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Autoantibodies reactive with glomerular endothelial cells and podocytes in patients with membranous nephropathy
Vojtech Petr1, Shrey Purohit2, Felix Poppelaars2
1Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
Rationale & Objective:
Membranous nephropathy (MN) is a glomerular disease caused by autoantibodies reactive with podocyte antigens. The most common antigen is the M-type phospholipase A2 receptor (PLA2R), but autoantibodies to other podocyte antigens have also been identified. Investigators have reported elevated levels of complement fragments in plasma. However, most complement fragments generated on podocytes are likely to pass into the urine and not enter the bloodstream. Further, anti-PLA2R antibodies are usually IgG4 subclass and do not activate the classical pathway of complement. To look for additional autoantibodies capable of generating endovascular complement fragments, we examined whether MN patients have antibodies reactive with endothelial cell antigens.
Study Design:
Retrospective cohort study.
Setting & Participants:
We analyzed plasma samples from 64 patients with MN, and results were compared to healthy controls and patients with chronic kidney disease.
Exposure:
Plasma and urine complement activation fragments, glomerular endothelial cell and podocyte antibody binding assays, anti-cardiolipin antibody enzyme linked immunosorbent assay.
Outcome:
Proteinuria, estimated glomerular filtration rate.
Analytical Approach:
Groups were compared with Wilcoxon, Kruskal-Wallis or chi-square tests. Correlations were performed using Pearson's correlation.
Results:
Plasma C3a, C4a, C5a, and sC5b-9 levels were elevated in MN patients. Some patients had IgG reacted with glomerular endothelial cells or with podocytes. These antibodies were seen in distinct subsets of patients and did not correlate with the presence of anti-PLA2R antibodies. Higher titers of anti-glomerular endothelial cell antibodies correlated with systemic complement activation, seen by sC5b-9, and disease severity, determined by proteinuria. Anti-cardiolipin IgG levels associated with proteinuria.
Limitations:
Assays used immortalized cell lines, and target antigens have not yet been identified.
Conclusions:
MN is a disease of autoimmunity directed against podocyte antigens, but some patients may also produce autoantibodies that target antigens on glomerular endothelial cells. The level of these antibodies correlates with adverse clinical findings.
Insights
Membranous nephropathy (MN) patients may have autoantibodies targeting glomerular endothelial cells, not just podocytes. These antibodies correlate with complement activation and disease severity, suggesting a role beyond anti-PLA2R antibodies.
Area of Science:
- Nephrology
- Immunology
- Glomerular Diseases
Background:
- Membranous nephropathy (MN) is a kidney disease driven by autoantibodies against podocyte antigens, primarily the M-type phospholipase A2 receptor (PLA2R).
- Elevated complement fragments are observed in MN, but their source and the role of antibodies targeting other glomerular cells remain unclear.
- Anti-PLA2R antibodies are typically IgG4 and do not activate the classical complement pathway, prompting investigation into other autoantibody targets.
Purpose of the Study:
- To investigate the presence and significance of autoantibodies targeting glomerular endothelial cells in patients with membranous nephropathy.
- To determine if antibodies against endothelial cells or podocytes correlate with complement activation and disease severity in MN.
- To explore potential autoantibody targets beyond PLA2R in the pathogenesis of MN.
Main Methods:
- A retrospective cohort study analyzed plasma samples from 64 MN patients, comparing them to healthy controls and chronic kidney disease patients.
- Assays included measurement of plasma and urine complement activation fragments (C3a, C4a, C5a, sC5b-9) and antibody binding to glomerular endothelial cells and podocytes.
- Anti-cardiolipin IgG levels were assessed using enzyme-linked immunosorbent assay.
Main Results:
- Plasma levels of complement fragments C3a, C4a, C5a, and sC5b-9 were elevated in MN patients compared to controls.
- A subset of MN patients exhibited IgG antibodies reactive with glomerular endothelial cells or podocytes, distinct from anti-PLA2R antibodies.
- Higher titers of anti-glomerular endothelial cell antibodies correlated with increased systemic complement activation (sC5b-9) and disease severity (proteinuria).
- Anti-cardiolipin IgG levels were also associated with proteinuria.
Conclusions:
- Membranous nephropathy involves autoimmunity directed at podocyte antigens, but some patients also develop autoantibodies targeting glomerular endothelial cells.
- These anti-endothelial cell antibodies are associated with systemic complement activation and clinical indicators of disease severity.
- The findings suggest that glomerular endothelial cells may be a target in a subset of MN patients, contributing to disease progression.
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