Mammalian STE20-Like Kinase 1 Deletion Alleviates Renal Ischaemia-Reperfusion Injury via Modulating Mitophagy and the AMPK-YAP Signalling Pathway.
Cell Physiol Biochem
; 51(5): 2359-2376, 2018.
Article
em En
| MEDLINE
| ID: mdl-30537740
ABSTRACT
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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fosfoproteínas
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Proteínas Quinases
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Traumatismo por Reperfusão
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Proteínas Serina-Treonina Quinases
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Deleção de Genes
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Proteínas Adaptadoras de Transdução de Sinal
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Mitofagia
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Nefropatias
Limite:
Animals
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article