Mammalian STE20-Like Kinase 1 Deletion Alleviates Renal Ischaemia-Reperfusion Injury via Modulating Mitophagy and the AMPK-YAP Signalling Pathway
Mammalian STE20-Like Kinase 1 Deletion Alleviates Renal Ischaemia-Reperfusion Injury via Modulating Mitophagy and the AMPK-YAP Signalling Pathway
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DOI：
10.1159/000495896
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发表时间：
2018-01-01
影响因子：
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通讯作者：
Li, Jingchun
中科院分区：
文献类型：
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作者：
Feng, Junxia;Li, Hongyan;Li, Jingchun
背景/目的：本研究旨在探讨哺乳动物STE20-like kinase1(Mst1)通过改变丝裂原吞噬和AMPK-Yap信号通路参与肾I/R损伤的分子机制。方法：建立WT小鼠和Mst1基因敲除小鼠在体肾缺血再灌注模型。体外用肾小管上皮细胞缺氧-复氧模型模拟肾I/R损伤。用Western blotting和免疫荧光法检测线粒体功能。采用信号通路阻断剂和siRNA基因敲除技术，研究AMPK-YAP信号通路在Mst1介导的线粒体凋亡中的作用。结果：在体大鼠肾脏I/R损伤后，Mst1表达上调，且Mst1含量升高与肾功能障碍和肾小管上皮细胞凋亡呈正相关。然而，Mst1的基因消融改善了肾功能，减轻了再灌注介导的肾小管上皮细胞凋亡，并减轻了肾脏对I/R损伤的易感性。在体外，Mst1上调导致线粒体损伤，包括线粒体电位降低、ROS超载、Cyt-c释放和caspase-9凋亡通路激活。在分子水平上，I/R通过抑制线粒体吞噬作用导致线粒体损伤，Mst1通过失活AMPK信号通路和下调OPA1表达抑制线粒体吞噬作用。AMPK-YAP-OPA1信号通路的重新激活通过抑制线粒体的分裂，为肾I/R损伤的肾小管上皮细胞提供了生存优势。结论：整体而言，肾I/R损伤的发病机制与Mst1表达增加和AMPK-YAP-OPA1信号通路失活密切相关。在此基础上，抑制Mst1表达和激活吞噬丝裂原的策略可作为治疗肾缺血再灌注损伤的靶点。(C)2018年作者(S)由S.Karger AG，巴塞尔出版
Background/Aims: The aim of our study is to investigate the molecular mechanism by which mammalian STE20-like kinase 1 (Mst1) participates in renal I/R injury through modifying mitophagy and the AMPK-YAP signalling pathway. Methods: WT mice and Mst1-knockout mice were subjected to renal ischaemia-reperfusion (I/R) in vivo. In vitro, the hypoxia-reoxygenation model was used with renal tubular epithelial cells to mimic renal I/R injury. Mitochondrial function was monitored via western blotting and immunofluorescence. Pathway blocker and siRNA knockout technology were used to establish the role of the AMPK-YAP signalling pathway in Mst1-mediated mitochondrial apoptosis in the setting of renal I/R injury. Results: Our data demonstrated that Mst1 expression was upregulated in response to renal I/R injury in vivo, and a higher Mst1 content was positively associated with renal dysfunction and more tubular epithelial cell apoptosis. However, genetic ablation of Mst1 improved renal function, alleviated reperfusion-mediated tubular epithelial cell apoptosis, and attenuated the vulnerability of kidney to I/R injury. In vitro, Mst1 upregulation induced mitochondrial damage including mitochondrial potential reduction, ROS overloading, cyt-c liberation and caspase-9 apoptotic pathway activation. At the molecular levels, I/R-mediated mitochondrial damage via repressing mitophagy and Mst1 suppressed mitophagy via inactivating AMPK signalling pathway and dowregulating OPA1 expression. Re-activation of AMPK-YAP-OPA1 signalling pathway provided a survival advantage for the tubular epithelial cell in the context of renal I/R injury by repressing mitochondrial fission. Conclusion: Overall, our results demonstrate that the pathogenesis of renal I/R injury is closely associated with an increase in Mst1 expression and the inactive AMPK-YAP-OPA1 signalling pathway. Based on this, strategies to repress Mst1 expression and activate mitophagy could serve as therapeutic targets to treat kidney ischaemia-reperfusion injury. (C) 2018 The Author(s) Published by S. Karger AG, Basel