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RESEARCHARTICLE
Year:2016|Volume:48|Issue:5|Page:544549

Therapeuticinsightintomolsidomine,anitricoxidedonorinstreptozotocininduceddiabetic
nephropathyinrats
NathaniMinaz,RemaRazdan
DepartmentofPharmacology,AlAmeenCollegeofPharmacy,Bengaluru560027,
Karnataka,India
DateofSubmission
DateofAcceptance
DateofWeb
Publication

03Jun2016
04Aug
2016
16Sep2016

CorrespondenceAddress:
NathaniMinaz
DepartmentofPharmacology,AlAmeenCollegeofPharmacy,Bengaluru560027,
Karnataka
India
SourceofSupport:None,ConflictofInterest:None

DOI:10.4103/02537613.190744

Abstract

Background:Diabetesinducedoxidativestressandhypertensionplayamajorroleinthe
developmentofnephropathy.Hence,thepresentstudywasundertakentoevaluatethe
protectiveeffectsofmolsidomine,anitricoxidedonorinstreptozotocin(STZ)induced
diabeticnephropathy(DN)inrats.
MaterialsandMethods:Type1diabeteswasinducedthroughasingledoseofSTZ(52
mg/kg,i.p.)inmaleWistarratsandthentreatedwithmolsidomine(5and10mg/kgp.o.)for8
weeks.Physicalparameters,vitalandrenalfunctiontestincludingbloodglucose,albuminuria,
bloodurinenitrogen,serumcreatinine,andkidneyindexweredetermined.Oxidativestress
andlipidperoxidationwereassessedinthekidneyhomogenatebymeansofantioxidant
enzymesandmalondialdehydelevels.
Results:DNratsexhibitedasignificantrenaldysfunctionwithareductioninbodyweight,
excessiveoxidativestress,andpathologicalchanges.Molsidominetreatmentsignificantly
improvedvitalsign,renalfunctions,andoxidativestressinDNratsinadosedependent
manner.Theprotectiveeffectofmolsidominewasalsosubstantiatedbypathologicalchanges
inthearchitectofthekidney.

Conclusion:MolsidomineshowsasignificantbeneficialeffectinType1DNinrats.

Keywords:Albuminuria,molsidomine,nitricoxide,oxidativestress
Howtocitethisarticle:
MinazN,RazdanR.Therapeuticinsightintomolsidomine,anitricoxidedonorin
streptozotocininduceddiabeticnephropathyinrats.IndianJPharmacol201648:5449
HowtocitethisURL:
MinazN,RazdanR.Therapeuticinsightintomolsidomine,anitricoxidedonorin
streptozotocininduceddiabeticnephropathyinrats.IndianJPharmacol[serialonline]2016
[cited2016Dec8]48:5449.Availablefrom:http://www.ijponline.com/text.asp?
2016/48/5/544/190744
Diabetesrelatedmorbidityandmortalityareaccountedforitscomplicationssuchas
nephropathy,neuropathy,andretinopathy.Chronichyperglycemiaistherootcauseforunique
changesinrenalstructure.Itisoneoftheleadingcausesofendstagerenaldisease.
Approximately,40%ofdiabeticpatientsdiagnosedwithnephropathyeitherrequirekidney
dialysisortransplantation.Diabeticnephropathy(DN)ischaracterizedbymicroalbuminuria,
renalhypertrophy,andmesangialexpansionwithglomerularbasementmembranethickening.
[1]Hypertension,smoking,anddyslipidemiaarethemajorcontributorsfortheprogressionof
nephropathy.AspertheUKProspectiveDiabetesStudy,tightcontrolonsystolicblood
pressure(SBP)lessenedtheriskforthedevelopmentofmicroalbuminuria.[2]
Streptozotocin(STZ)destroysthebetacellsofthepancreaswhichleadstohyperglycemia.
Themechanismforitscellinjuryisassociatedwiththegenerationofreactiveoxygenspecies
(ROS)andoxidativestress.[3]AnSTZinducedrodentmodelofType1diabetesdevelops
renalinjurywhichresemblestohumanDN.[4]Itisavaluableandbroadlyacceptedmodelfor
interpretationoftherapeuticinterventionsinpreclinicaldiabeticrenalinjury.
Nitricoxide(NO),apotentendogenousvasodilator,hasaroleinmaintainingsystemicblood
pressureandrenalfunctions.BasalproductionofNOiscrucialfortheroutineglomerular
functions.[5]Itsbioactivityisreducedbysuperoxide,amajorROS.[6]Reductionof
antioxidantenzymesindiabetesresultsinoverproductionofROSwhichconvertsNOinto
peroxynitriteandproducesnitrosativestress.Iqbaletal.haveshownthatexogenousNOdonor
administration,preventstheoxidativestress,andrestorestherenalfunctions.[7]
Molsidomine,anNOdonor,hasantioxidantandvasodilatoreffects.Itisusedforthetreatment
ofstableangina.Molsidominerelaxesvascularsmoothmusclebystimulatingguanylate
cyclase.[8]ThepurposeofthepresentstudywastoinvestigatewhetherNOdonorcan
attenuateDNinSTZinduceddiabeticrats.
MaterialsandMethods

