Long noncoding RNA is dysregulated in autosomal dominant polycystic kidney disease and regulates mTOR signaling.

Autosomal dominant polycystic kidney disease (ADPKD) is a debilitating disease that is characterized by the accumulation of numerous fluid-filled cysts in the kidney. ADPKD is primarily caused by mutations in two genes, and Long noncoding RNAs (lncRNA), defined by a length >200 nucleotides and absence of a long ORF, have recently emerged as epigenetic regulators of development and disease; however, their involvement in PKD has not been explored previously. Here, we performed deep RNA-Seq to identify lncRNAs that are dysregulated in two orthologous mouse models of ADPKD (kidney-specific and mutant mice). We identified a kidney-specific, evolutionarily conserved lncRNA called that was down-regulated in cystic kidneys from and mutant mice. The human ortholog was down-regulated in cystic kidneys from ADPKD patients. was highly expressed in renal tubules in adult WT mice, whereas its expression was lost in the cyst epithelium of mutant mice. To investigate the function of , we utilized CRISPR/Cas9 to knock out its expression in mIMCD3 cells. Deletion of resulted in increased phosphorylation of mTOR and its downstream targets, including p70 S6 kinase, ribosomal protein S6, and the translation repressor 4E-BP1. Consistent with activation of mTORC1 signaling, mutant cells displayed increased mitochondrial respiration. The mutant phenotype was partially rescued upon re-expression of in knockout cells. These findings identify as a novel lncRNA that is down-regulated in ADPKD and regulates mTOR signaling and mitochondrial respiration.