Abstract Background Excessive production of complement C5a detected in acute kidney injury (AKI) and during the development of chronic kidney disease (CKD) suggests its possible role in CKD progression, but the underlying mechanism remains unclear. Methods Global, tubule- and myeloid-specific C5aR1 knockout and PMX53-treated mice were subjected to bilateral ischemia reperfusion injury (BIRI). Cultured kidney tubular epithelial cells and bone marrow-derived macrophages were used to analyse the underlying cellular mechanisms. Results C5aR1 deficiency specifically in kidney tubular cells, but not in myeloid cells, impaired M1 and favored M2 macrophage polarization, resulting in attenuation of proinflammatory responses, oxidative stress and the subsequent tubulointerstitial fibrosis during the progression from AKI to CKD. Deletion of tubular C5aR1 also induced mitochondrial biogenesis with increased mitochondrial DNA copy number and ATP content and reduced cell apoptosis via induction of autophagy in kidney tubules. In vitro, treatment with the C5aR1 antagonist PMX53 attenuated cell apoptosis by enhancing BNIP3-regulated autophagy in C5a- and TNFα-stimulated kidney tubular epithelial cells, which in turn modulated macrophage polarization and inflammatory responses via a paracrine mechanism. Conclusions Our data reveal a detrimental role of the C5a/C5aR1 axis in AKI-to-CKD transition by triggering macrophage polarization towards a chronic inflammatory phenotype and disrupting mitochondrial homeostasis via the involvement of BNIP3-regulated autophagy in kidney tubular epithelial cells, leading to tubulointerstitial fibrosis and kidney dysfunction. Targeting C5aR1 may provide a promising therapeutic strategy for preventing CKD progression.
Ma et al. (2026) studied this question.