A Newly Identified Protective Role of C5a Receptor 1 in Kidney Tubules against Toxin-Induced Acute Kidney Injury.

Abstract

Acute kidney injury (AKI) remains a major reason for hospitalization with limited therapeutic options. Although complement activation is implicated in AKI, the role of C5a receptor 1 (C5aR1) in kidney tubular cells is unclear. We used aristolochic acid nephropathy (AAN) and folic acid nephropathy models to establish the role of C5aR1 in kidney tubules during AKI in germline C5ar1^-/- mice, myeloid cell-specific mice, and kidney tubule-specific C5ar1 knockout mice. After aristolochic acid and folic acid injection, C5ar1^-/- mice had increased AKI severity and a higher degree of tubular injury. Macrophage depletion in C5ar1^-/- mice or myeloid cell-specific C5ar1 deletion did not affect the outcomes of aristolochic acid-induced AKI. RNA-sequencing data from renal tubular epithelial cells (RTECs) showed that C5ar1 deletion was associated with the down-regulation of mitochondrial metabolism and ATP production transcriptional pathways. Metabolic studies confirmed reduced mitochondrial membrane potential at baseline and increased mitochondrial oxidative stress after injury in C5ar1^-/- RTECs. Moreover, C5ar1^-/- RTECs had enhanced glycolysis, glucose uptake, and lactate production on injury, corroborated by metabolomics analysis of kidneys from AAN mice. Kidney tubule-specific C5ar1 knockout mice recapitulated exacerbated AKI observed in C5ar1^-/- mice in AAN and folic acid nephropathy. Our data indicate that C5aR1 signaling in kidney tubules exerts renoprotective effects against toxin-induced AKI by limiting overt glycolysis and maintaining mitochondrial function, revealing a novel link between the complement system and tubular cell metabolism.