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. 2024 Mar 15;38(5):e23436.
doi: 10.1096/fj.202302041R.

FTO-mediated m6A mRNA demethylation aggravates renal fibrosis by targeting RUNX1 and further enhancing PI3K/AKT pathway

Da-Xi Wang  1   2 , Si-Yu Bao  1   2 , Na-Na Song  1   2   3   4 , Wei-Ze Chen  1   2 , Xiao-Qiang Ding  1   2   3   4 , Robert J Walker  5 , Yi Fang  1   2   3   4
Affiliations

FTO-mediated m6A mRNA demethylation aggravates renal fibrosis by targeting RUNX1 and further enhancing PI3K/AKT pathway

Da-Xi Wang et al. FASEB J. .

Abstract

Chronic kidney disease (CKD) is a global health burden, with ineffective therapies leading to increasing morbidity and mortality. Renal interstitial fibrosis is a common pathway in advanced CKD, resulting in kidney function and structure deterioration. In this study, we investigate the role of FTO-mediated N6-methyladenosine (m6A) and its downstream targets in the pathogenesis of renal fibrosis. M6A modification, a prevalent mRNA internal modification, has been implicated in various organ fibrosis processes. We use a mouse model of unilateral ureteral obstruction (UUO) as an in vivo model and treated tubular epithelial cells (TECs) with transforming growth factor (TGF)-β1 as in vitro models. Our findings revealed increased FTO expression in UUO mouse model and TGF-β1-treated TECs. By modulating FTO expression through FTO heterozygous mutation mice (FTO+/- ) in vivo and small interfering RNA (siRNA) in vitro, we observed attenuation of UUO and TGF-β1-induced epithelial-mesenchymal transition (EMT), as evidenced by decreased fibronectin and N-cadherin accumulation and increased E-cadherin levels. Silencing FTO significantly improved UUO and TGF-β1-induced inflammation, apoptosis, and inhibition of autophagy. Further transcriptomic assays identified RUNX1 as a downstream candidate target of FTO. Inhibiting FTO was shown to counteract UUO/TGF-β1-induced RUNX1 elevation in vivo and in vitro. We demonstrated that FTO signaling contributes to the elevation of RUNX1 by demethylating RUNX1 mRNA and improving its stability. Finally, we revealed that the PI3K/AKT pathway may be activated downstream of the FTO/RUNX1 axis in the pathogenesis of renal fibrosis. In conclusion, identifying small-molecule compounds that target this axis could offer promising therapeutic strategies for treating renal fibrosis.

Keywords: N6 methyladenosine; RUNX1; apoptosis; autophagy; renal fibrosis.

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References

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