Reduced Pax2 Gene Dosage Increases Apoptosis and Slows the Progression of Renal Cystic Disease

[摘要] Themurinecpkmousedevelopsarapid-onsetpolycystickidneydisease(PKD)withmanysimilaritiestohumanPKD.Duringkidneydevelopment,thetranscriptionfactorPax2isrequiredforthespecificationanddifferentiationoftherenalepithelium.Inhumans,Pax2isalsoexpressedinjuvenilecystickidneyswhereitcorrelateswithcellproliferation.Inthisreport,Pax2expressionisdemonstratedinthecysticepitheliumofthemousecpkkidneys.ToassesstheroleofPax2duringthedevelopmentofpolycystickidneydisease,theprogressionofrenalcystswasexaminedincpkmutantscarryingoneortwoallelesofPax2.ReducedPax2genedosageresultedinasignificantinhibitionofrenalcystgrowthwhilemaintainingmorenormalrenalstructures.Theinhibitionofcystgrowthwasnotduetoreducedproliferationofthecysticepithelium,rathertoincreasedcelldeathinthePax2heterozygotes.IncreasedapoptosiswithreducedPax2genedosagewasalsoobservedinnormaldevelopingkidneys.Thus,increasedcelldeathisanintegralpartofthePax2heterozygousphenotypeandmaybetheunderlyingcauseofPaxgenehaploinsufficiency.ThatthecysticepitheliumrequiresPax2forcontinuedexpansionunderscorestheembryonicnatureoftherenalcysticcellsandmayprovidenewinsightstowardgrowthsuppressionstrategies.