SOX9-dependent fibrosis drives renal function in nephronophthisis

Area of Science:

• Nephrology
• Molecular Biology
• Genetics

Background:

• Fibrosis is a hallmark of cystic kidney diseases, including autosomal recessive disorders like nephronophthisis (NPHP).
• The precise role of fibrosis in kidney function decline and its molecular underpinnings in NPHP remain incompletely understood.

Purpose of the Study:

• To investigate the role of FBW7 (F-box and leucine-rich repeat protein 7) in kidney fibrosis and function.
• To elucidate the molecular mechanisms linking FBW7 to kidney pathology in NPHP-like models.

Main Methods:

• Generated kidney-specific Fbxw7 knockout mice to model NPHP.
• Analyzed kidney pathology, fibrosis, and expression of key regulatory genes (SOX9, WNT4).
• Utilized compound mutant mice with heterozygous Sox9 deletion to assess pathway modulation.

Main Results:

• Kidney-specific deletion of Fbxw7 induced NPHP-like pathology, including cysts, tubular degeneration, severe fibrosis, and impaired kidney function.
• Loss of FBW7 led to increased expression of SOX9 and the pro-fibrotic factor WNT4.
• Reducing SOX9 levels in compound mutants normalized WNT4, decreased fibrosis, and preserved kidney function.

Conclusions:

• The FBW7-SOX9-WNT4 signaling axis is a critical driver of fibrosis and kidney function decline in NPHP.
• This pathway represents a potential therapeutic target for NPHP and other autosomal recessive kidney disorders.