Podocyte expression of human phospholipase A2 receptor 1 causes immune-mediated membranous nephropathy in mice

Kidney Int. 2023 Feb;103(2):297-303. doi: 10.1016/j.kint.2022.09.008. Epub 2022 Sep 30.

Abstract

Antibody-mediated autoimmune pathologies like membranous nephropathy are difficult to model, particularly in the absence of local target antigen expression in model organisms such as mice and rats; as is the case for phospholipase A2 receptor 1 (PLA2R1), the major autoantigen in membranous nephropathy. Here, we generated a transgenic mouse line expressing the full-length human PLA2R1 in podocytes, which has no kidney impairment after birth. Beginning from the age of three weeks, these mice spontaneously developed anti-human PLA2R1 antibodies, a nephrotic syndrome with progressive albuminuria and hyperlipidemia, and the typical morphological signs of membranous nephropathy with granular glomerular deposition of murine IgG in immunofluorescence and subepithelial electron-dense deposits by electron microscopy. Importantly, human PLA2R1-expressing Rag2-/- mice, which lack mature and functioning B and T lymphocytes, developed neither anti-PLA2R1 antibodies nor proteinuria. Thus, our work demonstrates that podocyte expression of human PLA2R1 can induce membranous nephropathy with an underlying antibody-mediated pathogenesis in mice. Importantly, this antibody-mediated model enables proof-of-concept evaluations of antigen-specific treatment strategies, e.g., targeting autoantibodies or autoantibody-producing cells, and may further help understand the autoimmune pathogenesis of membranous nephropathy.

Keywords: autoimmunity; membranous nephropathy; mouse model; phospholipase A2 receptor 1 (PLA2R1); podocyte.

MeSH terms

  • Animals
  • Autoantibodies
  • Autoantigens / genetics
  • Glomerulonephritis, Membranous* / diagnosis
  • Humans
  • Kidney Glomerulus / pathology
  • Mice
  • Mice, Transgenic
  • Podocytes* / pathology
  • Rats
  • Receptors, Phospholipase A2 / genetics

Substances

  • Autoantibodies
  • Autoantigens
  • PLA2R1 protein, human
  • Receptors, Phospholipase A2