دورية أكاديمية
أعرض في EDS

Quantifiable and reproducible phenotypic assessment of a constitutive knockout mouse model for congenital nephrotic syndrome of the Finnish type.

التفاصيل البيبلوغرافية
العنوان: Quantifiable and reproducible phenotypic assessment of a constitutive knockout mouse model for congenital nephrotic syndrome of the Finnish type.
المؤلفون: Lemberg K; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA., Mertens ND; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA., Yousef K; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA., Schneider R; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA., Merz LM; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.; Department of Pediatrics, University Hospital Leipzig, Leipzig, Germany., Mansour B; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA., Salmanullah D; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA., Kolvenbach CM; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.; Medical Faculty, Institute of Anatomy, University of Bonn, Bonn, Germany., Saida K; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA., Yu S; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA., Hölzel S; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA., Steinsapir A; Deerfield Discovery and Development, Deerfield Management Company, L.P. (Series C), New York, NY, USA., Goncalves KA; Deerfield Discovery and Development, Deerfield Management Company, L.P. (Series C), New York, NY, USA., Nicolas Frank C; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA., Franken GAC; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA., Shril S; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA., Buerger F; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.; University Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Hildebrandt F; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA. friedhelm.hildebrandt@childrens.harvard.edu.
المصدر: Scientific reports [Sci Rep] 2024 Jul 10; Vol. 14 (1), pp. 15916. Date of Electronic Publication: 2024 Jul 10.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE
أسماء مطبوعة: Original Publication: London : Nature Publishing Group, copyright 2011-
مواضيع طبية MeSH: Nephrotic Syndrome*/genetics , Nephrotic Syndrome*/pathology , Disease Models, Animal* , Membrane Proteins*/genetics , Phenotype* , Mice, Knockout* , Podocytes*/metabolism , Podocytes*/pathology, Animals ; Mice ; Male ; Female ; Glomerular Basement Membrane/pathology
مستخلص: Steroid-resistant nephrotic syndrome (SRNS) is the second most frequent cause of childhood chronic kidney disease. Congenital nephrotic syndrome of the Finnish type (CNF) (MIM# 256300) is caused by biallelic variants in the gene NPHS1, encoding nephrin, an integral component of the kidney filtration barrier. No causal treatments exist, and children inevitably require kidney replacement therapy. In preparation for gene replacement therapy (GRT) in CNF, we established a quantifiable and reproducible phenotypic assessment of the nephrin-deficient CNF mouse model: 129/Sv-Nphs1 tm1Rkl /J. We assessed the phenotypic spectrum of homozygous mice (Nphs1 tm1Rkl /Nphs1 tm1Rkl ) compared to heterozygous controls (Nphs1 tm1Rkl /Nphs1 WT ) by the following parameters: 1. cohort survival, 2. podocyte foot process (FP) density per glomerular basement membrane (GBM) using transmission electron microscopy, 3. tubular microcysts in brightfield microscopy, and 4. urinary albumin/creatinine ratios. Nphs1 tm1Rkl /Nphs1 tm1Rkl mice exhibited: 1. perinatal lethality with median survival of 1 day, 2. FP effacement with median FP density of 1.00 FP/µm GBM (2.12 FP/µm in controls), 3. tubular dilation with 65 microcysts per section (6.5 in controls), and 4. increased albumin/creatinine ratio of 238 g/g (4.1 g/g in controls). We here established four quantifiable phenotyping features of a CNF mouse model to facilitate future GRT studies by enabling sensitive detection of phenotypic improvements.
(© 2024. The Author(s).)
References: Lovric, S., Ashraf, S., Tan, W. & Hildebrandt, F. Genetic testing in steroid-resistant nephrotic syndrome: When and how?. Nephrol. Dial. Transplant. 31(11), 1802–1813 (2016). (PMID: 10.1093/ndt/gfv35526507970)
Kopp, J. B. et al. Podocytopathies. Nat. Rev. Dis. Primers 6(1), 68 (2020). (PMID: 10.1038/s41572-020-0196-7327924908162925)
Kestilä, M. et al. Positionally cloned gene for a novel glomerular protein–nephrin—Is mutated in congenital nephrotic syndrome. Mol. Cell 1(4), 575–582 (1998). (PMID: 10.1016/S1097-2765(00)80057-X9660941)
Warejko, J. K. et al. Whole exome sequencing of patients with steroid-resistant nephrotic syndrome. Clin. J. Am. Soc. Nephrol. 13(1), 53–62 (2018). (PMID: 10.2215/CJN.0412041729127259)
