Abstract: TH-PO0450
Interplay of C5aR1 with Soluble Urokinase Plasminogen Activator Receptor Is Implicated in ANCA-Associated Vasculitis
Session Information
- Glomerular Diseases: Autoimmune Diseases
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Recharla, Neeraja, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States
- Deb, Prashanta Kumar, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States
- Zhao, Haiqing, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States
- Geesala, Ramasatyaveni, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States
- Islam, Azharul, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States
- Li, Jing, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States
- Knott, Brenna, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States
- Valdebenito-Silva, Silvana, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States
- Wei, David Changli, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States
- Reiser, Jochen, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States
Background
Complement C5a receptor 1 (C5aR1) is a critical driver of inflammation in ANCA-associated vasculitis (AAV). While the increase of soluble urokinase receptor (suPAR) has been observed in patients with AAV, the role of suPAR in the pathogenesis of AAV is unclear.
Methods
An AAV model with anti-MPO antibodies was established in 3 different mouse strains, representing different levels of suPAR (normal/WT, elevated/suPAR-Tg and deficient/uPAR KO). Mice were sacrificed for kidney function, structure and molecular events evaluations at day 14 or 21. To determine protein-protein interaction (PPI), we performed a proteome-wide PPI screening, followed by AlphaFold 3 analysis. Thereafter, both HEK293 cell-based co-immunoprecipitation (Co-IP), and protein-based surface plasmon resonance (SPR) analysis were achieved to reveal the biophysical properties of the interested PPI.
Results
Histological examination indicates typical kidney injuries, including glomerular crescent formation, inflammation and interstitial fibrosis, suggestive of AAV development in all analyzed mice. The circulating suPAR was increased particularly in WT AAV mice. Overall, the renal infiltration of neutrophils, macrophages, B cells, and T cells, was much higher in suPAR-Tg as compared to uPAR KO mice. At day 14, immunostaining exhibits marked expression of C5aR1 in suPAR-Tg kidneys, whereas it is barely detectable in kidneys of uPAR KO mice. Accordingly, more prominent renal MPO staining was observed in suPAR-Tg as compared to uPAR KO mice. At day 21, the renal neutrophil infiltration declined, along with C5aR1 and MPO expression, whereas macrophage, CD4 and CD8 T cells infiltration increased. At protein level, the PPI profiling of suPAR interactome predicts a stable interaction between suPAR and C5aR1, which is verified by AlphaFold 3 analysis. Co-IP experiments demonstrate the interaction between C5aR1 and suPAR in HEK293 cells, while SPR assay indicates a strong binding affinity between the two proteins.
Conclusion
In this study, we found that circulating suPAR was elevated in the anti-MPO antibody-induced AAV in mice, where the renal C5aR1 expression could be suPAR dependent. As a strong biophysical suPAR-C5aR1 interaction was established, dual modulation of suPAR and C5aR1 activity may represent a novel therapeutic concept for the treatment of AAV.
Funding
- NIDDK Support