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Folliculin deletion in the mouse kidney results in cystogenesis of the loops of Henle via aberrant TFEB activation

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

  2. Author Address

    Department of Kidney Development, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan; Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt., Department of Kidney Development, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan., Department of Medical Laboratory Technology, Politeknik Kesehatan Kemenkes Denpasar, Bali 80224, Indonesia., Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy; Department of Translational Medical Sciences, University of Naples "Federico II", Italy., Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy; Department of Translational Medical Sciences, University of Naples "Federico II", Italy; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children 39;s Hospital, Houston, TX 77030, USA., Department of Anatomy, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan., Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA., Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA., Department of Medical Technology, Kumamoto Health Science University Faculty of Health Sciences, Kumamoto 861-5598, Japan., Department of Urology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan. Electronic address: babam@kumamoto-u.ac.jp., Department of Kidney Development, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan. Electronic address: ryuichi@kumamoto-u.ac.jp.,
    1. Year: 2025
    2. Date: Jun 09
    3. Epub Date: 2025 06 09
  2. Journal: The American Journal of Pathology
  4. Type of Article: Article
  1. 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 (BHD) 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. We report here that nephron-specific Flcn knockout mice exhibit 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 upregulated genes, especially in the knockout LoH. These genes include those related to lysosomal activity and mTORC1 activation and are likely targets of TFE3/TFEB. While the double Flcn/Tfe3 knockout only ameliorates the glomerular cysts, the double Flcn/Tfeb knockout largely reverses most of the phenotypes along the entire nephron. Thus, Flcn deletion leads to cystogenesis via aberrant TFEB activation. Our findings reveal the essential role of the FLCN-TFEB signaling pathway in nephron development, particularly in LoH, and shed light on the pathogenesis of BHD syndrome. Copyright © 2025. Published by Elsevier Inc.

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External Sources

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  2. DOI: 10.1016/j.ajpath.2025.05.010
  3. PMID: 40499782
  4. PII : S0002-9440(25)00192-0

Library Notes

  1. Fiscal Year: FY2024-2025
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