Involvement of YTHDF1 in renal fibrosis progression via up-regulating YAP
Jia Xing1, Yu-Chen He2, Kai-Yue Wang1
1Department of Histology and Embryology, China Medical University, Shenyang, China.
Abstract:
Renal fibrosis is a progressive, fatal renal disease characterized by the aberrant accumulation of myofibroblasts that produce excess extracellular matrix (ECM) in the renal interstitium and glomeruli. Yes-associated protein (YAP) has been regarded as a crucial modulator in myofibroblast transformation, but its upstream regulator remains a mystery. In the present study investigating the participation of m6A methylation during renal fibrosis through bioinformatics analysis, we identified YTHDF1, a modulator of m6A methylation, as a key contributor for renal fibrosis because it was highly expressed in human fibrotic kidneys and had a significant correction with YAP. Their co-localization in human fibrotic kidneys was additionally shown by immunofluorescence. We then found that YTHDF1 was also up-regulated in fibrotic mouse kidneys induced by unilateral ureteral obstruction (UUO), high-dose folic acid administration, or the unilateral ischemia-reperfusion injury, further supporting a causal role of YTHDF1 during renal fibrosis. Consistent with this notion, YTHDF1 knockdown alleviated the progression of renal fibrosis both in cultured cells induced by transforming growth factor-beta administration and in the UUO mouse model. Meanwhile, YAP was accordingly down-regulated when YTHDF1 was inhibited. Furthermore, the specific binding of YTHDF1 to YAP mRNA was detected using RNA Binding Protein Immunoprecipitation, and the up-regulation of fibrotic related molecules in cultured cells induced by YTHDF1 over-expression plasmid was attenuated by YAP siRNA. Taken together, our data highlight the potential utility of YTHDF1 as an indicator for renal fibrosis and suggest that YTHDF1 inhibition might be a promising therapeutic strategy to alleviate renal fibrosis via downregulating YAP.
Insights
YTHDF1, an m6A methylation regulator, is highly expressed in fibrotic kidneys and drives renal fibrosis by upregulating Yes-associated protein (YAP). Inhibiting YTHDF1 alleviates fibrosis, suggesting YTHDF1 as a therapeutic target.
Area of Science:
- Nephrology
- Molecular Biology
- Epigenetics
Background:
- Renal fibrosis involves excessive extracellular matrix accumulation driven by myofibroblasts.
- Yes-associated protein (YAP) is a key regulator of myofibroblast transformation, but its upstream control is unclear.
- m6A methylation's role in renal fibrosis requires further investigation.
Purpose of the Study:
- To investigate the role of m6A methylation in renal fibrosis.
- To identify upstream regulators of YAP in renal fibrosis.
- To explore YTHDF1 as a potential therapeutic target for renal fibrosis.
Main Methods:
- Bioinformatics analysis to identify key m6A regulators.
- Immunofluorescence to confirm protein co-localization.
- In vivo studies using mouse models of renal fibrosis (UUO, folic acid, ischemia-reperfusion).
- In vitro studies using TGF-β-induced cells.
- RNA Binding Protein Immunoprecipitation (RIP) to detect mRNA binding.
Main Results:
- YTHDF1 was highly expressed in human and mouse fibrotic kidneys and correlated with YAP.
- YTHDF1 upregulation was observed in various kidney injury models.
- YTHDF1 knockdown ameliorated renal fibrosis and reduced YAP levels in vitro and in vivo.
- YTHDF1 directly binds to YAP mRNA.
- YAP inhibition attenuated YTHDF1-induced fibrotic gene expression.
Conclusions:
- YTHDF1 is a crucial mediator of renal fibrosis, acting upstream of YAP.
- YTHDF1 is a potential biomarker for renal fibrosis.
- Targeting YTHDF1 may offer a novel therapeutic strategy for renal fibrosis by downregulating YAP.
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