Patrakka, J. et al. Congenital nephrotic syndrome (NPHS1): Features resulting from different mutations in Finnish patients. Kidney Int. 58(3), 972–980 (2000). (PMID: 10.1046/j.1523-1755.2000.00254.x10972661)
Boyer, O. et al. Management of congenital nephrotic syndrome: Consensus recommendations of the ERKNet-ESPN Working Group. Nat. Rev. Nephrol. 17(4), 277–289 (2021). (PMID: 10.1038/s41581-020-00384-1335149428128706)
Ding, W. Y. et al. Adeno-associated virus gene therapy prevents progression of kidney disease in genetic models of nephrotic syndrome. Sci. Transl. Med. 15(708), 8226 (2023). (PMID: 10.1126/scitranslmed.abc8226)
Zhao, P. et al. Efficacy of AAV9-mediated SGPL1 gene transfer in a mouse model of S1P lyase insufficiency syndrome. JCI Insight 6(8), e145936 (2021). (PMID: 10.1172/jci.insight.145936337555998119223)
Hamano, Y. et al. Determinants of vascular permeability in the kidney glomerulus. J. Biol. Chem. 277(34), 31154–31162 (2002). (PMID: 10.1074/jbc.M20480620012039968)
Verma, R. et al. Nephrin is necessary for podocyte recovery following injury in an adult mature glomerulus. PLoS ONE 13(6), e0198013 (2018). (PMID: 10.1371/journal.pone.0198013299247956010211)
Villarreal, R. et al. Nephrin contributes to insulin secretion and affects mammalian target of rapamycin signaling independently of insulin receptor. J. Am. Soc. Nephrol. 27(4), 1029–1041 (2016). (PMID: 10.1681/ASN.201502021026400569)
Kurki, M. et al. FinnGen provides genetic insights from a well-phenotyped isolated population. Nature 613, 508–518 (2023). (PMID: 10.1038/s41586-022-05473-8366535629849126)
Jia, X. et al. Common risk variants in NPHS1 and TNFSF15 are associated with childhood steroid-sensitive nephrotic syndrome. Kidney Int. 98(5), 1308–1322 (2020). (PMID: 10.1016/j.kint.2020.05.029325540428101291)
Picconi, J. L. et al. Kidney-specific expression of GFP by in-utero delivery of pseudotyped adeno-associated virus 9. Mol. Ther. Methods Clin. Dev. 1, 14014 (2014). (PMID: 10.1038/mtm.2014.14260159584362350)
Autio-Harmainen, H. Renal pathology of fetuses with congenital nephrotic syndrome of the Finnish type. 2. A qualitative and quantitative electron microscopic study. Acta Pathol. Microbiol. Scand. Sect. A Pathol. 89(3), 215–22 (1981).
Khoshnoodi, J. et al. Nephrin promotes cell–cell adhesion through homophilic interactions. Am. J. Pathol. 163(6), 2337–2346 (2003). (PMID: 10.1016/S0002-9440(10)63590-0146336071892394)
Ahvenainen, E. K., Hallman, N. & Hjelt, L. Nephrotic syndrome in newborn and young infants. Ann. Paediatr. Fenniae 2(3), 227–241 (1956).
Autio-Harmainen, H. & Rapola, J. Renal pathology of fetuses with congenital nephrotic syndrome of the Finnish type. A qualitative and quantitative light microscopic study. Nephron 29(3–4), 158–163 (1981). (PMID: 10.1159/0001823437329491)
Tryggvason, K. & Kouvalainen, K. Number of nephrons in normal human kidneys and kidneys of patients with the congenital nephrotic syndrome. A study using a sieving method for counting of glomeruli. Nephron 15(1), 62–68 (1975). (PMID: 10.1159/0001804931093062)
Tryggvason, K. Morphometric studies on glomeruli in the congenital nephrotic syndrome. Nephron 22(4–6), 544–550 (1978). (PMID: 10.1159/000181531740116)
Huttunen, N. P., Rapola, J., Vilska, J. & Hallman, N. Renal pathology in congenital nephrotic syndrome of Finnish type: A quantitative light microscopic study on 50 patients. Int. J. Pediatr. Nephrol. 1(1), 10–16 (1980). (PMID: 7343522)
Giles, H. M., Pugh, R. C., Darmady, E. M., Stranack, F. & Woolf, L. I. The nephrotic syndrome in early infancy: A report of three cases. Arch. Dis. Childhood 32(163), 167–180 (1957). (PMID: 10.1136/adc.32.163.167)
Hallman, N., Norio, R. & Rapola, J. Congenital nephrotic syndrome. Nephron 11(2), 101–110 (1973). (PMID: 10.1159/0001802234127143)
Rapola, J. Renal pathology of fetal congenital nephrosis. Acta Pathol. Microbiol. Scand. Sect. A Pathol. 89(1), 63–64 (1981).
معلومات مُعتمدة: Project No.: 461126211 German Research Foundation; Project No.: 456136540 German Research Foundation; Project No.: 499462148 German Research Foundation; Project No.: 404527522 German Research Foundation; 5T32-DK007726-37 United States NH NIH HHS; 3T32DK007726-38S1 United States NH NIH HHS; T32-DK007726 United States NH NIH HHS; RC-2-DK1222397 United States NH NIH HHS; 202260295 JSPS Overseas Research Fellowship; Rubicon: 452022311 Netherlands Organization for Scientific Research
المشرفين على المادة: 0 (nephrin)
0 (Membrane Proteins)
SCR Disease Name: Nephrosis, congenital
تواريخ الأحداث: Date Created: 20240710 Date Completed: 20240710 Latest Revision: 20240714
رمز التحديث: 20240714
مُعرف محوري في PubMed: PMC11237045
DOI: 10.1038/s41598-024-64883-y
PMID: 38987283
قاعدة البيانات: MEDLINE
الوصف
تدمد:2045-2322
DOI:10.1038/s41598-024-64883-y