1. Academic Validation
  2. mmu-lncRNA 121686/hsa-lncRNA 520657 induced by METTL3 drive the progression of AKI by targeting miR-328-5p/HtrA3 signaling axis

mmu-lncRNA 121686/hsa-lncRNA 520657 induced by METTL3 drive the progression of AKI by targeting miR-328-5p/HtrA3 signaling axis

  • Mol Ther. 2022 Jul 21;S1525-0016(22)00435-X. doi: 10.1016/j.ymthe.2022.07.014.
Jian Pan 1 Yuxin Xie 1 Huiling Li 2 Xiaozhou Li 1 Junxiang Chen 3 Xiangfeng Liu 4 Jun Zhou 4 Xianming Tang 5 Zhibiao He 1 Zhenyu Peng 1 Hongliang Zhang 1 Yijian Li 6 Xudong Xiang 1 Yunchang Yuan 7 Dongshan Zhang 8
Affiliations

Affiliations

  • 1 Department of Emergency Medicine, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China; Emergency Medicine and Difficult Diseases Institute, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China; Hunan Clinical Medical Research Center for Acute Organ Injury and Repair, Changsha, Hunan 410011, People's Republic of China.
  • 2 Department of Ophthalmology, Second Xiangya Hospital, Changsha, Hunan 410011, People's Republic of China.
  • 3 Department of Nephrology, Second Xiangya Hospital, Changsha, Hunan 410011, People's Republic of China.
  • 4 Department of General Surgery, Second Xiangya Hospital, Changsha, Hunan 410011, People's Republic of China; Hunan Clinical Medical Research Center for Acute Organ Injury and Repair, Changsha, Hunan 410011, People's Republic of China.
  • 5 Department of Chest Surgery, Second Xiangya Hospital, Changsha, Hunan 410011, People's Republic of China; Hunan Clinical Medical Research Center for Acute Organ Injury and Repair, Changsha, Hunan 410011, People's Republic of China.
  • 6 Department of Urinary Surgery, Second Xiangya Hospital, Changsha, Hunan 410011, People's Republic of China.
  • 7 Department of Chest Surgery, Second Xiangya Hospital, Changsha, Hunan 410011, People's Republic of China.
  • 8 Department of Emergency Medicine, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China; Emergency Medicine and Difficult Diseases Institute, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China; Hunan Clinical Medical Research Center for Acute Organ Injury and Repair, Changsha, Hunan 410011, People's Republic of China. Electronic address: dongshanzhang@csu.edu.cn.
Abstract

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.

Keywords

AKI; METTL3; hsa_lncRNA 520657; miR-328-5pHtrA3; mmu_lncRNA 121686.

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