2. Academic Validation
  3. 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.
PMID: 35869629 DOI: 10.1016/j.ymthe.2022.07.014
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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