IgM Hyposialylation Modulates Podocyte Vulnerability in Patients With Idiopathic Nephrotic Syndrome

Altered Ig glycosylation has been implicated in antibody-mediated podocytopathies; however, the functional relevance of IgM sialylation remains poorly defined. Previous evidence suggests that circulating cationic or hyposialylated IgM may contribute to podocyte vulnerability in idiopathic nephrotic syndrome (iNS).

Serum IgM from 86 pediatric and adult patients with podocytopathies, 20 patients with membranous nephropathy (MN), 20 patients with lupus nephritis (LN), and 30 healthy controls were analyzed by lectin-based enzyme-linked immunosorbent assay (ELISA) using biotinylated lectins to assess terminal N-glycan residues, including Sambucus nigra agglutinin (SNA) and Ricinus communis agglutinin I (RCA-I). Serum levels of the sialyltransferase ST6GAL1 and the sialidases neuraminidase-1 (NEU1) and neuraminidase-3 (NEU3) were quantified. Cultured human podocytes were exposed to native, desialylated, or resialylated IgM and analyzed by confocal microscopy, quantitative proteomics, phosphoproteomics, and metabolic assays.

IgM from patients with iNS showed reduced SNA binding, which inversely correlated with proteinuria and circulating NEU1/NEU3 levels. In paired samples, SNA reactivity decreased during relapse and increased during remission. ST6GAL1 was undetectable across all groups, whereas phospholipase A2 receptor 1(PLA2R1)-positive MN displayed reduced RCA-I binding. Podocytes exposed to hyposialylated or desialylated IgM exhibited disorganization of the actin cytoskeleton, reduced nephrin signal, increased lipid peroxidation, and decreased ATP levels. Resialylated IgM displayed podocyte morphological and metabolic features not statistically distinguishable from those observed under control conditions. Proteomic and phosphoproteomic analyses highlighted modulation of mitogen-activated protein kinase (MAPK)-, mechanistic Target of Rapamycin (mTOR-), adenosine monophosphate-activated protein kinase (AMPK), and cytoskeleton-related pathways.

IgM sialylation status tracks disease activity and modulates podocyte structural, metabolic, and signaling responses, supporting immune glycan remodeling as a disease-associated modifier of podocyte vulnerability in iNS.