Aberrant Glycosylation of IgG in Children With Active Lupus Nephritis Alters Podocyte Metabolism and Causes Podocyte Injury

作者：Rhea Bhargava, Rohit Upadhyay, Cong Zhao, Prasad V. G. Katakam, Scott E. Wenderfer, Jing Chen, Hua He, Richard D. Cummings, Maria Tsokos, George C. Tsokos · 发表于：Arthritis & Rheumatology · 年份：2025 · DOI：10.1002/art.43200 · 被引用次数：14 · 研究领域：Renal Diseases and Glomerulopathies、Glycosylation and Glycoproteins Research、Monoclonal and Polyclonal Antibodies Research

OBJECTIVE: Podocytes are integral to the maintenance of the glomerular filtration barrier. Their injury results in proteinuria and disease progression in lupus nephritis (LN). Aberrant IgG glycosylation drives podocyte injury in LN and leads to cytoskeletal rearrangement, motility changes, and decreased nephrin production. Based on these findings, we hypothesized that IgG glycosylation patterns differentiate systemic lupus erythematosus (SLE) with and without LN and that this aberrant glycosylation reprograms podocyte metabolism. METHODS: IgG was isolated from 40 pediatric SLE and from 7 healthy control samples. N-glycan analysis was performed using mass spectrometry. IgG deglycosylation was performed through enzymatic treatment by Peptide N-Glycosidase F for functional studies in podocytes. Untargeted metabolomics was performed in cultured podocytes after exposure to healthy IgG, LN-derived IgG, or deglycosylated LN-IgG and analyzed by metabolite set enrichment analysis. Digital droplet polymerase chain reaction was used to evaluate urine cells and podocytes in culture for pyruvate kinase expression. RESULTS: The glycosylation pattern of IgG from children with LN was different from that in children with SLE without kidney involvement. Successful treatment led to normalization of IgG glycosylation. Cultured podocytes treated with LN-derived IgG had a lower rate of glycolysis compared to podocytes incubated with deglycosylated LN-IgG or IgG from healthy volunteers. Untargeted ...