Department of Nephrology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Department of Urology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
J Cell Biochem. 2020 Jan;121(1):524-533. doi: 10.1002/jcb.29258. Epub 2019 Jul 18.
Renal ischemia-reperfusion injury (IRI) is one of the most common causes of acute kidney injury (AKI), which is closely related to high morbidity and mortality. However, the pathogenesis underlying renal IRI is complex and not fully defined. N6-methyladenosine (m6A) was recently found to be an abundant modification in mammalian messenger RNAs. It is implicated in various biological processes, while the role of m6A in IRI is not illustrated. Here we show that the m6A-methylated RNA level and its methyltransferase METTL14 are elevated in human AKI renal tissues and IRI HK-2 cells. Moreover, METTL14 knockdown protects the kidney against IRI in vitro and in vivo. Mechanistically, we identified that YAP1 is a direct target of METTL14 in AKI progression. Inhibition of YAP1-TEAD signaling by peptide 17 abrogates the protective effect of METTL14 against IRI in vitro and in vivo. Taken together, these results reveal that the N6-methyladenosine mRNA methylase METTL14 promotes the renal IRI via suppressing YAP1. The discovery of the METTL14-YAP1 pathway provides an important new perspective for understanding AKI and is conducive to revealing new therapeutic strategies and targets.
肾缺血再灌注损伤（IRI）是急性肾损伤（AKI）最常见的原因之一，与高发病率和死亡率密切相关。然而，肾 IRI 的发病机制复杂，尚未完全明确。N6-甲基腺苷（m6A）最近被发现是哺乳动物信使 RNA 中一种丰富的修饰。它参与了各种生物学过程，而 m6A 在 IRI 中的作用尚未得到说明。在这里，我们发现在人类 AKI 肾组织和 IRI HK-2 细胞中，m6A-甲基化 RNA 水平及其甲基转移酶 METTL14 升高。此外，METTL14 的敲低可在体外和体内保护肾脏免受 IRI。在机制上，我们确定 YAP1 是 AKI 进展中 METTL14 的直接靶标。肽 17 抑制 YAP1-TEAD 信号传导可消除 METTL14 对体外和体内 IRI 的保护作用。总之，这些结果表明，N6-甲基腺苷 mRNA 甲基转移酶 METTL14 通过抑制 YAP1 促进肾 IRI。METTL14-YAP1 通路的发现为理解 AKI 提供了一个重要的新视角，有利于揭示新的治疗策略和靶点。
