دورية أكاديمية
Quantitative phenotyping of Nphs1 knockout mice as a prerequisite for gene replacement studies.
| العنوان: | Quantitative phenotyping of Nphs1 knockout mice as a prerequisite for gene replacement studies. |
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| المؤلفون: | Buerger F; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States.; University Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Merz LM; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States.; Department of Pediatrics, University Leipzig, Leipzig, Germany., Saida K; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States., Yu S; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States., Salmanullah D; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States., Lemberg K; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States., Mertens ND; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States., Mansour B; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States., Kolvenbach CM; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States.; Institute of Anatomy, Medical Faculty, University of Bonn, Bonn, Germany., Yousef K; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States., Hölzel S; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States., Braun A; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States., Franken GAC; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States., Goncalves KA; Deerfield Discovery and Development, Deerfield Management Company, L.P. (Series C), New York, New York, United States., Steinsapir A; Deerfield Discovery and Development, Deerfield Management Company, L.P. (Series C), New York, New York, United States., Endlich N; NIPOKA GmbH, Greifswald, Germany., Schneider R; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States., Shril S; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States., Hildebrandt F; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States. |
| المصدر: | American journal of physiology. Renal physiology [Am J Physiol Renal Physiol] 2024 May 01; Vol. 326 (5), pp. F780-F791. Date of Electronic Publication: 2024 Mar 14. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Physiological Society Country of Publication: United States NLM ID: 100901990 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1522-1466 (Electronic) Linking ISSN: 15221466 NLM ISO Abbreviation: Am J Physiol Renal Physiol Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Bethesda, Md. : American Physiological Society, c1997- |
| مواضيع طبية MeSH: | Membrane Proteins*/genetics , Membrane Proteins*/metabolism , Phenotype* , Mice, Knockout* , Nephrotic Syndrome*/genetics , Nephrotic Syndrome*/therapy , Podocytes*/metabolism, Animals ; Female ; Male ; Disease Models, Animal ; Genetic Therapy/methods ; Mice ; Genetic Vectors |
| مستخلص: | Steroid-resistant nephrotic syndrome (SRNS) is the second most frequent cause of chronic kidney disease before the age of 25 yr. Nephrin, encoded by NPHS1, localizes to the slit diaphragm of glomerular podocytes and is the predominant structural component of the glomerular filtration barrier. Biallelic variants in NPHS1 can cause congenital nephrotic syndrome of the Finnish type, for which, to date, no causative therapy is available. Recently, adeno-associated virus (AAV) vectors targeting the glomerular podocyte have been assessed as a means for gene replacement therapy. Here, we established quantitative and reproducible phenotyping of a published, conditional Nphs1 knockout mouse model ( Nphs1 tm1.1Pgarg /J and Nphs2-Cre + ) in preparation for a gene replacement study using AAV vectors. Nphs1 knockout mice ( Nphs1 fl/fl Nphs2-Cre + ) exhibited 1 ) a median survival rate of 18 days (range: from 9 to 43 days; males: 16.5 days and females: 20 days); 2 ) an average foot process (FP) density of 1.0 FP/µm compared with 2.0 FP/µm in controls and a mean filtration slit density of 2.64 µm/µm 2 compared with 4.36 µm/µm 2 in controls; 3 ) a high number of proximal tubular microcysts; 4 ) the development of proteinuria within the first week of life as evidenced by urine albumin-to-creatinine ratios; and 5 ) significantly reduced levels of serum albumin and elevated blood urea nitrogen and creatinine levels. For none of these phenotypes, significant differences between sexes in Nphs1 knockout mice were observed. We quantitatively characterized five different phenotypic features of congenital nephrotic syndrome in Nphs1 fl/fl Nphs2-Cre + mice. Our results will facilitate future gene replacement therapy projects by allowing for sensitive detection of even subtle molecular effects. NEW & NOTEWORTHY To evaluate potential, even subtle molecular, therapeutic effects of gene replacement therapy (GRT) in a mouse model, prior rigorous quantifiable and reproducible disease phenotyping is necessary. Here, we, therefore, describe such a phenotyping effort in nephrin ( Nphs1 ) knockout mice to establish the basis for GRT for congenital nephrotic syndrome. We believe that our findings set an important basis for upcoming/ongoing gene therapy approaches in the field of nephrology, especially for monogenic nephrotic syndrome. |
| معلومات مُعتمدة: | T32 DK007726 United States DK NIDDK NIH HHS |
| فهرسة مساهمة: | Keywords: glomerular; monogenic; nephrin; nephrotic; therapy |
| المشرفين على المادة: | 0 (Membrane Proteins) 0 (nephrin) |
| تواريخ الأحداث: | Date Created: 20240314 Date Completed: 20240502 Latest Revision: 20240502 |
| رمز التحديث: | 20240503 |
| DOI: | 10.1152/ajprenal.00412.2023 |
| PMID: | 38482553 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1522-1466 |
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| DOI: | 10.1152/ajprenal.00412.2023 |