AP214amelioratessepsis-inducedacutekidneyinjuryandmorNIHPublicAccessAuthorManuscriptKidneyInt.Authormanuscript;availableinPMC2021June1.Publishedinfinaleditedformas:KidneyInt.2021June;73(11):1266–1274.NIH-PAAuthorManuscriptNIH-PAAuthorManuscriptNIH-PAAuthorManuscriptAP214,ananalogueofα-melanocyte-stimulatinghormone,amelioratessepsis-inducedacutekidneyinjuryandmortalityKentDoi,M.D.,Ph.D.1,XuzhenHu1,PeterS.T.Yuen,Ph.D.1,AsadaLeelahavanichkul,M.D.1,HideoYasuda,M.D.,Ph.D.1,SooMiKim,Ph.D.1,JrgenSchnermann,Ph.D.1,ThomasE.N.Jonassen,M.D.2,4,JrgenFrkir,M.D.3,4,SrenNielsen,M.D.,Ph.D.3,4,andRobertA.Star,M.D.11NationalInstituteofDiabetesandDigestiveandKidneyDiseases,NationalInstitutesofHealth,Bethesda,MD2DepartmentofPharmacology,UniversityofCopenhagen,Copenhagen,Denmark3TheWaterandSaltResearchCenter,UniversityofAarhus,Aarhus,Denmark4ActionPharma,Aarhus,DenmarkAbstractSepsisremainsaseriousproblemincriticallyillpatientswiththemortalityincreasingtooverhalfwhenthereisattendantacutekidneyinjury.α-Melanocyte-stimulatinghormoneisapotentantiinflammatorycytokinethatinhibitsmanyformsofinflammationincludingthatwithacutekidneyinjury.Wetestedwhetheranewα-melanocyte-stimulatinghormoneanalogue(AP214),whichhasincreasedbindingaffinitytomelanocortinreceptors,improvessepsis-inducedkidneyinjuryandmortalityusingacecalligationandpuncturemousemodel.Inthelethalcecalligation-puncturemodelofsepsis,severehypotensionandbradycardiaresultedandAP214attenuatedacutekidneyinjuryofthelethalmodelwithabell-shapeddose-responsecurve.AnoptimumAP214dosereducedacutekidneyinjuryevenwhenitwasadministered6hraftersurgeryanditsignificantlyimprovedbloodpressureandheartrate.AP214reducedserumTNF-αandIL-10levelswithabell-shapeddoseresponsecurve.Additionally;NF-κBactivationinthekidneyandspleen,andsplenocyteapoptosisweredecreasedbythetreatment.AP214significantlyimprovedsurvivalinbothlethalandsublethalmodels.WehaveshownthatAP214improveshemodynamicfailure,acutekidneyinjury,mortalityandsplenocyteapoptosisattenuatingpro-andanti-inflammatoryactionsduetosepsis.Sepsisisoneofthemajorcausesofmortality,andtheincidenceofsepsisintheUnitedStatesisstillincreasing.1Acutekidneyinjury(AKI)isalsoassociatedwithahighmortalityrate2andAKIandsepsisincreasemortalitysynergistically;septicAKIpatientsshowworsemortalitycomparedwithnon-septicAKIpatients,3whereasrenaldysfunctioninsepticpatientsincreasesmortality.4Howevertherapiestotreatorpreventsepsis-inducedAKIarelargelyineffective,andnoveldrugsavailableatclinicalsettingsareurgentlyrequired.Severalpre-clinicalanimalmodelshavebeendevelopedtoevaluatethepossibleefficacyofdrugsonsepsis-inducedAKI.5Amongthem,thececalligationandpuncture(CLP)modeliswidelyusedbecausetheresultingpolymicrobialsepsismimicsmanyfeaturesofhumansepsis.6WehavealreadydemonstratedtheefficacyofseveraldrugsbyaclinicallyrelevantsepsisinducedAKImodelbasedonCLP.7-9Inthismodel,animalsweretreatedwithfluidresuscitationandantibioticssimilartosepticpatientsinanintensivecareunit.AKIcanbeAddressforcorrespondence:RobertA.Star,M.D.,RenalDiagnosticsandTherapeuticsUnit,NIDDK,NIH,10CenterDrive,Room3N108,Bethesda,MD20892-1268,Phone:301-402-6749,Fax:301-402-0014,E-mail:Robert_Star@nih.gov.detectedwithin6hraftersurgerybyasensitiveMRItechnique9andwithin12hrafterCLPbymeasurementofserumcreatinine.7Moreover,ourmodelshowsnotonlykidneyinjurybutmultipleorganfailuresu...