Intrarenal synthesis of complement C3 localized to distinct vascular compartments in ANCA-associated renal vasculitis.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a small vessel vasculitis affecting multiple organ systems, including the kidney. The activation of the complement system contributes essentially to its pathogenesis by autoantibody-antigen recognition directed against host cells in ANCA-associated renal vasculitis. We herein provide evidence for intrarenal synthesis of complement C3 localized to distinct vascular compartments in ANCA-associated renal vasculitis that associated with distinct inflammatory signaling pathways. Therefore, a total number of 43 kidney biopsies with ANCA-associated renal vasculitis were retrospectively included and evaluated for presence/absence of C3 deposits localized to distinct vascular compartments in association with clinicopathological biopsy findings. In addition, intrarenal C3 mRNA expression levels specifically from microdissected tubulointerstitial and glomerular compartments were extracted from transcriptome datasets. C3 deposits were present in the glomerular tuft, interlobular arteries, peritubular capillaries, and venules in ANCA-associated renal vasculitis. Most C3 deposits are localized to the glomerular tuft overlapping with peritubular capillaries. The presence of C3 deposits in the glomerular tuft correlated with impaired kidney function and overall short-term survival. Intrarenal complement C3 deposits were not associated with consumption of respective serum levels, supporting the concept of intrarenal C3 synthesis. Finally, intrarenal synthesis of complement C3 was linked to distinct inflammatory signaling pathways in the kidney that is especially relevant in ANCA-associated renal vasculitis. Considering recent advances in AAV therapy with the emergence of new therapeutics that inhibit complement activation, we here provide novel insights into intrarenal complement synthesis and associated inflammatory signaling pathways in ANCA-associated renal vasculitis.

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Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of competing interest SH, DT, EB, IAK, PS and BT have no conflicts of interest to report related to this study.