The pathogenesis of acute kidney injury (AKI) is still not fully understood, and effective interventions are lacking. Here, we explored whether methyltransferase 3 (METTL3) was involved in the progression of AKI via regulation of cell death. We reported that PT（proximal tubule）-METTL3-knockout (KO) noticeably suppressed ischemic-induced AKI via inhibition of renal cell apoptosis. Furthermore, we also found that the expression of mmu-long non-coding RNA (lncRNA) 121686 was upregulated in antimycin-treated Boston University mouse proximal tubule (BUMPT) cells and a mouse ischemia-reperfusion (I/R)-induced AKI model. Functionally, mmu-lncRNA 121686 could promote I/R-induced mouse renal cell apoptosis. Mechanistically, mmu-lncRNA 121686 acted as a competing endogenous RNA (ceRNA) to prevent microRNA miR-328-5p-mediated downregulation of high-temperature requirement factor A 3 (Htra3). PT-mmu-lncRNA 121686-KO mice significantly ameliorated the ischemic-induced AKI via the miR-328-5p/HtrA3 axis. In addition, hsa-lncRNA 520657, homologous with lncRNA 121686, sponged miR-328-5p and upregulated Htra3 to promote I/R-induced human renal cell apoptosis. Interestingly, we found that mmu-lncRNA 121686/hsa-lncRNA 520657 upregulation were dependent on METTL3 via N⁶-methyladenosine (m⁶A) modification. The mmu-lncRNA 121686/miR-328-5p or hsa-lncRNA 520657/miR-328-5p /HtrA3 axis was induced in vitro by METTL3 overexpression; in contrast, this effect was attenuated by METTL3 small interfering RNA (siRNA). Furthermore, we found that PT-METTL3-KO or METTL3 siRNA significantly suppressed ischemic, septic, and vancomycin-induced AKI via downregulation of the mmu-lncRNA 121686/miR-328-5p/HtrA3 axis. Taken together, our data indicate that the METTL3/mmu-lncRNA 121686/hsa-lncRNA 520657/miR-328-5p/HtrA3 axis potentially acts as a therapeutic target for AKI.

急性肾损伤（AKI）的发病机制尚不完全清楚，缺乏有效的干预措施。在这里，我们探讨了甲基转移酶 3 (METTL3) 是否通过调节细胞死亡参与 AKI 的进展。我们报道，PT（近端小管）-METTL3 敲除（KO）通过抑制肾细胞凋亡，显着抑制缺血诱导的 AKI。此外，我们还发现，在抗霉素处理的波士顿大学小鼠近曲小管（BUMPT）细胞和小鼠缺血再灌注（I/R）诱导的 AKI 模型中，mmu 长非编码 RNA（lncRNA）121686 的表达上调。从功能上讲，mmu-lncRNA 121686 可以促进 I/R 诱导的小鼠肾细胞凋亡。从机制上讲，mmu-lncRNA 121686 充当竞争性内源 RNA (ceRNA)，以防止 microRNA miR-328-5p 介导的高温需求因子 A 3 (Htra3) 下调。 PT-mmu-lncRNA 121686-KO 小鼠通过 miR-328-5p/HtrA3 轴显着改善缺血诱导的 AKI。此外，与lncRNA 121686同源的hsa-lncRNA 520657通过海绵miR-328-5p并上调Htra3来促进I/R诱导的人肾细胞凋亡。有趣的是，我们发现 mmu-lncRNA 121686/hsa-lncRNA 520657 上调依赖于 METTL3 通过 N ⁶ -甲基腺苷 (m ⁶ A) 修饰。 mmu-lncRNA 121686/miR-328-5p 或 hsa-lncRNA 520657/miR-328-5p/HtrA3 轴在体外通过 METTL3 过表达诱导；相反，METTL3 小干扰 RNA (siRNA) 减弱了这种效应。此外，我们发现 PT-METTL3-KO 或 METTL3 siRNA 通过下调 mmu-lncRNA 121686/miR-328-5p/HtrA3 轴，显着抑制缺血、脓毒症和万古霉素诱导的 AKI。 综上所述，我们的数据表明 METTL3/mmu-lncRNA 121686/hsa-lncRNA 520657/miR-328-5p/HtrA3 轴可能作为 AKI 的治疗靶点。