Phenotypic quantification of Nphs1-deficient mice

• Published in: Journal of nephrology 2024-07
• Main Authors: Schneider, Ronen, Mansour, Bshara, Kolvenbach, Caroline M, Buerger, Florian, Salmanullah, Daanya, Lemberg, Katharina, Merz, Lea M, Mertens, Nils D, Saida, Ken, Yousef, Kirollos, Franken, Gijs A C, Bao, Aaron, Yu, Seyoung, Hölzel, Selina, Nicolas-Frank, Camille, Steinsapir, Andrew, Goncalves, Kevin A, Shril, Shirlee, Hildebrandt, Friedhelm
• Format: Article
• Language: English
• ISSN: 1724-6059; 1724-6059
• DOI: 10.1007/s40620-024-01987-8

Steroid-resistant nephrotic syndrome (SRNS) is the second most frequent cause of chronic kidney disease in children and young adults. The most severe form of steroid-resistant nephrotic syndrome is congenital nephrotic syndrome Finnish type (CNSF), caused by biallelic loss-of-function variants in NPHS1, encoding nephrin. Since each of the 68 monogenic causes of steroid-resistant nephrotic syndrome represents a rare cause of the disease, tailoring therapeutic interventions to multiple molecular targets remains challenging, suggesting gene replacement therapy (GRT) as a viable alternative. To set the ground for a gene replacement study in vivo, we established rigorous, quantifiable, and reproducible phenotypic assessment of a conditional Nphs1 knockout mouse model. By breeding a floxed Nphs1 mouse (Nphs1 /J) previously studied for pancreatic β-cell survival with a podocin promoter-driven Cre recombinase mouse model (Tg(NPHS2-Cre) /J), we generated mice with podocyte-specific nephrin deficiency (Nphs1 NPHS2-Cre +). We observed a median survival to postnatal day P5 in nephrin-deficient mice, whereas heterozygous control mice and wild type (WT) control group showed 90% and 100% survival, respectively (at P50 days). Light microscopy analysis showed a significantly higher number of renal-tubular microcysts per kidney section in nephrin-deficient mice compared to the control groups (P