التفاصيل البيبلوغرافية
| العنوان: |
Humanized C3 Mouse: A Novel Accelerated Model of C3 Glomerulopathy |
| المؤلفون: |
Devalaraja-Narashimha, Kishor, Meagher, Karoline, Luo, Yifan, Huang, Cong, Kaplan, Theodore, Muthuswamy, Anantharaman, Halasz, Gabor, Casanova, Sarah, O’Brien, John, Peyser Boiarsky, Rebecca, McWhirter, John, Gartner, Hans, Bai, Yu, MacDonnell, Scott, Liu, Chien, Hu, Ying, Latuszek, Adrianna, Wei, Yi, Prasad, Srinivasa, Huang, Tammy, Yancopoulos, George, Murphy, Andrew, Olson, William, Zambrowicz, Brian, Macdonald, Lynn, Morton, Lori G. |
| المساهمون: |
Regeneron Pharmaceuticals |
| المصدر: |
Journal of the American Society of Nephrology ; volume 32, issue 1, page 99-114 ; ISSN 1046-6673 1533-3450 |
| بيانات النشر: |
Ovid Technologies (Wolters Kluwer Health) |
| سنة النشر: |
2020 |
| الوصف: |
Significance Statement C3 glomerulopathy (C3G) is a rare, progressive kidney disease, characterized by alternative pathway hyperactivation and glomerular complement deposition. Animal models are valuable to explore modulators of C3G progression. A severe C3G mouse model was developed by replacing the mouse C3 gene with the human equivalent. The humanized C3 mice mimic pathologic features of patients with C3G, potentially due to dysregulated interaction of human C3 protein with mouse complement regulators. A C5-blocking antibody showed that C5 dominates pathogenesis of humanized C3 mice. C3b- and complement factor B–blocking antibodies provide benefit, indicating that alternative-pathway hyperactivation drives pathology in these mice. The humanized model exhibits rapid, severe renal disease, offering the opportunity to genetically and pharmacologically dissect critical contributors to complement-driven renal pathology. Background C3 glomerulopathy (C3G) is characterized by the alternative-pathway (AP) hyperactivation induced by nephritic factors or complement gene mutations. Mice deficient in complement factor H (CFH) are a classic C3G model, with kidney disease that requires several months to progress to renal failure. Novel C3G models can further contribute to understanding the mechanism behind this disease and developing therapeutic approaches. Methods A novel, rapidly progressing, severe, murine model of C3G was developed by replacing the mouse C3 gene with the human C3 homolog using VelociGene technology. Functional, histologic, molecular, and pharmacologic assays characterize the presentation of renal disease and enable useful pharmacologic interventions in the humanized C3 (C3 hu/hu ) mice. Results The C3 hu/hu mice exhibit increased morbidity early in life and die by about 5–6 months of age. The C3 hu/hu mice display elevated biomarkers of kidney dysfunction, glomerulosclerosis, C3/C5b-9 deposition, and reduced circulating C3 compared with wild-type mice. Administration of a C5-blocking mAb improved ... |
| نوع الوثيقة: |
article in journal/newspaper |
| اللغة: |
English |
| DOI: |
10.1681/asn.2020050698 |
| DOI: |
10.1681/ASN.2020050698 |
| الإتاحة: |
https://doi.org/10.1681/asn.2020050698Test |
| رقم الانضمام: |
edsbas.D8B90558 |
| قاعدة البيانات: |
BASE |
