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Lookup NU author(s): Professor John SayerORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2025.Fibrosis is a key feature of a broad spectrum of cystic kidney diseases, especially autosomal recessive kidney disorders such as nephronophthisis (NPHP). However, its contribution to kidney function decline and the underlying molecular mechanism(s) remains unclear. Here, we show that kidney-specific deletion of Fbxw7, the recognition receptor of the SCFFBW7 E3 ubiquitin ligase, results in a juvenile-adult NPHP-like pathology characterized by slow-progressing corticomedullary cysts, tubular degeneration, severe fibrosis, and gradual loss of kidney function. Expression levels of SOX9, a known substrate of FBW7, and WNT4, a potent pro-fibrotic factor and downstream effector of SOX9, were elevated upon loss of FBW7. Heterozygous deletion of Sox9 in compound mutant mice led to the normalization of WNT4 levels, reduced fibrosis, and preservation of kidney function without significant effects on cystic dilatation and tubular degeneration. These data suggest that FBW7-SOX9-WNT4-induced fibrosis drives kidney function decline in NPHP and, possibly, other forms of autosomal recessive kidney disorders.
Author(s): Patel MM, Gerakopoulos V, Lettenmaier B, Petsouki E, Zimmerman KA, Sayer JA, Tsiokas L
Publication type: Article
Publication status: Published
Journal: EMBO Molecular Medicine
Year: 2025
Volume: 17
Issue: 6
Pages: 1238-1258
Print publication date: 12/06/2025
Online publication date: 10/04/2025
Acceptance date: 26/03/2025
Date deposited: 23/05/2025
ISSN (print): 1757-4676
ISSN (electronic): 1757-4684
Publisher: Springer Science and Business Media Deutschland GmbH
URL: https://doi.org/10.1038/s44321-025-00233-3
DOI: 10.1038/s44321-025-00233-3
Data Access Statement: The proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository (https:// www.ebi.ac.uk/pride/archive/projects/PXD061542). Source data for images have been submitted to BioImage Archive (https:// www.ebi.ac.uk/biostudies/bioimages/studies/S-BIAD1704? key=404186c2-0aee-4454-80d9-6f0451acf532). The source data of this paper are collected in the following database record: biostudies:S-SCDT-10_1038-S44321-025-00233-3. Expanded view data, supplementary information, appendices are available for this paper at https://doi.org/10.1038/s44321-025-00233-3.
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