#2543 Complement Receptor C5aR1 Correlates with Inflammatory Responses Driven by Glomerular Upar Upregulation in Renal Vasculitides

Abstract Background and Aims Avacopan is a novel promising treatment for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) targeting the complement system by blocking C5a receptor C5aR1. We here pursued a transcriptome array-based approach to dissect molecular signatures associated with C5aR1 in renal vasculitis. Method C5aR1 mRNA expression levels (reporter ID: 210845_s_at, platform: Affymetrix Human Genome U133 Plus 2.0 Array, altCDF v10) were extracted from microdissected samples of renal vasculitis (glomerular: n = 23, tubulointerstitial: n = 21). Pathway analysis was performed for gene enrichment associated with PLAUR mRNA expression with a correlation threshold of ≥0.5 by using reactome (http://reactome.org), pathways with a predefined entities value of p≤0.001 were included. Results We here identified a predominant glomerular expression of C5aR1 in renal vasculitis as compared to the tubulointerstitial compartment (p < 0.0001). Furthermore, glomerular C5aR1 induction correlated with impaired kidney function (eGFR: 0.0193). Gene set enrichment identified various inflammatory signatures including neutrophil degranulation and innate immunity, and particularly enrichment of urokinase plasminogen activator receptor (uPAR). uPAR itself also correlated with impairment of kidney function in renal vasculitis and particularly active glomerular lesions (cellular crescents and necrosis, p < 0.0001). Conclusion The therapeutic implications of targeting uPAR in renal vasculitis are promising, and ongoing research endeavors are aimed at unraveling the complexities of uPAR as a potential diagnostic marker and therapeutic target for this challenging renal pathology. We here expand our current knowledge and link C5aR1 to inflammatory responses driven by glomerular uPAR upregulation in renal vasculitis.