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

Authors

Ola Shalaby
Tomoko Ohmori
Koichiro Miike
Shunsuke Tanigawa
Luh Ade Wilan Krisna
Alessia Calcagnì
Andrea Ballabio
Yoshiaki Kubota
Laura S Schmidt
W Marston Linehan
Takaaki Ito
Masaya Baba
Ryuichi Nishinakamura

Language

English

Publication Date

9-1-2025

Journal

American Journal of Pathology

DOI

10.1016/j.ajpath.2025.05.010

PMID

40499782

PMCID

PMC12489385

PubMedCentral® Posted Date

6-9-2025

PubMedCentral® Full Text Version

Post-print

Abstract

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.

Keywords

Animals, Mice, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Mice, Knockout, Birt-Hogg-Dube Syndrome, Tumor Suppressor Proteins, Proto-Oncogene Proteins, Cysts, Nephrons, Kidney Diseases, Cystic, Gene Deletion

Published Open-Access

yes

Recommended Citation

Shalaby, Ola; Ohmori, Tomoko; Miike, Koichiro; et al., "Folliculin Deletion in the Mouse Kidney Results in Cystogenesis of the Loops of Henle via Aberrant TFEB Activation" (2025). Duncan NRI Faculty and Staff Publications. 137.
https://digitalcommons.library.tmc.edu/duncar_nri_pub/137