Abstract: SA-PO0301
METTL3-Mediated m6A Modification of NDRG1 Promotes AKI Sensitivity in Diabetic Models
Session Information
- Diabetic Kidney Disease: Basic and Translational Science Advances - 2
November 08, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 701 Diabetic Kidney Disease: Basic
Authors
- Li, Haidi, Anhui Medical University, Hefei, Anhui, China
- Wang, Jianan, Anhui Medical University, Hefei, Anhui, China
- Wei, Biao, The University of Hong Kong, Hong Kong, Hong Kong
- Guo, Jianbo, The University of Hong Kong, Hong Kong, Hong Kong
- Shao, Baoyi, The University of Hong Kong, Hong Kong, Hong Kong
- Wang, Yifan, The University of Hong Kong, Hong Kong, Hong Kong
- Meng, Xiaoming, Anhui Medical University, Hefei, Anhui, China
- Chen, Hai-Yong, The University of Hong Kong, Hong Kong, Hong Kong
Background
Incidence of acute kidney injury (AKI) in diabetic populations exhibit a progressive increase, yet the molecular mechanism driving this susceptibility remain poorly elucidated. This study aims to investigate the roles and mechanism of METTL3 in promoting AKI sensitivity in diabetic conditions.
Methods
The mendelian randomization analysis were conducted to evaluate causal relationship between AKI and diabetic kidney disease (DKD). METTL3 expression and m6A levels were determined in type 1 (streptozotocin [STZ]-induced) and type 2 (db/db) mouse models undergoing AKI. METTL3 knockout or silencing was performed to evaluate its functional consequences on ischemia-reperfusion (I/R)-induced AKI in the two diabetic models. Parallel in vitro experiments utilized renal tubular epithelial cells (mTECs) exposed to and hypoxia-reoxygenation (H/R) and high glucose (HG) conditions. The m6A RNA immunoprecipitation sequencing (MeRIP-seq) was employed to identify METTL3 downstream targets, followed by validations.
Results
The causal relationship analysis of GWAS data from 4111 DKD patients and 5908 AKI patients revealed a 16% higher risk of AKI in patients with DKD. Our findings revealed that I/R or H/R resulted more severe AKI in two diabetic mouse models and HG-treated mTECs, associated with the increase of the m6A levels and METTL3 expression. Both knockout of METTL3 in tubular epithelial cells in STZ-treated conditional knockout mice and silencing METTL3 in db/db mice alleviated I/R-induced AKI. MeRIP-seq analysis identified N-myc downstream regulated 1 (NDRG1) as a target of METTL3. We further revealed that METTL3-mediated m6A modification of NDRG1 stabilized it in an IGF2BP2-dependent manner. Overexpression of METTL3 in H/R and HG-treated mTECs increased inflammation and NDRG1 level while knockdown of METTL3 reduced the inflammation and NDRG1 level. Mechanistically, downregulation of NDRG1 inhibited NF-κB p65 by enhancing the activity NUR77.
Conclusion
METTL3 enhances AKI susceptibility in DKD through m6A modification of NDRG1 and enhances its stability via IGF2BP2-dependent mechanisms, thereby exacerbating inflammation by NDRG1/NUR77/NF-κB signaling pathway.