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

TY - JOUR

T1 - Podocyte expression of human phospholipase A2 receptor 1 causes immune-mediated membranous nephropathy in mice

AU - Tomas, Nicola M

AU - Dehde, Silke

AU - Meyer-Schwesinger, Catherine

AU - Huang, Ming

AU - Hermans-Borgmeyer, Irm

AU - Maybaum, Johanna

AU - Lucas, Renke

AU - von der Heide, Jennie L

AU - Kretz, Oliver

AU - Köllner, Sarah M S

AU - Seifert, Larissa

AU - Huber, Tobias B

AU - Zahner, Gunther

N1 - Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

PY - 2023/2

Y1 - 2023/2

N2 - 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.

AB - 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.

U2 - 10.1016/j.kint.2022.09.008

DO - 10.1016/j.kint.2022.09.008

M3 - SCORING: Journal article

C2 - 36191868

VL - 103

SP - 297

EP - 303

JO - KIDNEY INT

JF - KIDNEY INT

SN - 0085-2538

IS - 2

ER -