دورية أكاديمية
Phenotypic quantification of Nphs1-deficient mice.
| العنوان: | Phenotypic quantification of Nphs1-deficient mice. |
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| المؤلفون: | 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. |
| المصدر: | Journal of nephrology [J Nephrol] 2024 Jul 14. Date of Electronic Publication: 2024 Jul 14. |
| Publication Model: | Ahead of Print |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Springer Country of Publication: Italy NLM ID: 9012268 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1724-6059 (Electronic) Linking ISSN: 11218428 NLM ISO Abbreviation: J Nephrol Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2014- : Heidelberg : Springer Original Publication: Rome : Acta Medica, |
| مستخلص: | 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.) |
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| معلومات مُعتمدة: | RC-2-DK1222397 United States DK NIDDK NIH HHS; 5T32-DK007726-37 United States DK NIDDK NIH HHS; 3T32DK007726-38S1 United States DK NIDDK NIH HHS; T32-DK007726 United States DK NIDDK NIH HHS; 404527522 ASN Foundation for Kidney Research |
| فهرسة مساهمة: | Keywords: Congenital nephrotic syndrome; Gene replacement therapy; Nephrin-deficient mouse model |
| تواريخ الأحداث: | Date Created: 20240714 Latest Revision: 20240714 |
| رمز التحديث: | 20240714 |
| DOI: | 10.1007/s40620-024-01987-8 |
| PMID: | 39003671 |
| قاعدة البيانات: | MEDLINE |
Find this article in full text from Springer Verlag. 
Full Text Finder | تدمد: | 1724-6059 |
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| DOI: | 10.1007/s40620-024-01987-8 |