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 SCF^FBW7 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.

Keywords: FBW7; Fibrosis; Kidney Function; Nephronophthisis; SOX9.

© 2025. The Author(s).

纤维化是囊性肾病的一个关键特征，尤其是常染色体隐性肾脏疾病如肾小管萎缩症（NPHP）。然而，它对肾功能下降的贡献及其潜在分子机制仍然不清楚。在这里，我们显示特异性删除Fbxw7（SCF^FBW7 E3泛素连接酶的识别受体）会导致青少年-成年型类似NPHP的病理特征，表现为进展缓慢的皮质髓质囊肿、小管退化、严重纤维化和肾功能逐渐丧失。在失去FBW7的情况下，SOX9（已知是FBW7的底物）和WNT4（一种强大的促纤维化因子及SOX9下游效应器）的表达水平升高。复合突变小鼠中的Sox9杂合子删除导致了WNT4水平的正常化、纤维化的减少以及肾功能的保留，而对囊性扩张和小管退化没有显著影响。这些数据表明FBW7-SOX9-WNT4诱导的纤维化驱动NPHP和其他形式的常染色体隐性肾脏疾病的肾功能下降。

关键词：FBW7；纤维化；肾功能；肾小管萎缩症（Nephronophthisis）；SOX9.

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