelioratesalbumin- forpredictionofdiabetesandDNandmayalsobeservicedasatar-
uria, glomerular hyperfiltration, glomerular hypertrophy, and getfordrugdevelopment.Toreachthesetwoobjectives,however,
mesangial matrix expansion in the diabetic rats without chang- weneedtocontinuouslyputeffortsintothestudyof ICAM1in
ing blood pressure or body weight. Furthermore, Matsui etal. diabetesresearch.First,geneticpolymorphismsintheICAM1gene
(2010)havereportedthatnifedipine,acalcium-channelblocker, areassociatedwithT1D,T2DandDNinT1D.But,nogeneticasso-
blockstheadvancedglycationendproduct(AGE)-inducedtubu- ciationwithDNinT2Dhasbeenreported.Althoughitisknown
lar damage and also inhibits ICAM1 gene activity in tubular thatmethylationmodificationofgenomicDNAsandhistonepro-
cells, which may have benefits in treatment of DN. Liu etal. teinsisinvolvedintheregulationofICAM1geneexpression,no
(2010) have suggested that berberine can ameliorate renal dys- epigeneticstudyof thisgeneindiabetesandDNhasbeendone.
function in diabetic rats by decreasing ICAM1 gene expression Second,clinicalobservationsindiabetespatientsandexperimen-
and nuclear factor-kappa B (NF-kappaB) activation. Taking tal studies with diabetic animal models have demonstrated that
together, the data from these studies suggest that ICAM1 may elevationofserumICAM1levelsandoverexpressionofthegene
be a good candidate as target for drug development. Inhibition inkidneytissues. Inhibitionof ICAM1geneactivitywithagents
of ICAM1 gene activity may benefit in treatment of diabetes mayimprovethekidneyfunction,suggestingthatICAM1maybe
andDN. atargetfordrugdevelopmentintreatmentofdiabetesandDN.
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