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- Title
Inhibition of METTL3 attenuates renal injury and inflammation by alleviating TAB3 m6A modifications via IGF2BP2-dependent mechanisms.
- Authors
Wang, Jia-nan; Wang, Fang; Ke, Jing; Li, Zeng; Xu, Chuan-hui; Yang, Qin; Chen, Xin; He, Xiao-yan; He, Yuan; Suo, Xiao-guo; Li, Chao; Yu, Ju-tao; Jiang, Ling; Ni, Wei-jian; Jin, Juan; Liu, Ming-ming; Shao, Wei; Yang, Chen; Gong, Qian; Chen, Hai-yong
- Abstract
The role of N6-methyladenosine (m6A) modifications in renal diseases is largely unknown. Here, we characterized the role of N6-adenosine-methyltransferase-like 3 (METTL3), whose expression is elevated in renal tubules in different acute kidney injury (AKI) models as well as in human biopsies and cultured tubular epithelial cells (TECs). METTL3 silencing alleviated renal inflammation and programmed cell death in TECs in response to stimulation by tumor necrosis factor–α (TNF-α), cisplatin, and lipopolysaccharide (LPS), whereas METTL3 overexpression had the opposite effects. Conditional knockout of METTL3 from mouse kidneys attenuated cisplatin- and ischemic/reperfusion (I/R)–induced renal dysfunction, injury, and inflammation. Moreover, TAB3 [TGF-β–activated kinase 1 (MAP3K7) binding protein 3] was identified as a target of METTL3 by m6A methylated RNA immunoprecipitation sequencing and RNA sequencing. The stability of TAB3 was increased through binding of IGF2BP2 (insulin-like growth factor 2 binding protein 2) to its m6A-modified stop codon regions. The proinflammatory effects of TAB3 were then explored both in vitro and in vivo. Adeno-associated virus 9 (AAV9)–mediated METTL3 silencing attenuated renal injury and inflammation in cisplatin- and LPS-induced AKI mouse models. We further identified Cpd-564 as a METTL3 inhibitor that had better protective effects against cisplatin- and ischemia/reperfusion-induced renal injury and inflammation than S-adenosyl-l-homocysteine, a previously identified METTL3 inhibitor. Collectively, METTL3 promoted m6A modifications of TAB3 and enhanced its stability via IGF2BP2-dependent mechanisms. Both genetic and pharmacological inhibition of METTL3 attenuated renal injury and inflammation, suggesting that the METTL3/TAB3 axis is a potential target for treatment of AKI. Minimizing METTL3: N6-methyladenosine (m6A) modifications to mRNA can affect splicing, translation, and stability of transcripts, but the role of these modifications in acute kidney injury (AKI) has not been well defined. Here, Wang and colleagues identified that methyltransferase-like 3 (METTL3) was induced in human and murine AKI. METTL3 contributed to the pathogenesis of AKI through m6A modification of TAB3 [TGF-β–activated kinase 1 (MAP3K7) binding protein 3] mRNA, leading to increased stability of the transcript. The authors further identified a METTL3 inhibitor that attenuated renal injury and inflammation in mouse models of AKI when given within 24 hours of injury, suggesting that the METTL3-TAB3 axis could be a potential target in the prevention and treatment of this condition.
- Subjects
CISPLATIN; INSULIN-like growth factor-binding proteins; PROGRAMMED cell death 1 receptors; APOPTOSIS; EPITHELIAL cell culture; ACUTE kidney failure; KIDNEY tubules
- Publication
Science Translational Medicine, 2022, Vol 14, Issue 640, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.abk2709