C5a-C5aR1 axis activation drives neutrophil extracellular trap formation in SARS-CoV-2 N protein-mediated acute kidney injury.

The mechanism of COVID-19-associated acute kidney injury (AKI) remains incompletely understood. This study aimed to investigate the regulatory role of the C5a-C5aR1 axis in neutrophil extracellular trap (NET) formation in SARS-CoV-2 nucleocapsid (N) protein-induced AKI. An AKI mouse model with kidney-specific N protein expression was established using ultrasound-microbubble-mediated technology, and interventions with the C5aR1 inhibitor DF2593A or DNase I (Pulmozyme) were administered to detect renal neutrophil infiltration, NET deposition, C5a-C5aR1 expression, and renal function indices. The results showed that N protein expression significantly induced neutrophil infiltration and NET formation, accompanied by elevated serum C5a and upregulated C5aR1. Inhibition of C5aR1 or degradation of NETs effectively attenuated renal tubular injury and decreased serum creatinine, blood urea nitrogen, and kidney injury molecule-1 (KIM-1) levels. In conclusion, activation of the C5a-C5aR1 axis contributes to N protein-mediated AKI by driving NET formation, and targeting this axis may provide a potential therapeutic strategy for COVID-19-associated renal injury.