ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on X

Kidney Week

Abstract: SA-PO913

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

Session Information

Category: Pathology and Lab Medicine

  • 1800 Pathology and Lab Medicine

Authors

  • Long, Yinyi, Southern Medical University Nanfang Hospital, Guangzhou, Guangdong, China
  • Fu, Haiyan, Southern Medical University Nanfang Hospital, Guangzhou, Guangdong, China
  • Liu, Youhua, Southern Medical University Nanfang Hospital, Guangzhou, Guangdong, China
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.