IgG Glycosylation-Dependent CLEC7A Signaling Drives Podocyte Dysfunction in Lupus Nephritis

Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE) that can lead to end-stage kidney disease and increased mortality. IgG from patients with LN displays abnormal glycosylation, contributing to podocyte injury. CLEC7A (C-type lectin domain family 7 member A) is a transmembrane lectin receptor that recognizes fucose on IgG. This study investigates the role of lectin-glycan interactions in LN-related podocyte dysfunction.

IgG isolated from patients with active LN and healthy controls was exposed to differentiated human podocytes. Gene and protein responses were assessed by quantitative polymerase chain reaction, Western blotting, immunofluorescence, phalloidin staining, calcium flux, and wound-healing assays. Human kidney biopsies and MRL/lpr mouse kidneys were examined to validate CLEC7A-spleen tyrosine kinase (SYK) pathway activation and the glycan-dependent effects of LN-IgG.

Human podocytes exposed to the CLEC7A ligand curdlan or LN-IgG, but not healthy control IgG or IgG from patients with SLE without nephritis, showed increased CLEC7A expression, impaired motility, cytoskeleton disruption, and reduced nephrin expression. Deglycosylation of LN-IgG blocked CLEC7A binding and preserved podocyte function. Mechanistically, curdlan and LN-IgG increased calcium flux and activated SYK. MRL/lpr mice with nephritis exhibited elevated podocyte CLEC7A and SYK expression. Similarly, podocytes in kidney biopsies from patients with active LN exhibit increased expression of SYK and CLEC7A compared with healthy controls. Pharmacological SYK inhibition or CLEC7A silencing prevented podocyte injury.

We reveal a novel IgG lectin-glycan-CLEC7A-SYK axis involved in the pathogenesis of LN, which can be targeted therapeutically in patients with LN.