Impact of miR-192 and miR-194 on cyst enlargement through EMT in autosomal dominant polycystic kidney disease

Abstract

AlteredmiRNA(miR) expression occurs in various diseases.However, the therapeutic effect ofmiRNAs in autosomal dominant polycystic kidney disease (ADPKD) is unclear. Genome-wide analyses of miRNA expression and DNA methylation status were conducted to identify crucial miRNAs in end-stage ADPKD. miR-192 and -194 levels were down-regulated with hypermethylation at these loci, mainly in the intermediate and late stages, not in the early stage, of cystogenesis, suggesting their potential impact on cyst expansion. Cyst expansion has been strongly associated with endothelial-mesenchymal transition (EMT). Zinc finger E-box-binding homeobox-2 and cadherin-2,which are involved in EMT,were directly regulated by miR-192 and -194.The therapeutic effect ofmiR- 192 and -194 in vivo and in vitro were assessed. Restoring these miRs by injection of precursors influenced the reduced size of cysts in Pkd1 conditional knockoutmice.miR-192 and -194may act as potential therapeutic targets to control the expansion and progression of cysts in patients with ADPKD.