ChemicalsandReagents
MolsidominewasprocuredasagiftsamplefromTajPharmaceutical,Mumbai,withquality
controlreport.STZwaspurchasedfromtheMPBiomedicalIndiaPvt.Ltd.Thekitsusedfor
biochemicalanalysiswereprocuredfromtheAutospandiagnostic,Surat,India.Other
chemicalsandreagentsusedwereofanalyticalgrade.
Animals
Healthyweightmatched(250300g)maleWistarratswereselectedandhousedin
polypropylenecageslayeredwithhuskandkeptfor12hlight/12hindarkcyclewithfree
accesstowaterandstandardpelletdiet.Theuseofexperimentalanimalswasapprovedbythe
InstitutionalAnimalEthicalCommitteeofAlAmeenCollegeofPharmacy(ApprovalNo:
AACP/IAEC/Aug2014/01).TheexperimentwasconductedaccordingtotheCPCSEA
guidelines.
InductionofDiabetesandExperimentalDesign

InductionofDiabetesandExperimentalDesign
Type1diabeteswasinducedbyasingleintraperitonealinjectionofSTZ(52mg/kg)infreshly
preparedcitratebuffer(0.1M,pH4.5).[9]Ratsweregiven5%w/vglucosesolutionfor48h
topreventhypoglycemiainducedmortality.Aweeklater,theratswithfastingbloodglucose
(FBG)values230mg/dLwereconsideredtobediabeticandusedinthestudy.Total24
Wistarratswererandomlydividedintofourgroupsofsixanimalseach.
GroupIservedasnormalcontrol.
GroupIIservedasDNcontrol.
GroupIIIandIVservedasatestgroup,(diabeticratswereadministeredmolsidomine[5
and10mg/kg,p.o.]for8weeks).

Dosesofmolsidominewerechosenbasedonthepreviousstudyinwhichithasshownthe
nephroprotectiveeffectanddidnotproduceanysideeffects.[10]
MeasurementofPhysicalParameter
Theanimalsweremonitoredforphysicalparameterssuchasbodyweight(BW),weakness,
andmortalitythroughoutthestudy.BWwasmeasuredbeforeinductionofdiabetesandatthe
8thweekusingdigitalbalance(EssaeDS252).Percentagechangewascalculatedfromthe
BWofbeginningandattheendofthestudy.
MeasurementofVitalSigns
ProgressionofDNisstronglyassociatedwithhypertension.Hence,SBPwasmeasuredatthe
8thweekofthestudybytailcuffmethod.[11],[12]Eachmeasurementwasrepeated56times
andvalues,notdifferentbymorethan3mmHg,wereconsideredvalid.Themeanofthethree
measurementswasthenrecordedandreportedasthevalueofSBPforeachanimal.
MeasurementofRenalFunction
Onthe8thweek,anindividualratfromeachgroupwasplacedinmetaboliccagesfor24hto
collecturinewithfreeaccesstofoodandwaterurinevolume(ml/24h)wasmeasured.
Urinaryalbuminlevelsweredetectedusingassaykitsbyautoanalyzeraccordingtothemanual
providedbythemanufacturer.Urinaryalbuminexcretionrate(UAER),anindicationof
albuminuria,wascalculatedbytheformula,UAER(mg/24h)=24hurinevolumeurinary
albumin(mg/dl).Overnightfastedanimalswereanesthetizedbloodwaswithdrawnthrough
retroorbitalandcollectedinclotactivatorVacutainerthencentrifugedat3000RPMfor10
mintoseparatetheserum.FBG,bloodurinenitrogen,andserumcreatinine(Scr)were
determinedbyautoanalyzer.Allkitswereusedinaccordancewithmanufacturerinstructions.
Then,animalsweresacrificed,andtheirkidneyswereisolatedandweighed.Thekidneyindex
wascalculatedas100kidneyweight/BW.Rightkidneyswereusedforhomogenate
preparationandleftkidneyswerestoredinformalinforhistopathologystudy.
MeasurementofOxidativeStress
Kidneyswerewashedwithsaline,choppedonice,andhomogenate(10%,w/v)wasprepared
with0.1Mphosphatebufferandcentrifugedat3000gfor10minat4CusingSorvall
refrigeratedcentrifugeandsupernatantwasusedforbiochemicalestimations.
Lipidperoxidationormalondialdehyde(MDA)formationwasdeterminedbythemethodof
SlaterandSawyer.[13]Catalase(CAT)activitywasdetectedbythemethodofAebi's
description[14]andglutathione(GSH)wasdeterminedbythemethodofMoronetal.[15]
superoxidedismutase(SOD)wasdeterminedbythemethodofMisraandFridovich.[16]
Histopathology
Paraffinembeddedspecimenswerecutinto5mthicksectionsandstainedwithhematoxylin
andeosin.Thesectionswereexaminedunderalightmicroscopeforthepresenceof
pathologicalchangesandphotomicrographsweretaken.Thepathologistwasblindedtothe
animaltreatmentgroup.
StatisticalAnalysis

