Injury induced renal fibrosis promotes cystogenesis and cyst growth in adult mice with autosomal dominant polycystic kidney disease

Abstract

AbstractAutosomal dominant polycystic kidney disease (ADPKD) is a life-long disease and caused by mutations inPKD1orPKD2gene. Fibrosis is a hallmark of chronic kidney disease and is positively correlated with renal cyst growth, however the role of fibrosis in ADPKD is still controversial. In this study, we established renal fibrosis by toxic or surgical injuries in adult mice, andPkdgene was inactivated at different time point before or after renal injury according to the pattern of fibrosis progression in different injury models. Here we showed that renal injury before or afterPkdgene inactivation can both induce renal cysts in adultPkd1orPkd2mice, and the extent of cystic burden was tightly correlated with the baseline levels of fibrosis when three hits (injury and gene inactivation) occurred. Inactivation ofPkd1gene at the recovery stage after surgery induced less renal cysts in adultPkd1mice. Enhanced renal fibrosis by repeated toxic injuries before gene inactivation accelerated renal cyst growth inPkd1mice. We further showed that the rate of cyst formation at the early stage in adultPkd1mice was positively correlated with the baseline levels of renal fibrosis. Finally, we showed that conditional knockout ofEzh2gene attenuated renal fibrosis and cyst growth in adultPkd1mice with pre-existing renal fibrosis. We conclude that the fibrotic response after renal injury 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. Importantly, our study suggests that there is a time window for intervention upon acute kidney injury in adult ADPKD patients.Translational StatementAutosomal dominant polycystic kidney disease (ADPKD) is a life-long disease and caused by mutations inPKD1orPKD2gene. Fibrosis is a hallmark of chronic kidney disease and is positively correlated with renal cyst growth, however the role of renal fibrosis in ADPKD is controversial. In this study, we found that renal cysts were formed in adultPkd1orPkd2mice with established renal fibrosis induced by toxic or ischemia reperfusion injuries. Cyst formation or growth in adult ADPKD mice was tightly correlated with baseline levels of renal fibrosis after third hits. Enhanced renal fibrosis beforePkd1gene deletion in adult mice accelerated cyst growth. Inhibition of renal fibrosis through targeting EZH2 delayed cyst growth in adult ADPKD mice. Thus, renal fibrosis is a trigger of cyst formation and growth in adult ADPKD mice, and therapeutically targeting EZH2 might be new strategy to treat adult patients with ADPKD. Our study suggests that there is a time window for intervention upon acute kidney injury in adult ADPKD patients.