Aristolocholic acid I promotes renal tubular epithelial fibrosis by upregulating matrix metalloproteinase-9 expression via activating the C3a/C3aR axis of macrophages

Aristolochic acid I (AAI) can cause nephrotoxicity and is characterized by interstitial fibrosis. The C3a/C3aR axis of macrophages and matrix metalloproteinase-9 (MMP-9) play important roles in fibrosis, but whether they are involved in AAI-induced renal interstitial fibrosis and are related remains to be elucidated. In this study, we investigated whether C3a/C3aR axis of macrophages promotes renal interstitial fibrosis by regulating MMP-9 in aristolochic acid nephropathy (AAN). Intraperitoneal injection of AAI for 28 days successfully induced AAN in C57bl/6 mice. The content of C3a in the kidney of AAN mice was increased, and there was a significant dis-tribution of macrophages in the renal tubules. The same results were observed in the in vitro experiment. We also explored the role and mechanism of macrophages after AAI administration in the epithelial-mesenchymal transformation (EMT) of renal tubular epithelial cells (RTECs) and found that AAI could activate the C3a/C3aR axis of macrophages to upregulate p65 expression in macrophages. p65 upregulated MMP-9 expression in macrophages not only directly but also by promoting the secretion if interleukin-6 by macrophages and then activating STAT3 in RTECs. The upregulation of MMP-9 expression could promote the EMT of RTECs. Taken together, our study demonstrated that the AAI-activated the C3a/C3aR axis of macrophages, which induced MMP-9 production, was one of the causes of renal interstitial fibrosis. Therefore, targeting the C3a/C3aR axis of macrophages is an effective therapeutic strategy for the prevention and treatment of renal interstitial fibrosis in AAN.

Automated summary

Aristolochic acid I (AAI) can induce nephrotoxicity and interstitial fibrosis. This study investigated the role of the C3a/C3aR axis of macrophages in AAI-induced renal interstitial fibrosis. The results showed that AAI increased the content of C3a in the kidney and promoted the distribution of macrophages in the renal tubules. AAI also activated the C3a/C3aR axis to upregulate p65 expression in macrophages, which in turn upregulated MMP-9 expression and promoted the epithelial-mesenchymal transformation (EMT) of renal tubular epithelial cells (RTECs) by activating STAT3 through the secretion of interleukin-6 by macrophages. Targeting the C3a/C3aR axis of macrophages may be a promising therapeutic strategy for renal interstitial fibrosis in AAI-induced nephropathy.