Renalase attenuates mitochondrial fission in cisplatin-induced acute kidney injury via modulating sirtuin-3

Acute kidney injury (AKI) can limit the clinical use of cisplatin in cancer treatment. The drivers of cisplatin-induced AKI include oxidative stress, mitochondrial dysfunction and apoptosis. Previous studies showed renalase protected cultured human renal proximal tubular cell (HK-2) against cisplati...

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Bibliographic Details
Published in:Life sciences (1973) 2019-04, Vol.222, p.78-87
Main Authors: Huang, Zhimin, Li, Qing, Yuan, Yanggang, Zhang, Chengning, Wu, Lin, Liu, Xi, Cao, Wei, Guo, Honglei, Duan, Suyan, Xu, Xueqiang, Zhang, Bo, Xing, Changying
Format: Article
Language:English
Subjects:
Apoptosis
Cancer
Cell viability
Cisplatin
Cisplatin nephrotoxicity
Fission
Injury prevention
Kidneys
Mice
Mitochondria
Mitochondrial fission
Necrosis
Oxidative stress
Proteins
Reactive oxygen species
Renal cell carcinoma
Renal function
Renalase
siRNA
Sirtuin-3
Transfection
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Summary:Acute kidney injury (AKI) can limit the clinical use of cisplatin in cancer treatment. The drivers of cisplatin-induced AKI include oxidative stress, mitochondrial dysfunction and apoptosis. Previous studies showed renalase protected cultured human renal proximal tubular cell (HK-2) against cisplatin induced necrosis, and renalase-knockout mice subjected to cisplatin showed exacerbated kidney injury. Therefore, it is necessary to determine the exact mechanisms of renalase in cisplatin-induced nephrotoxicity. To study the protective effect of renalase on cell viability, renal function, apoptosis, reactive oxygen species (ROS) production and mitochondrial dynamics, cultured HK-2 cells and male mice were subjected to cisplatin. Signaling proteins related to apoptosis, survival, and mitochondrial fission were analyzed by Western blot. In this study, we showed that the protective effect of recombinant renalase in cisplatin-induced AKI was associated with the regulation of ROS production, mitochondrial dynamics and sirtuin-3 (Sirt3) levels in vivo and in vitro. After cisplatin treatment, recombinant renalase restored Sirt3 expression, reduced mitochondrial fission and ROS generation. In HK-2 cells, downregulation of endogenous Sirt3 expression by siRNA transfection abrogated the renalase cytoprotection. Our study suggests that renalase protects against cisplatin-induced AKI by improving mitochondrial function and inhibiting oxidative stress, and in vitro, it functions in a Sirt3-dependent manner.
ISSN:0024-3205
1879-0631
DOI:10.1016/j.lfs.2019.02.042