#3971 INJURY INDUCED RENAL FIBROSIS PROMOTES CYSTOGENESIS AND CYST GROWTH IN ADULT MICE WITH AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE

Abstract

Abstract Background and Aims Acute kidney injury (AKI) is not a merely transient event, which can lead to a subsequent progression to chronic kidney disease (CKD). Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent inherited kidney disease caused by mutations in PKD1 or PKD2 gene. Previous studies showed that acute kidney injuries promote cystogenesis in adult mice with ADPKD. Fibrosis is a hallmark of AKI to CKD (AKI-CKD) transition, and positively correlated with renal cyst growth in humans. All these data imply a role of AKI-CKD transition in ADPKD.In this study, we aimed to determine the role of AKI-CKD transition in the ADPKD. Method We established AKI-CKD transition model by toxic or surgical injuries, and Pkd gene inactivation in adult mice was performed in different time point of AKI-CKD transition. The progression of renal fibrosis was shown by Western blotting analysis in toxic or surgical injury induced AKI-CKD transition model. Results We showed that renal injury before or after Pkd gene inactivation can both induce renal cyst formation in adult Pkd1 or Pkd2 mice, and the extent of cyst formation was correlated with the initial fibrosis level of three hits (injury and gene inactivation). Inactivation of Pkd1 gene at fibrosis recovery stage in surgery induced less cyst formation in adult Pkd1 mice. Enhanced renal fibrosis by repeated toxic injuries before gene inactivation accelerated renal cyst growth in Pkd1 mice. We further showed that the speed of cyst growth at the early stage in adult Pkd1 mice was decided by the baseline of renal fibrosis. Finally, we showed that conditional knockout of Ezh2 gene attenuated renal fibrosis and cyst growth in adult Pkd1 mice with established renal fibrosis. Conclusion Fibrotic responses in AKI-CKD transition is a driving force for renal cyst formation and growth in adult kidneys and inhibition of renal fibrosis through targeting EZH2 might be new therapeutic strategy for adult ADPKD.