Abstract: SA-PO746
Podocyte Expression of the Human PLA2R1 Causes Immune-Mediated Membranous Nephropathy in Mice
Session Information
- Glomerular Diseases: Podocyte Biology - II
November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1302 Glomerular Diseases: Immunology and Inflammation
Authors
- Tomas, Nicola M., Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
- Dehde, Silke, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
- Meyer-Schwesinger, Catherine, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
- Seifert, Larissa, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
- Lucas, Renke, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
- Köllner, Sarah, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
- Huang, Ming, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
- Huber, Tobias B., Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
- Zahner, Gunther, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
Background
Antibody-mediated autoimmune pathologies like membranous nephropathy (MN) are difficult to model, particularly in the absence of target antigen expression in typical model organisms such as mice and rats, which is the case for PLA2R1, the major autoantigen in this disease.
Methods
We generated a mouse line expressing the full-length human PLA2R1 specifically in podocytes (hPLA2R1-positive mice). Mice were characterized during the first weeks of life using urinary albumin measurements, serum analyses, light microscopic and immunofluorescence microscopy as well as electron microscopy. The mouse line was also crossed to Rag2-/- mice, which lack mature B and T lymphocytes.
Results
Human PLA2R1-positive mice were healthy after birth. Beginning from the age of three weeks, however, mice developed a nephrotic syndrome with progressive albuminuria and hyperlipidemia. This was preceded by the development of anti-PLA2R1 antibodies, which primarily bound the PLA2R1 extracellular domains that are also recognized by patient autoantibodies (CysR, CTLD1, CTLD7/8). After disease onset, histological analyses in hPLA2R1-positive mice revealed the typical morphological signs of MN with granular glomerular deposition of murine IgG in immunofluorescence and subepithelial electron-dense deposits in electron microscopy. Importantly, hPLA2R1-positive Rag2-/- mice did neither develop anti-PLA2R1 antibodies nor proteinuria.
Conclusion
Our work demonstrates that podocyte expression of human PLA2R1 in mice can induce immune-mediated, PLA2R1-associated MN.
Funding
- Government Support – Non-U.S.