Valuesareexpressedasmeanstandarderrorofmean(SEM).Statisticalsignificancewith
respecttoDNcontrolwasevaluatedusingonewayANOVAfollowedbyTukey'sttestusing
GraphPadPrismsoftware(Version5.0,GraphPadPrismSoftwareInc.,SanDiego,CA).
Results

EffectofMolsidomineonPhysicalParameter
Inthepresentstudy,therewasacontinuousreductioninBWofDNratsthroughoutthestudy,
whiletherewasagainintheBWofnormalrats.Atthe8thweek,thepercentagechangein
BWofdiabeticandnormalratswas53.28and3.97,respectively.Treatmentwith
molsidominesignificantly(P<0.001)preventedthepercentagechangeinBWdose
dependentlycomparedtodiabeticrats.MolsidominepreventedthediabeticratsfromvastBW
loss[Table1].
Table1:Effectofmolsidomineoninbodyweight,kidney
index,andrenalfunctionrelatedparametersinrats
Clickheretoview

EffectofMolsidomineonVitalFunction
Atthe8thweek,SBPofDNratswas30mmHghigherthanthatofthenormalcontrolrats.
Molsidominetreatedratssignificantly(P<0.001)reducedtheelevatedbloodpressurelevel
dosedependentlycomparedtodiabeticrats[Figure1].
Figure1:Effectofmolsidomineonsystolicbloodpressure
(mmHg)inrats.NCNormalcontrol,DNC=Diabetic
nephropathycontrol,MOL5=Molsidomine(5mg/kg),
MOL10=Molsidomine(10mg/kg).Valuesarerepresented
asmeanstandarderrorofthemean(n=6).***P<0.001
versusdiabeticnephropathycontrolgroup
Clickheretoview

EffectofMolsidomineonRenalFunctions
TheFBGlevelintheDNcontrolratswas330mg/dL,nearly3timeshighercomparedto
normalcontrolrats.Bycontrast,molsidominetreatedratssignificantlydecreasedtheelevated
fastingserumglucoselevel(P<0.001)comparedtodiabeticrats[Figure2].
Figure2:Effectofmolsidomine(5and10mg/kg,p.o.)on
fastingbloodglucoselevelinrats.(mg/dl).NC=Normal
control,DNC=Diabeticnephropathycontrol,MOL5=
Molsidomine(5mg/kg),MOL10=Molsidomine(10mg/kg).
Valuesarerepresentedasmeanstandarderrorofthemean
(n=6).**P<0.01,***P<0.001versusdiabetic
nephropathycontrolgroup
Clickheretoview

