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Involvement of phosphatase and tensin homolog-induced putative kinase 1-Parkin-mediated mitophagy in septic acute kidney injury

摘要:

Background:Studies have reported mitophagy activation in renal tubular epithelial cells (RTECs) in acute kidney injury (AKI).Phosphatase and tensin homolog-induced putative kinase 1 (PINK1) and E3 ubiquitin-protein ligase Parkin are involved in mitophagy regulation;however,little is known about the role of PINK1-Parkin mitophagy in septic AKI.Here we investigated whether the PINK1-Parkin mitophagy pathway is involved in septic AKI and its effects on cell apoptosis in vitro and on renal functions in vivo.Methods:Mitophagy-related gene expression was determined using Western blot assay in human RTEC cell line HK-2 stimulated with bacterial lipopolysaccharide (LPS) and in RTECs from septic AKI rats induced by cecal ligation and perforation (CLP).Autophagy-related ultrastructural features in rat RTECs were observed using electron microscopy.Gain-and loss-of-function approaches were performed to investigate the role of the PINK1-Parkin pathway in HK-2 cell mitophagy.Autophagy activators and inhibitors were used to assess the effects of mitophagy modulation on cell apoptosis in vitro and on renal functions in vivo.Results:LPS stimulation could significantly induce LC3-Ⅱ and BECN-1 protein expression (LC3-Ⅱ:1.72 ± 0.05 vs.1.00 ± 0.05,P<0.05;BECN-1:5.33±0.57 vs.1.00±0.14,P< 0.05) at 4 h in vitro.Similarly,LC3-Ⅱ,and BECN-1 protein levels were significantly increased and peaked at 2 h after CLP (LC3-Ⅱ:3.33 ± 0.12 vs.1.03 ± 0.15,P < 0.05;BECN-1:1.57± 0.26 vs.1.02 ± 0.11,P < 0.05) in vivo compared with those after sham operation.Mitochondrial deformation and mitolysosome-mediated mitochondria clearance were observed in RTECs from septic rats.PINK1 knockdown significantly attenuated LC3-Ⅱ protein expression (1.35 ± 0.21 vs.2.38 ± 0.22,P < 0.05),whereas PINK 1 overexpression markedly enhanced LC3-Ⅱ protein expression (2.07± 0.21 vs.1.29 ± 0.19,P < 0.05) compared with LPS-stimulated HK-2 cells.LPS-induced proapoptotic protein expression remained unchanged in autophagy activator-treated HK-2 cells and was significantly attenuated in PINK1-overexpressing cells,but was remarkably upregulated in autophagy inhibitor-treated and in HNK1-depleted cells.Consistent results were observed in flow cytometric apoptosis assay and in renal function indicators in rats.Conclusion:PINK1-Parkin-mediated mitophagy might play a protective role in septic AKI,serving as a potential therapeutic target for septic AKI.

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作者单位: Department of Intensive Care Unit, Xiangya Hospital, Central South University, Changsha, Hunan 410078, China;Department of Critical Care Medicine, The First People's Hospital of Chenzhou, Chenzhou, Hunan 423000, China [1] Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China [2] Department of Critical Care Medicine, The First People's Hospital of Chenzhou, Chenzhou, Hunan 423000, China [3] Department of Intensive Care Unit, Xiangya Hospital, Central South University, Changsha, Hunan 410078, China [4]
期刊: 《中华医学杂志(英文版)》2019年132卷19期 2340-2347页 SCIMEDLINEISTICCSCDBP
栏目名称: Original Articles
DOI: 10.1097/CM9.0000000000000448
发布时间: 2019-11-19
基金项目:
grants from the National Natural Science Foundation of China the Natural Science Foundation of Hunan Province,China
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