Folliculin Deletion in the Mouse Kidney Results in Cystogenesis of the Loops of Henle via Aberrant TFEB Activation.

The mammalian kidney contains numerous nephrons connected to the collecting ducts, and each nephron consists of a glomerulus, a proximal tubule, the loop of Henle (LoH), and a distal tubule. Folliculin (FLCN) is a causative gene for Birt-Hogg-Dubé syndrome, which is characterized by a variety of manifestations, including renal cysts and cancer. Although deletion of Flcn in the mouse collecting duct and distal nephron leads to cyst formation, its precise role in the entire nephron remains unclear. Herein, nephron-specific Flcn knockout mice exhibited cystogenesis along the entire nephron segments, most prominent in the LoH, preceded by an irregularly shaped lumen lined by enlarged epithelia. Single-cell RNA sequencing revealed many up-regulated genes, especially in the knockout LoH. These genes included those related to lysosomal activity and mammalian target of rapamycin complex 1 activation and are likely targets of transcription factor E3 (TFE3)/transcription factor EB (TFEB). Although the double Flcn/Tfe3 knockout only ameliorated the glomerular cysts, the double Flcn/Tfeb knockout largely reversed most of the phenotypes along the entire nephron. Thus, Flcn deletion led to cystogenesis via aberrant TFEB activation. These findings show the essential role of the FLCN-TFEB signaling pathway in nephron development, particularly in LoH, and shed light on the pathogenesis of Birt-Hogg-Dubé syndrome.