InDNrats,allmentionedrenalparametersweresignificantly(P<0.001)increasedcompared
tonormalcontrolrats,showingthatdiabeticratswereprogressingtonephropathy.Asdepicted
in[Table1],treatmentwithmolsidominepreventeddiabetesinducedrenalabnormality
comparedtodiabeticcontrolratsindosedependentmannerbypreservingitsnormal
functions.
EffectofMolsidomineonOxidativeStressandLipidPeroxidation
DNcontrolratsexhibitedasignificant(P<0.001)decreaseinSOD,reducedglutathioneand
CATactivity[Figure3]comparedtonormalcontrolrats.
Figure3:Effectofmolsidomineonrenalantioxidant
enzymesinrats.NC=Normalcontrol,DNC=Diabetic

enzymesinrats.NC=Normalcontrol,DNC=Diabetic
nephropathycontrol,MOL5=Molsidomine(5mg/kg),
MOL10=Molsidomine(10mg/kg).Valuesarerepresented
asmeanstandarderrorofthemean(n=6).***P<0.001
versusdiabeticnephropathycontrolgroup
Clickheretoview

TheMDAlevelwhichistheendproductoflipidperoxidationwasincreasedsignificantlyin
kidneyhomogenateofdiabeticrats(P<0.001)whencomparedtonormalcontrolrats.
MolsidominetreatedratssignificantlyreducedMDAlevelindosedependentmanner
comparedtoDNrats[Figure4].
Figure4:Effectofmolsidomineonrenalmalondialdehyde
(M/mgprotein).NC=Normalcontrol,DNC=Diabetic
nephropathycontrol,MOL5=Molsidomine(5mg/kg),
MOL10=Molsidomine(10mg/kg).Valuesarerepresented
asmeanstandarderrorofthemean(n=6).***P<0.001
versusdiabeticnephropathycontrolgroup
Clickheretoview

EffectofMolsidomineonRenalPathologicalChanges
Thehistopathologicalexaminationofkidneytissueofnormalratsshowedthenormal
appearance.RenaltissuesectionofDNcontrolratsshowedglomerulosclerosis,tubular
degeneration,mononuclearcell(MNC)infiltration,andthickeningofglomerularbasement
membrane.ThetreatmentwithMol5showedamoderateglomerularnecrosisandMNC
infiltration.However,thetreatmentwithMol10showednoabnormalityandthearchitectof
kidneytissueappearednormal[Figure5]ad.
Figure5:Histopathologyofkidneytissueofnormalcontrol,
diabeticnephropathycontrol,andtreatedgroupsrats.(a)
Sectionofnormalratkidneytissueshowingnormal
appearanceofglomerulusandtubules.(b)Sectionofdiabetic
ratkidneytissueshowingglomerulosclerosis,tubular
degeneration,andmononuclearcellinfiltration.(c)Section
ofdiabeticratkidneytissuetreatedwithmol5mg/kg
showingmoderateglomerularnecrosisandmononuclearcell
infiltration.(d)Sectionofdiabeticratkidneytissuetreated
withmol10mg/kgshowingnoabnormality(10)
Clickheretoview

Discussion

DNisoneoftheleadingcausesofmorbidityandmortalityindiabeticpatientsglobally.
PreventingtheprogressionofDNhasbeenachallengeinbiomedicalresearch.Hypertensionis
ariskfactorforprogressionofDN.Reductionofbloodpressureisbeneficialinpreventing
progressionofDN.Onotherhand,manystudieshaveshownthatoxidativestressplaysa
majorroleinthedevelopmentdiabeticrenalinjuries.Molsidomine(NOdonor)has
antioxidativeandvasodilatoreffects.Hence,thepresentstudywasundertakentoevaluatethe
effectsofmolsidomineinDN.
STZinduceddiabeticratsaremoreliabletodevelophypertension.[17]Elevatedblood
pressurehasadamagingeffectonkidney.Inthepresentstudy,theSBPwassignificantly
higher(P<0.001)inDNgroupcomparedtothenormalgroup,andthisrisewaspreventedby
molsidominetreatment.Theantihypertensiveeffectofmolsidomineisthemajorintervention
inthepreventionofalbuminuriawhichisduetoitsvasodilatationeffect.
Microalbuminuria(definedasUAER30300mg/day)isconsideredapredictorofworse
outcomesforbothkidneyandheartpatients.[18]Highbloodpressuremaycause
microalbuminuriabyincreasingglomerularfiltrationpressureandsubsequentrenaldamage.
Thefindingsofourstudyrevealedthattreatmentwithmolsidominehassignificantlyprevented

