Objectives: Diabeticnephropathy(DN)isarepresentativediseasethataccountsforabouthalfofchronickidneydisease(CKD).RenalfibrosisisknowntobethemostimportantpathologicalchangeinDN.DeregulationoftheCa2+signalhasbeenimplicatedinthedevelopmentofDN,directlyand/orindirectly.Store-operatedCa2+entry(SOCE)istheprimaryCa2+entrymechanisminthenon-excitablecellsincludingpodocytesandisproposedasapotentialtherapeutictargetforDN.Recently,itisreportedthattheblockadeofSOCEprotectspodocytopathybyrestoringitsstructuralandfunctionalchanges.Here,weexaminedwhethertheOrai1inhibitorexertstherapeuticeffectsinleptin-deficientBTBRob/obmouse,awell-establishedtypeIIdiabeticmousemodel. Methods: Orai1inhibitor(GSK7975A)wasintroducedviaanosmoticminipumpfor4weeks,andasalineosmoticpumpwasusedforthevehicle.Glomerulartuftareaandmesangialmatrix(byMethenaminesilverstain),andpodocytedensity(byimmunohistochemicalstainingwithWT1)werequantifiedbyimageanalyzerandcomparedamonggroups.Glomerularbasementmembrane(GBM)thicknesswasanalyzedbyelectronmicroscopy. Results: Orai1inhibitorsignificantlyreducedmesangialmatrixintheBTBRob/obmicecomparedwiththatofsaline-treatedoruntreatedBTBRob/obmice.PodocytedensitywasdiminishedinBTBRob/obmice,andwassignificantlyamelioratedbyOrai1inhibitoradministration(Fig.1).Furthermore,GBMthicknesswasalsodecreasedinOrai1inhibitor-treatedBTBRob/obmicecomparedtothatofsalineinfusion. Conclusions: Takentogether,ourdatademonstratethattheblockadeofOrai1activitymayrestorethepathologicchangesofDNinBTBRob/obmouse,andproposedOrai1asanoveltherapeutictargetforDN.