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

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.

• Authors: Zhimin Huang, Qing Li, Yanggang Yuan, Chengning Zhang, Lin Wu, Xi Liu, Wei Cao, Honglei Guo, Suyan Duan, Xueqiang Xu, Bo Zhang, Changying Xing
• Journal: Life sciences (Life Sci) Vol. 222 Pg. 78-87 (Apr 01 2019) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 30797821 (Publication Type: Journal Article)
• Copyright: Copyright © 2019. Published by Elsevier Inc.

Chemical References

• Antineoplastic Agents
• Reactive Oxygen Species
• Sirt3 protein, mouse
• Monoamine Oxidase
• renalase
• Sirtuin 3
• Cisplatin

Topics

• Acute Kidney Injury (chemically induced, metabolism, prevention & control)
• Animals
• Antineoplastic Agents (toxicity)
• Cell Line
• Cisplatin (toxicity)
• Humans
• Kidney Tubules, Proximal (drug effects, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mitochondrial Dynamics (drug effects, physiology)
• Monoamine Oxidase (pharmacology, therapeutic use)
• Random Allocation
• Reactive Oxygen Species (antagonists & inhibitors, metabolism)
• Sirtuin 3 (antagonists & inhibitors, biosynthesis)