%0 Journal Article
%T Phenotypic quantification of Nphs1-deficient mice.
%A Schneider R
%A Mansour B
%A Kolvenbach CM
%A Buerger F
%A Salmanullah D
%A Lemberg K
%A Merz LM
%A Mertens ND
%A Saida K
%A Yousef K
%A Franken GAC
%A Bao A
%A Yu S
%A Hölzel S
%A Nicolas-Frank C
%A Steinsapir A
%A Goncalves KA
%A Shril S
%A Hildebrandt F
%J J Nephrol
%V 0
%N 0
%D 2024 Jul 14
%M 39003671
%F 4.393
%R 10.1007/s40620-024-01987-8
%X <B>BACKGROUND: </B>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.<BR><B>METHODS: </B>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 +).<BR><B>RESULTS: </B>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.<BR><B>CONCLUSIONS: </B>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.