Complement C5aR blockade attenuates LPS-induced acute kidney injury by regulating ferroptosis via nuclear factor-erythroid 2-related factor 2 signaling in mice

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Acute kidney injury (AKI) is a prevalent and severe condition characterized by sudden renal dysfunction. In this investigation, we explored the therapeutic potential of C5a receptor (C5aR) blockade in a murine model of lipopolysaccharide (LPS)-induced AKI. Our findings reveal that LPS administration disrupts renal morphology, while treatment with the C5aR antagonist W54011 effectively reverses these changes. Moreover, W54011 significantly reduces renal iron content, implying its possible involvement in ferroptosis. C5aR blockade not only attenuates LPS-induced AKI by lowering levels of N-acetyl-β-D-glucosaminidase (NAG) and proinflammatory cytokines but also modulates markers related to oxidative stress. Transmission electron microscopy analysis indicated the role of W5401 in safeguarding tubular epithelial cells from mitochondrial damage, underscoring its protective effects against ferroptosis-induced cellular structural deterioration. Further analyses via Western blot and immunofluorescence detection illustrate that C5aR blockade suppresses p38 phosphorylation, thus restoring the activity of the Nrf2/SLC7A11/GPX4 signaling pathway within the kidney. This restoration leads to heightened expression of antioxidant enzymes and cytoprotective proteins. In summary, our study underscores that W54011-mediated C5aR blocking alleviates LPS-induced AKI by modulating the p38/Nrf2/SLC7A11/GPX4 signaling axis. These findings accentuate the potential therapeutic significance of targeting the C5aR pathway to counteract ferroptosis in kidney-related ailments.

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