IgM hyposialylation drives podocyte injury in pediatric and young adult patients with podocytopathies.

IntroductionAltered immunoglobulin glycosylation has been implicated in antibody-mediated podocytopathies, yet the functional impact of IgM sialylation remains unclear. Previous evidence suggested that circulating cationic or hyposialylated IgM may contribute to podocyte injury in idiopathic nephrotic syndrome (iNS). MethodsSerum IgM from pediatric and young adult patients with podocytopathies, membranous nephropathy (MN), lupus nephritis (LN), and healthy controls were analyzed by lectin-based ELISA using a panel of six biotinylated lectins to detect terminal N-glycan residues. Among these, Sambucus nigra agglutinin (SNA) binds 2,6-linked sialic acid, and Ricinus communis agglutinin I (RCA-I) recognizes {beta}1,4-linked galactose. Serum levels of the 2,6-sialyltransferase ST6GAL1 and the sialidases neuraminidase-1 (NEU1) and neuraminidase-3 (NEU3) were quantified. Cultured human podocytes were exposed to patient-derived, control, or enzymatically modified IgM (desialylated/resialylated) and analyzed by confocal microscopy, quantitative proteomics, phosphoproteomics, and metabolic assays. ResultsIgM from patients with podocytopathies showed reduced SNA binding, which inversely correlated with proteinuria (r = -0.69, P < 0.0001) and with serum sialidases NEU1/NEU3 (r = -0.67/-0.59, P < 0.0001). In paired samples, SNA reactivity decreased during relapse and normalized in remission, indicating dynamic modulation with disease activity. ST6GAL1 was undetectable in all groups. In contrast, PLA2R1-positive MN, in which pathogenic antibodies target podocyte PLA2R1, displayed reduced RCA-I binding. Podocytes exposed to hyposialylated or desialylated IgM exhibited actin disorganization, loss of nephrin signal, increased lipid peroxidation, and decreased ATP synthesis. In contrast, resialylated IgM preserved morphology and metabolism comparable to controls. Proteomic and phosphoproteomic profiling revealed enrichment of MAPK, mTOR, AMPK, and cytoskeletal remodeling pathways. ConclusionsIgM hyposialylation, driven by extracellular sialidases up-regulation, correlates with disease activity and promotes oxidative stress, mitochondrial dysfunction, and cytoskeletal remodeling in podocytes, identifying immune glycan remodeling as a modifiable determinant of podocyte injury and a potential biomarker of disease activity. Translational StatementAltered glycosylation of circulating immunoglobulins is emerging as a key mechanism underlying glomerular injury. Here, we demonstrate that hyposialylated IgM, resulting from elevated serum sialidases NEU1 and NEU3, directly induces podocyte cytoskeletal disorganization, oxidative stress, and metabolic impairment. In contrast, enzymatic resialylation maintains podocyte morphology and function at levels indistinguishable from controls, indicating that sialic acid loss is a modifiable determinant of podocyte injury. Clinically, reduced IgM sialylation correlates with proteinuria and disease activity in idiopathic nephrotic syndrome, supporting its potential as a biomarker of relapse and remission. Targeting the sialidase-sialic acid pathway may therefore represent a promising strategy to preserve podocyte integrity and improve outcomes in antibody-negative podocytopathies.