Dataset Information

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

ABSTRACT: Altered 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). Serum 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 α2,6-linked sialic acid, and Ricinus communis agglutinin I (RCA-I) recognizes β1,4-linked galactose. Serum levels of the α2,6-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. IgM 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. IgM 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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Podocyte

SUBMITTER: Nicole Grinovero

LAB HEAD: Andrea Petretto

PROVIDER: PXD070406 | Pride | 2026-06-29

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	20240715_091753_Bruschi_podociti.sne	Other
	Bruschi_podociti_A_1_03.raw	Raw
	Bruschi_podociti_A_2_04.raw	Raw
	Bruschi_podociti_A_3_05.raw	Raw
	Bruschi_podociti_A_4_06.raw	Raw

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Publications

IgM Hyposialylation Modulates Podocyte Vulnerability in Patients With Idiopathic Nephrotic Syndrome.

Spinelli Sonia S Gaudiano Sofia S Garbarino Andrea A Lugani Francesca F La Porta Edoardo E Petretto Andrea A Bartolucci Martina M Lavarello Chiara C Grinovero Nicole N Musante Ilaria I Scudieri Paolo P Trivelli Antonella A Piaggio Giorgio G Magnasco Alberto A Degl'Innocenti Maria Ludovica ML Granata Simona S Zaza Gianluigi G Verrina Enrico E Candiano Giovanni G Bruschi Maurizio M

Kidney international reports 20260513 8

<h4>Introduction</h4>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).<h4>Methods</h4>Serum IgM from 86 pediatric and adult patients with podocytopathies, 20 patients with membranous nephropathy (MN), 20 patients with lupus nephritis ...[more]

PMID: 42318532

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Project description:Glomerular podocytes are highly differentiated cells that are key components of the kidney filtration units. The podocyte cytoskeleton builds the basis for the dynamic podocyte cytoarchitecture and plays a central role for proper podocyte function. Recent studies implicate that immunosuppressive agents including the mTOR-inhibitor everolimus have a protective role directly on the stability of the podocyte cytoskeleton. To elucidate mechanisms underlying mTOR-inhibitor mediated cytoskeletal rearrangements, we carried out microarray gene expression studies to identify target genes and corresponding pathways in response to everolimus. We analyzed the effect of everolimus in a puromycin aminonucleoside experimental in vitro model of podocyte injury. Upon treatment with puromycin aminonucleoside, microarray analysis revealed gene clusters involving cytoskeletal-associated pathways, adhesion, migration and extracellular matrix composition to be affected. Everolimus is capable of protecting podocytes from injury, both on the transcriptome and protein level. Rescued genes included TUBB2B and DCDC2, both involved in microtubule structure formation in neuronal cells but not identified in podocytes so far. Confirming gene expression data, Western-blot analysis in cultured podocytes showed an increase of TUBB2B and DCDC2 protein after everolimus treatment, and immunohistochemistry in healthy control kidneys confirmed a podocyte-specific expression. Microtubule-inhibitor experiments led to a maldistribution of TUBB2B and DCDC2 as well as an aberrant reorganization of the actin cytoskeleton. Tubb2bbrdp/brdp mice showed a delay in glomerular podocyte and capillary development. Taken together, our study suggests that off-target, non-immune mediated effects of the mTOR-inhibitor everolimus on the podocyte cytoskeleton might involve regulation of microtubules, revealing a potential novel role of TUBB2B and DCDC2 in glomerular podocyte development We analyzed the effect of everolimus on gene expression in a puromycin aminonucleoside experimental in vitro model of podocyte injury using microarrays