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Journal of Nephrology

14-07-2024 | Nephrotic Syndrome | Original Article

Phenotypic quantification of Nphs1-deficient mice

Authors: Ronen Schneider, Bshara Mansour, Caroline M. Kolvenbach, Florian Buerger, Daanya Salmanullah, Katharina Lemberg, Lea M. Merz, Nils D. Mertens, Ken Saida, Kirollos Yousef, Gijs A. C. Franken, Aaron Bao, Seyoung Yu, Selina Hölzel, Camille Nicolas-Frank, Andrew Steinsapir, Kevin A. Goncalves, Shirlee Shril, Friedhelm Hildebrandt

Published in: Journal of Nephrology

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Abstract

Background

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.

Methods

By breeding a floxed Nphs1fl/− mouse (Nphs1tm1Afrn/J) previously studied for pancreatic β-cell survival with a podocin promoter-driven Cre recombinase mouse model (Tg(NPHS2-Cre)295Lbh/J), we generated mice with podocyte-specific nephrin deficiency (Nphs1fl/fl NPHS2-Cre +).

Results

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 < 0.0022). Transmission electron microscopy demonstrated reduced foot process (FP) density in nephrin-deficient mice compared to controls (P < 0.0001). Additionally, proteinuria quantitation using urine albumin-to-creatinine ratio (UACR) was significantly higher in nephrin-deficient mice compared to controls.

Conclusions

This study represents the first comprehensive description of the kidney phenotype in a nephrin-deficient mouse model, laying the foundation for future gene replacement therapy endeavors.

Graphical abstract

Appendix
Available only for authorised users
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Metadata
Title
Phenotypic quantification of Nphs1-deficient mice
Authors
Ronen Schneider
Bshara Mansour
Caroline M. Kolvenbach
Florian Buerger
Daanya Salmanullah
Katharina Lemberg
Lea M. Merz
Nils D. Mertens
Ken Saida
Kirollos Yousef
Gijs A. C. Franken
Aaron Bao
Seyoung Yu
Selina Hölzel
Camille Nicolas-Frank
Andrew Steinsapir
Kevin A. Goncalves
Shirlee Shril
Friedhelm Hildebrandt
Publication date
14-07-2024
Publisher
Springer International Publishing
Published in
Journal of Nephrology
Print ISSN: 1121-8428
Electronic ISSN: 1724-6059
DOI
https://doi.org/10.1007/s40620-024-01987-8

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