METTL3/CXCL10 axis contributes to renal fibrosis by promoting the apoptosis of tubular epithelial cells.

Abstract

In response to tubular cell injury, the injured tubular cells undergoing apoptosis initiate the progression of renal fibrosis by releasing profibrotic factors and mediating intercellular communications. However, the regulatory mechanisms underlying tubular cell apoptosis remain elusive. In this study, we found that METTL3, the core methyltransferase of RNA N-methyladenosine (mA) modification, is significantly increased in tubular cells in various renal fibrosis models. Knockdown of METTL3 ameliorated ischemia-reperfusion injury (IRI)- and unilateral ureteral obstruction (UUO)- induced renal fibrosis in mice. Transcriptome sequencing analysis revealed a causal role METTL3 in promoting CXCL10 expression and activating the proapoptotic pathways in tubular epithelial cells (TECs). Our mechanistic study showed that METTL3-catalzed mA modification of CXCL10 mRNA increased mRNA stability, and, thus, led to the upregulation of CXCL10 in the injured TECs both in vitro and in vivo. While CXCL10 induced the apoptosis of TECs at a time- and dose-dependent manner, application of neutralizing antibody against CXCL10 significantly suppressed the METTL3-mediated apoptosis of TECs, and protected TECs from HO- and cisplatin-induced apoptosis as well. Finally, heterozygous deletion of METTL3 in vivo protected the mice from renal fibrosis through suppressing tubular cell apoptosis, but systemic administration of CXCL10 abolished the protective effect of METTL3 deletion on tubular cell apoptosis and subsequent renal fibrosis. In conclusion, our findings identify the METTL3/CXCL10 axis and its proapoptotic functions on TECs as an important pathogenic cause of renal fibrosis, thereby suggesting a potential therapeutic option in kidney diseases.