c-MYC-induced long noncoding RNA MEG3 aggravates kidney ischemia–reperfusion injury through activating mitophagy by upregulation of RTKN to trigger the Wnt/β-catenin pathway
Autor: | Xiaotong Zheng, Dajun Liu, Ying Liu, Naiquan Liu |
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Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
Male
0301 basic medicine Cancer Research Apoptosis urologic and male genital diseases Kidney Tubules Proximal 0302 clinical medicine Mitophagy Wnt Signaling Pathway MEG3 Chemistry lcsh:Cytology Wnt signaling pathway Acute Kidney Injury female genital diseases and pregnancy complications Mitochondria Up-Regulation medicine.anatomical_structure Reperfusion Injury 030220 oncology & carcinogenesis Female RNA Long Noncoding Renal cortex Immunology Article Cell Line Proto-Oncogene Proteins c-myc 03 medical and health sciences Cellular and Molecular Neuroscience Downregulation and upregulation GTP-Binding Proteins medicine Animals Humans cardiovascular diseases lcsh:QH573-671 Renal ischemia urogenital system fungi Cell Biology Mice Inbred C57BL Disease Models Animal MicroRNAs 030104 developmental biology Catenin Long non-coding RNAs Cancer research Apoptosis Regulatory Proteins |
Zdroj: | Cell Death and Disease, Vol 12, Iss 2, Pp 1-16 (2021) Cell Death & Disease |
ISSN: | 2041-4889 |
Popis: | Ischemia–reperfusion injury (IRI)-induced acute kidney injury (AKI) is a life-threatening disease. The activation of mitophagy was previously identified to play an important role in IRI. Maternally expressed 3 (MEG3) can promote cerebral IRI and hepatic IRI. The present study was designed to study the role of MEG3 in renal IRI. Renal IRI mice models were established, and HK-2 cells were used to construct the in vitro models of IRI. Hematoxylin–eosin staining assay was applied to reveal IRI-triggered tubular injury. MitoTracker Green FM staining and an ALP kit were employed for detection of mitophagy. TdT-mediated dUTP-biotin nick-end labeling assay was used to reveal cell apoptosis. The results showed that renal cortex of IRI mice contained higher expression of MEG3 than that of sham mice. MEG3 expression was also elevated in HK-2 cells following IRI, suggesting that MEG3 might participate in the development of IRI. Moreover, downregulation of MEG3 inhibited the apoptosis of HK-2 cells after IRI. Mitophagy was activated by IRI, and the inhibition of MEG3 can restore mitophagy activity in IRI-treated HK-2 cells. Mechanistically, we found that MEG3 can bind with miR-145-5p in IRI-treated cells. In addition, rhotekin (RTKN) was verified to serve as a target of miR-145-5p. MEG3 upregulated RTKN expression by binding with miR-145-5p. Further, MEG3 activated the Wnt/β-catenin pathway by upregulation of RTKN. The downstream effector of Wnt/β-catenin pathway, c-MYC, served as the transcription factor to activate MEG3. In conclusion, the positive feedback loop of MEG3/miR-145-5p/RTKN/Wnt/β-catenin/c-MYC promotes renal IRI by activating mitophagy and inducing apoptosis, which might offer a new insight into the therapeutic methods for renal IRI in the future. |
Databáze: | OpenAIRE |
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