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Life Sci. 2019 Apr 1;222:78-87. doi: 10.1016/j.lfs.2019.02.042. Epub 2019 Feb 21.

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

Author information

1
Department of Nephrology, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China.
2
Department of Nephrology, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China. Electronic address: cyxing@njmu.edu.cn.

Abstract

AIMS:

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.

MAIN METHODS:

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.

KEY FINDINGS:

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.

SIGNIFICANCE:

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.

KEYWORDS:

Cisplatin nephrotoxicity; Mitochondrial fission; Renalase; Sirtuin-3

PMID:
30797821
DOI:
10.1016/j.lfs.2019.02.042
[Indexed for MEDLINE]

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