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

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.

• Authors: Nicola M Tomas, Silke Dehde, Catherine Meyer-Schwesinger, Ming Huang, Irm Hermans-Borgmeyer, Johanna Maybaum, Renke Lucas, Jennie L von der Heide, Oliver Kretz, Sarah M S Köllner, Larissa Seifert, Tobias B Huber, Gunther Zahner
• Journal: Kidney international (Kidney Int) Vol. 103 Issue 2 Pg. 297-303 (Feb 2023) ISSN: 1523-1755 [Electronic] United States
• PMID: 36191868 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Chemical References

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

Topics

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