ST6Gal1 is up‐regulated and associated with aberrant IgA1 glycosylation in IgA nephropathy: An integrated analysis of the transcriptome

Galactose‐deficient IgA1 (Gd‐IgA1) plays a crucial role in the development of Immunoglobulin A nephropathy (IgAN), however, the underlying pathogenic mechanisms driving Gd‐IgA1 production in B cells are not well understood. In this study, RNA‐seq analysis identified 337 down‐regulated and 405 up‐regulated genes in B cells from 17 patients with IgAN and 6 healthy controls. Among them, ST6Gal1, which was associated with IgAN in a previous genome‐wide association study (GWAS), was up‐regulated in IgAN and significantly positive correlated with elevated Gd‐IgA1. In addition, we identified increased plasma ST6Gal1 levels in 100 patients with IgAN, which were associated with higher levels of proteinuria, plasma IgA, Gd‐IgA1 levels, greater degrees of systemic complement activation including C3a, Bb, C4d, MAC and a lower proportion classified as C2 grade (crescent proportion ≥25%). Interesting, in vitro, recombinant ST6Gal1 (rST6Gal1) exposure reduced the production of Gd‐IgA1 in cultured peripheral blood mononuclear cells from IgAN patients. rST6Gal1 stimuli also increased expression of C1GALT1, which were well‐known proportional to the decrease in galactose deficiency of IgA1. In conclusions, we identified increased plasma ST6Gal1 levels and the association of ST6Gal1 with disease severity of IgAN. Additionally, rST6Gal1 administration in vitro increased expression of C1GALT1 and reduced the production of Gd‐IgA1.