Abstract: FR-PO823
Fc Receptor TRIM21 Degrades Mesangial Intracellular IgA and Inhibits Cell Proliferation in IgA Nephropathy
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
- Liu, Haiyang, The Second Xiangya Hospital of Central South University Department of Nephrology, Changsha, Hunan, China
- Liu, Hong, The Second Xiangya Hospital of Central South University Department of Nephrology, Changsha, Hunan, China
Group or Team Name
- The Second Xiangya Hospital of Central South University.
Background
IgA nephropathy (IgAN) characterized by abnormal deposition of IgA in the mesangial area in renal biopsy. Mesangial cells have the function of transferring IgA into cells' cytoplasm. Tripartite motif containing-21 (TRIM21) is a cytosolic ubiquitin ligase and antibody receptor, studies showed that IgA neutralizes adenovirus infection in an intracellular TRIM21- dependent manner.
Methods
1. Screening IgA receptor in IgAN patients
The expression level of IgA receptor genes in the glomerulus in IgAN was screened using datasets GSE93798 in the Gene Expression Omnibus (GEO). The protein expression were confirmed by staining utilized in the renal biopsy samples.
2. Knock out or over-expression TRIM21 in vivo and vitro model of IgAN
The vivo mice IgAN model was made by oral mucosal immunization. The vitro model was made by aggregated IgA1 (aIgA1) added to human mesangial cells (HMCs).
3. Inhibit ubiquitin-proteasome pathway in vitro IgAN model
MG132 or a corresponding amount of DMSO was added to the medium for different time intervals before the vitro experiment.
Results
1.TRIM21 is upregulated and expressed in the mesangial cells of IgAN.
2. The upregulation of TRIM21 in the glomeruli of IgAN patients is associated with higher serum creatinine levels.
3. The upregulation of TRIM21 in the glomeruli was co-localizes with IgA.
4. Loss of TRIM21 in IgAN mice induces massive IgA deposition in the mesangial region.
5. Inhibiting TRIM21 in IgAN causes serious mesangial cell proliferation both In Vivo and In Vitro.
6. IgA enters the mesangial cells and is degraded through the ubiquitin-proteasome pathway.
7. TRIM21 regulates IgA degradation in mesangial cells via the ubiquitin-proteasome pathway.
Conclusion
This study illustrates that the increased TRIM21 in the glomeruli of IgAN could degrade the IgA in mesangial cells and inhibit cells proliferation, the mechanism involves the protease ubiquitination pathway. These results suggest TRIM21 may be a novel therapeutic target for degrading IgA in mesangial cells of IgAN.
Funding
- Government Support – Non-U.S.