Shalaby Ola, Ohmori Tomoko, Miike Koichiro, Tanigawa Shunsuke, Wilan Krisna Luh Ade, Calcagnì Alessia, Ballabio Andrea, Kubota Yoshiaki, Schmidt Laura S, Linehan W Marston, Ito Takaaki, Baba Masaya, Nishinakamura Ryuichi
Department of Kidney Development, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan; Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
Department of Kidney Development, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan.
Am J Pathol. 2025 Jun 9. doi: 10.1016/j.ajpath.2025.05.010.
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. 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 up-regulated genes, especially in the knockout LoH. These genes include those related to lysosomal activity and mammalian target of rapamycin complex 1 activation and are likely targets of transcription factor E3/transcription factor EB (TFEB). Although 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 show the essential role of the FLCN-TFEB signaling pathway in nephron development, particularly in LoH, and they shed light on the pathogenesis of Birt-Hogg-Dubé syndrome.
哺乳动物的肾脏包含众多与集合管相连的肾单位，每个肾单位由一个肾小球、一个近端小管、亨氏袢（LoH）和一个远端小管组成。卵泡抑素（FLCN）是Birt-Hogg-Dubé综合征的致病基因，该综合征具有多种表现，包括肾囊肿和癌症。尽管在小鼠集合管和远端肾单位中删除Flcn会导致囊肿形成，但其在整个肾单位中的精确作用仍不清楚。我们在此报告，肾单位特异性Flcn基因敲除小鼠在整个肾单位段均表现出囊肿形成，在亨氏袢中最为明显，在此之前有由增大的上皮细胞衬里的形状不规则的管腔。单细胞RNA测序揭示了许多上调基因，尤其是在基因敲除的亨氏袢中。这些基因包括与溶酶体活性和雷帕霉素复合物1激活的哺乳动物靶点相关的基因，并且可能是转录因子E3/转录因子EB（TFEB）的靶点。尽管双Flcn/Tfe3基因敲除仅改善了肾小球囊肿，但双Flcn/Tfeb基因敲除在很大程度上逆转了整个肾单位的大多数表型。因此，Flcn缺失通过异常的TFEB激活导致囊肿形成。我们的研究结果表明FLCN-TFEB信号通路在肾单位发育中，特别是在亨氏袢中的重要作用，并为Birt-Hogg-Dubé综合征的发病机制提供了线索。
