Phenotypic quantification of Nphs1-deficient mice.

Autor: Schneider R; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, USA., Mansour B; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, USA., Kolvenbach CM; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, USA.; Institute of Anatomy and Cell Biology, Medical Faculty, University of Bonn, Bonn, Germany., Buerger F; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, USA., Salmanullah D; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, USA., Lemberg K; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, USA., Merz LM; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, USA.; Department of Pediatrics, University Leipzig, Leipzig, Germany., Mertens ND; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, USA., Saida K; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, USA., Yousef K; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, USA., Franken GAC; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, USA., Bao A; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, USA., Yu S; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, USA., Hölzel S; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, USA., Nicolas-Frank C; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, USA., Steinsapir A; Deerfield Discovery and Development, Deerfield Management Company, L.P. (Series C), New York, USA., Goncalves KA; Deerfield Discovery and Development, Deerfield Management Company, L.P. (Series C), New York, USA., Shril S; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, USA., Hildebrandt F; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, USA. friedhelm.hildebrandt@childrens.harvard.edu.
Jazyk: angličtina
Zdroj: Journal of nephrology [J Nephrol] 2024 Jul 14. Date of Electronic Publication: 2024 Jul 14.
DOI: 10.1007/s40620-024-01987-8
Abstrakt: 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 Nphs1 fl/- mouse (Nphs1 tm1Afrn /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 (Nphs1 fl/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.
(© 2024. The Author(s) under exclusive licence to Italian Society of Nephrology.)
Databáze: MEDLINE
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