Abstract: FR-PO795
Desialylated IgM by Idiopathic Nephrotic Syndrome Subjects Induce Proteinuria and Podocyte Injury
Session Information
- Glomerular Diseases: Inflammation and Immunology
October 25, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Kajana, Xhuliana, Istituto Giannina Gaslini, Genova, Liguria, Italy
- Spinelli, Sonia, Istituto Giannina Gaslini, Genova, Liguria, Italy
- Caridi, Gianluca, Istituto Giannina Gaslini, Genova, Liguria, Italy
- Ghiggeri, Gian Marco, Istituto Giannina Gaslini, Genova, Liguria, Italy
- Bruschi, Maurizio, Istituto Giannina Gaslini, Genova, Liguria, Italy
- Cravedi, Paolo, Icahn School of Medicine at Mount Sinai, New York, New York, United States
- Angeletti, Andrea, Istituto Giannina Gaslini, Genova, Liguria, Italy
Background
IgM deposition is a common finding in the glomeruli of patients with idiopathic nephrotic syndrome (INS) and represents a risk factor for poor treatment response and disease progression. However, the pathological role of IgM in INS is controversial. Sialylation is a post-translational modification that significantly affects IgM function, but its role in the pathogenesis of INS is unknown.
Methods
IgM derived from patients with INS and controls (HC) were injected in 8 Sprague-Dawley rats. Sialylation induces an anionic charge to proteins, therefore, we tested the charge of IgM derived by 12INS and 12HC, as an indirect sign of sialylation, measuring IgM migration through an electrophoretic assay. To test a larger cohort (220 INS and 75 HC), we developed an ELISA and we measured the sialylation of IgM through incubation with biotinylated Sambucus nigra agglutinin. Immortalized human podocytes were exposed to total and desialylated IgM (obtained through desialylation of total IgM).
Results
IgM from INS induced higher levels of proteinuria compared to IgM from HC in rats. (Fig1A). IgM purified from patients with INS (red) had a significative higher cationic charge than IgM from controls (black) (Fig1B), as summarised in Fig1C. In a larger cohort, the ratio between the sialylation of IgM and total IgM was significantly lower in INS than HC (Fig1D). Co-incubation with desialylated IgM, but not total IgM altered the cytoskeletal protein phalloidinin of human podocytes, as evidenced in Fig1E.
Intact IgM is internalized, while desialylated IgM remains on the podocyte surface (Fig1F), suggesting a different interaction of these types of IgM with podocytes.
Conclusion
IgM sialylation in INS is lower than HC and de-sialylated IgM induces in vivo proteinuria and in vitro podocyte damage. We recently demonstrated a causal link between IgM and disease relapse in a clinical study of patients with INS (DOI: 10.1016/j.ekir.2024.04.006). Overall, these data support that sialylation of IgM may play a pathogenic role in INS.