Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 131, Issue 5, Pages -Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI140453
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Funding
- University of Zurich [Forschungskredit FK-14-035]
- IKPP2 fellowship (from the European Union's Seventh Framework Programme for research technological development and demonstration) [608847]
- Swiss National Science Foundation (SNSF) grant [31003A_179347]
- National Center for Excellence in Research, Kidney.CH - Kidney Control of Homeostasis
- CNRS
- Fondation Maladies Rares [LAM-RD 20170304]
- National Research Agency grants MNaims [ANR-17-CE17-0012-01]
- Investments for the Future Laboratory of Excellence SIGNALIFE (a network for innovation on signal transduction pathways in life sciences) [ANR-11-LABX-0028-01]
- Fondation de la Recherche Medicale [DEQ20180339193]
- NIH [R01 DK090029, T32 DK007053, R01 DK097053]
- National Research, Development and Innovation Office [K119374, K118386, PD124261]
- Swiss National Science Foundation (SNF) [31003A_179347] Funding Source: Swiss National Science Foundation (SNF)
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In primary membranous nephropathy, anti-PLA2R1 IgG4 can induce podocyte injury by activating the lectin pathway. The study results indicate that aberrantly glycosylated IgG4 directly binds to mannose-binding lectin and induces proteolysis of synaptopodin and NEPH1 proteins through two distinct proteolytic pathways.
Primary membranous nephropathy (pMN) is a leading cause of nephrotic syndrome in adults. In most cases, this autoimmune kidney disease is associated with autoantibodies against the M-type phospholipase A2 receptor (PLA2R1) expressed on kidney podocytes, but the mechanisms leading to glomerular damage remain elusive. Here, we developed a cell culture model using human podocytes and found that anti-PLA2R1-positive pMN patient sera or isolated IgG4, but not IgG4-depleted sera, induced proteolysis of the 2 essential podocyte proteins synaptopodin and NEPH1 in the presence of complement, resulting in perturbations of the podocyte cytoskeleton. Specific blockade of the lectin pathway prevented degradation of synaptopodin and NEPH1. Anti-PLA2R1 IgG4 directly bound mannose-binding lectin in a glycosylation-dependent manner. In a cohort of pMN patients, we identified increased levels of galactose-deficient IgG4, which correlated with anti-PLA2R1 titers and podocyte damage induced by patient sera. Assembly of the terminal C5b-9 complement complex and activation of the complement receptors C3aR1 or C5aR1 were required to induce proteolysis of synaptopodin and NEPH1 by 2 distinct proteolytic pathways mediated by cysteine and aspartic proteinases, respectively. Together, these results demonstrated a mechanism by which aberrantly glycosylated IgG4 activated the lectin pathway and induced podocyte injury in primary membranous nephropathy.
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