m6A RNA Methylation Drives Kidney Fibrosis by Upregulating β-Catenin Signaling

Background: The N6-methyladenosine (m6A) methylation plays a crucial role in various biological processes and the pathogenesis of human diseases. However, its role and mechanism in kidney fibrosis remain elusive. Methods: The level of m6A methylation and the expression of METTL3 were assessed in mouse models and human kidney biopsies of chronic kidney disease (CKD). Conditional knockout mice with proximal tubule-specific deletion of METTL3 and mice with overexpression of METTL3 were used to corroborate a role of METTL3/β-catenin in kidney fibrosis. Results: The overall level of m6A methylated RNA was upregulated and the m6A methyltransferase METTL3 was induced in kidney tubular epithelial cells in mouse models and human kidney biopsies of chronic kidney disease (CKD). Proximal tubule-specific knockout of METTL3 in mice protected kidneys against developing fibrotic lesions after injury. Conversely, overexpression of METTL3 aggravated kidney fibrosis in vivo. Through bioinformatics analysis and experimental validation, we identified β-catenin mRNA as a major target of METTL3-mediated m6A modification, which could be recognized by a specific m6A reader, the insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3). METTL3 stabilized β-catenin mRNA, increased β-catenin protein and induced its downstream profibrotic genes, whereas either knockdown of IGF2BP3 or inhibiting β-catenin signaling abolished its effects. Conclusion: These results indicate that METTL3 promotes kidney fibrosis by stimulating the m6A modification of β-catenin mRNA, leading to its stabilization and its downstream profibrotic genes expression. Our findings suggest that targeting METTL3/IGF2BP3/β-catenin pathway may be a novel strategy for the treatment of fibrotic CKD. Funding: Government Support – Non-U.S.