Abstract: FR-PO843
A Novel Lectin-Glycan Axis in Lupus Nephritis
Session Information
- Glomerular Diseases: Inflammation and Immunology
October 25, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Upadhyay, Rohit, Tulane University School of Medicine, New Orleans, Louisiana, United States
- Li, Hao, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
- Tsokos, George C., Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
- Bhargava, Rhea, Tulane University School of Medicine, New Orleans, Louisiana, United States
Background
Lupus nephritis (LN) is one of the most serious complications of systemic lupus erythematosus (SLE) that can lead to end-stage kidney disease and increased mortality. We have previously demonstrated that immunoglobulin (IgG) in LN patients is aberrantly glycosylated and can lead to podocyte injury. Specifically, fucose on IgG can be pathogenic to podocytes while galactose can be protective. CLEC7A (C-type lectin domain containing 7A or Dectin1) is a transmembrane lectin receptor which functions as a pattern-recognition receptor and is the only known mammalian receptor to recognize fucose on IgG. Here, we evaluated the role of this lectin-glycan axis in podocyte injury in LN.
Methods
Human podocytes were exposed to serum/ IgG from healthy subjects, SLE, LN and LN-remission patients. Curdlan (ligand for CLEC7A) was used to activate inflammatory response and CLEC7A signaling. Flow-cytometry assisted calcium flux, immunocytochemistry, qPCR, western blotting, wound healing assay, phalloidin staining and silencing of CLEC7A were utilized to delineate CLEC7A signaling in human podocytes. Frozen kidney biopsies from individuals with LN and controls were stained with CLEC7A and SYK.
Results
Podocytes exposed to serum or IgG from LN patients, overexpressed CLEC7A and inflammatory pathway genes. Curdlan and LN-derived IgG (LN-IgG) altered podocyte cytoskeleton and motility along with decreasing nephrin expression. IgG bound to CLEC7A in podocytes while deglycosylation of LN-IgG disrupted CLEC7A binding and normalized podocyte cytoskeleton, motility and nephrin expression. In addition, curdlan and LN-IgG increased Ca flux compared to deglycosylated LN-IgG. More importantly, we found that curdlan and LN-IgG activated spleen tyrosine kinase (Syk) in human podocytes and its pharmacological inhibition effectively prevented LN-IgG induced podocyte injury. Translationally immunofluorescence staining of kidney biopsy tissue revealed increased podocyte CLEC7A and Syk expression in LN. Furthermore, de-glycosylation of LN-IgG and silencing CLEC7A protected podocytes from injury in LN.
Conclusion
To our knowledge this is the first study to demonstrate the role of lectins recognizing specific carbohydrates in podocyte injury and LN. Our data provides a novel mechanistic insight and reveals several novel therapeutic targets for LN.
Funding
- Other NIH Support