Podocyte-specific Nup160 knockout mice develop nephrotic syndrome and glomerulosclerosis

Area of Science:

• Genetics and Molecular Biology
• Nephrology
• Developmental Biology

Background:

• Steroid-resistant nephrotic syndrome (SRNS) is a severe kidney disorder linked to mutations in over 60 monogenic genes.
• Previous research implicated mutations in nucleoporin 160 kD (NUP160), a nuclear pore complex component, in SRNS.
• A recent report described siblings with NUP160 mutations presenting with SRNS and neurological issues, necessitating a mammalian model to confirm causality.

Purpose of the Study:

• To establish and characterize a podocyte-specific Nup160 knockout (Nup160podKO) mouse model.
• To investigate whether Nup160 deficiency in podocytes recapitulates nephrotic syndrome (NS)-associated phenotypes.
• To validate NUP160 as a causative gene for SRNS using a mammalian model.

Main Methods:

• Generation of a podocyte-specific Nup160 knockout mouse model utilizing CRISPR/Cas9 and Cre/loxP technologies.
• Verification of Nup160 gene and protein ablation in the Nup160podKO mice.
• Phenotypic analysis of Nup160podKO mice, including assessment of proteinuria (albumin/creatinine ratio) and serum albumin levels, and histological examination for glomerulosclerosis.

Main Results:

• Successful and efficient knockout of Nup160 in podocytes of Nup160podKO mice at both DNA and protein levels.
• Nup160podKO mice developed hallmark features of NS, including significant proteinuria (mean ACR 15.06 mg/mg) and hypoalbuminemia (mean serum albumin 13.13 g/l) by 26–30 weeks.
• Histological analysis revealed glomerulosclerosis in Nup160podKO mice, contrasting with control littermates.

Conclusions:

• Podocyte-specific knockout of Nup160 in mice leads to the development of nephrotic syndrome and glomerulosclerosis.
• These findings provide strong evidence that NUP160 mutations are a cause of SRNS.
• The generated Nup160podKO mouse model serves as a valuable tool for studying the pathogenesis of NUP160-associated SRNS.