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IgG Glycosylation-Dependent CLEC7A Signaling Drives Podocyte Dysfunction in Lupus Nephritis
Rohit Upadhyay1, Alexia Orellana1, George C Tsokos2
1John W. Deming Department of Medicine, Section of Nephrology & Hypertension, Tulane University School of Medicine, New Orleans, Louisiana.
Arthritis & Rheumatology (Hoboken, N.J.)
|June 22, 2026
Summary
Abnormal IgG glycosylation in lupus nephritis (LN) activates CLEC7A and SYK in podocytes, causing kidney injury. Targeting this lectin-glycan-CLEC7A-SYK axis offers a new therapeutic strategy for LN patients.
Area of Science:
- Nephrology
- Immunology
- Molecular Biology
Background:
- Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE).
- Abnormal immunoglobulin G (IgG) glycosylation in LN patients contributes to podocyte injury.
- CLEC7A (C-type lectin domain family 7 member A) recognizes fucose on IgG, implicating lectin-glycan interactions in LN pathogenesis.
Purpose of the Study:
- To investigate the role of lectin-glycan interactions in LN-related podocyte dysfunction.
- To elucidate the CLEC7A-SYK pathway in LN-induced podocyte injury.
- To identify potential therapeutic targets for LN.
Main Methods:
- Assessed human podocyte responses to LN-IgG and CLEC7A ligand curdlan using qPCR, western blotting, and functional assays.
- Examined human kidney biopsies and MRL/lpr mouse kidneys for CLEC7A-SYK pathway activation.
- Investigated the effect of deglycosylation, CLEC7A silencing, and SYK inhibition on podocyte function.
Main Results:
- LN-IgG and curdlan increased podocyte CLEC7A expression, impaired motility, disrupted cytoskeleton, and reduced nephrin expression.
- Deglycosylation of LN-IgG prevented CLEC7A binding and preserved podocyte function.
- LN-IgG and curdlan activated calcium flux and the SYK pathway; CLEC7A and SYK were upregulated in LN kidney samples and MRL/lpr mice; SYK inhibition or CLEC7A silencing protected podocytes.
Conclusions:
- A novel IgG lectin-glycan-CLEC7A-SYK axis is involved in LN pathogenesis.
- This pathway mediates LN-related podocyte injury.
- Targeting the CLEC7A-SYK axis presents a potential therapeutic strategy for LN.
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