Thefindingsofourstudyrevealedthattreatmentwithmolsidominehassignificantlyprevented
microalbuminuriainthediabeticgroup.
InsulindeficiencyinType1diabetespreventstheentryofglucoseintothecells.Asaresult,
cellsstartstarvationandlossofBWoccurs.BWwasobservedinconcurrencewiththe
continuationofdiabetesinthestudy.MolsidominetreatmentpreventedmassivelossofBW.
Severalstudieshaveshownthatmultiplefactorscausedbyhyperglycemiaplayaroleinthe
developmentofdiabetickidneydisease.Thehyperglycemicconditionresultsinirreversible
tissuedamagethroughtheproteinglycationreactionthatleadstotheformationof
glycosylatedproteinandadvancedglycationendproduct.[19],[20]Inthepresentstudy,
molsidominehaspreventedthehyperglycemiaofdiabeticratswhichshowsitsrolein
nephroprotection.
Inourstudy,STZinduceddiabeticratssuccessfullydevelopedDNwhichwasevidencedby
polyurea,albuminuria,andincreasedinmetabolicwastesintheblood.Scrisconsideredasa
markerofalteredglomerularfiltrationrate(GFR)inDN.[21]However,molsidominetreatment
showedasignificantdecreaseinurinevolume,albuminuria,andalsoimprovedtheGFR.
Theseresultsareinaccordancewiththerecentstudyinwhichithadshownthatmolsidomine
hasabeneficialeffectincisplatininducednephrotoxicity.[22]Ontheotherhand,ithasbeen
reportedthatprotectiveeffectofmolsidomineinironinducednephrotoxicityisduetoitsNO
donatingproperty,[10]asNOplayanimportantroleinmaintainingnormalphysiologyof
kidney.
Oxidativestresshasalinkinthepathogenesisofdiabeticcomplications,includingDN.
HyperglycemiainducedactivationofseveralpathwaysresultsintheexcessiveformationROS
thatistoxictothecell.Theyalsointeractwiththelipidbilayerandproducelipidperoxidation
productlikeMDAwhichfurtherdamagesthecells.SOD,CAT,andGSHareresponsiblefor
thedetoxificationoftheROS.[23]Duganetal.[24]revealedthatmitochondrialderived
superoxideanionproductionisreducedindiabetesandplaysapivotalroleinpreservingrenal
functionduringhyperglycemia.Inourstudy,theabilityofmolsidominetoincreaserenal
antioxidantenzymelevelisinlinewiththefindingofChanderandChopra[8]whofoundthat
molsidominerestoredthedepletedrenalantioxidantenzymelevelinischemiareperfusion
renalinjury.Theyalsosuggestedthatthebeneficialantioxidanteffectofmolsidomineisdueto
thedecreasingneutrophilinfiltrationandreducingplasmalevelsofproinflammatory
mediators,whichincreaseoxidativestressandtheseverityofinflammationprocess.Attiaet
al.[25]foundthatNOdeficiencyresultedinpodocytestressinhypercholesterolemicrats,
whilemolsidominepreventedpodocyteinjurysuggestingitsadditionalroleinourstudyforits
nephroprotectiveaction.Thehistopathologyresultsobtainedfromthestudyfurtherconfirmed
ourbiochemicalfindings.Alongwithimprovingrenalfunction,molsidomineprevented
diabetesinducedtubulardegeneration,andglomerulosclerosis.However,furtherresearchis
requiredtoinvestigateitsmolecularmechanismanditscomparativeefficacytotheavailable
treatmentofDN.
Conclusion

Treatmentwithmolsidominepreventedrenaldysfunctiondosedependentlyindiabeticrats.
Nephroprotectiveeffectofmolsidomineisduetoitsantihypertensive,antihyperglycemic,and
antioxidanteffect.MolsidominemaybepromisingasadrugfordelayingandpreventingType
1DNinrats.
FinancialSupportandSponsorship
Nil.
ConflictsofInterest
Therearenoconflictsofinterest.

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Figures
[Figure1],[Figure2],[Figure3],[Figure4],[Figure5]

Tables
[Table1]

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