Complement C5aR-Mediated Tubular Mitochondrial Dysregulation in Kidney Ischemia-Reperfusion Injury-Induced AKI to CKD

Background: Activation of C5a/C5aR axis contributes to the progression of kidney ischemia-reperfusion injury (IRI), but the mechanisms remain unclear. Potential harm to mitochondrial homeostasis can cause biological disturbances, the production of reactive oxygen species and ultimately cell death and kidney dysfunction. In this study, we aim to explore the role of tubular C5aR1 on mitochondrial homeostasis during IRI-induced acute kidney injury (AKI) to chronic kidney disease (CKD). Methods: Tubule-specific C5aR1 knockout mice (C5aR1lox/lox, KspCre; KO) and their littermates without Cre allele (C5aR1lox/lox; WT) were subjected to kidney bilateral ischemia/reperfusion injury (BIRI) and sacrificed 7 days later. Kidney damage was assessed by evaluating kidney function, histopathological changes and expression levels of pro-inflammatory, fibrotic, oxidative stress, apoptotic and mitochondrial function related markers. Results: C5aR1 KO mice exhibited significant decrease in serum BUN and creatinine levels and showed a markedly reduction in the expression levels of kidney injury marker Kim1 and NGAL in the 7-day BIRI model compared to WT controls. Along with the improvement in kidney function, the number of apoptotic tubular cells and cleaved caspase-3 expression were reduced, resulting in less tubular injury in KO mice. The expression levels of inflammation and fibrosis markers were significantly decreased in kidney tissues of KO mice after BIRI. Mitochondrial function was improved with a decrease in oxidative stress markers (NOX2 and 8-OHdG) and an increase in mitochondrial DNA copy number (ND1) and biogenesis (PGC1α) in KO mice after BIRI. Conclusion: Tubular deficiency of C5aR1 mitigates IRI-induced kidney damage and apoptosis by reducing mitochondrial dysfunction and oxidative stress. Funding: Research Grants Council of Hong Kong (General Research Fund, grant no. 17108222), Hong Kong Society of Nephrology Research Grant (2021)