Introduction of a novel chimeric active immunization mouse model of PLA2R1-associated membranous nephropathy

Kidney Int. 2023 Nov;104(5):916-928. doi: 10.1016/j.kint.2023.07.024. Epub 2023 Aug 19.

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.

Keywords: complement system; membranous nephropathy; mouse model; phospholipase A2 receptor 1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoantibodies
  • Autoimmune Diseases*
  • Complement C3
  • Disease Models, Animal
  • Glomerulonephritis, Membranous*
  • Humans
  • Mice
  • Mice, Transgenic
  • Nephrotic Syndrome*
  • Receptors, Phospholipase A2 / genetics
  • Vaccination

Substances

  • Receptors, Phospholipase A2
  • Autoantibodies
  • Complement C3
  • PLA2R1 protein, human