1. Introduction of a novel chimeric active immunization mouse model of PLA2R1-associated membranous nephropathy.
- Author
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Tomas NM, Schnarre A, Dehde S, Lucas R, Hermans-Borgmeyer I, Kretz O, Koellner SMS, Wiech T, Koch-Nolte F, Seifert L, Huber TB, and Zahner G
- Subjects
- Humans, Mice, Animals, Receptors, Phospholipase A2 genetics, Autoantibodies, Mice, Transgenic, Vaccination, Complement C3, Disease Models, Animal, Glomerulonephritis, Membranous, Nephrotic Syndrome, Autoimmune Diseases
- Abstract
The phospholipase A2 receptor 1 (PLA2R1) is the major target antigen in patients with membranous nephropathy (MN), an antibody-mediated autoimmune glomerular disease. Investigation of MN pathogenesis has been hampered by the lack of reliable animal models. Here, we overcome this issue by generating a transgenic mouse line expressing a chimeric PLA2R1 (chPLA2R1) consisting of three human PLA2R1 domains (cysteine-rich, fibronectin type-II and CTLD1) and seven murine PLA2R1 domains (CTLD2-8) specifically in podocytes. Mice expressing the chPLA2R1 were healthy at birth and showed no major glomerular alterations when compared to mice with a wild-type PLA2R1 status. Upon active immunization with human PLA2R1 (hPLA2R1), chPLA2R1-positive mice developed anti-hPLA2R1 antibodies, a nephrotic syndrome, and all major histological features of MN, including granular deposition of mouse IgG and complement components in immunofluorescence and subepithelial electron-dense deposits and podocyte foot process effacement in electron microscopy. In order to investigate the role of the complement system in this model, we further crossed chPLA2R1-positive mice with mice lacking the central complement component C3 (C3
-/- mice). Upon immunization with hPLA2R1, chPLA2R1-positive C3-/- mice had substantially less severe albuminuria and nephrotic syndrome when compared to chPLA2R1-positive mice with a wild-type C3 status. In conclusion, we introduce a novel active immunization model of PLA2R1-associated MN and demonstrate a pathogenic role of the complement system in this model., (Copyright © 2023 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)- Published
- 2023
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