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.
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: Sara J Holditch; Carolyn N Brown; Andrew M Lombardi; Khoa N Nguyen; Charles L Edelstein Journal: Int J Mol Sci Date: 2019-06-20 Impact factor: 5.923
Authors: Basmah Safdar; Melinda Wang; Xiaojia Guo; Charles Cha; Hyung J Chun; Yanhong Deng; James Dziura; Joe M El-Khoury; Fred Gorelick; Albert I Ko; Alfred I Lee; Robert Safirstein; Michael Simonov; Bin Zhou; Gary V Desir Journal: PLoS One Date: 2022-03-08 Impact factor: 3.240
Authors: Magda Wiśniewska; Natalia Serwin; Violetta Dziedziejko; Małgorzata Marchelek-Myśliwiec; Barbara Dołęgowska; Leszek Domański; Kazimierz Ciechanowski; Krzysztof Safranow; Tomasz Gołębiowski; Andrzej Pawlik Journal: Int J Environ Res Public Health Date: 2021-06-10 Impact factor: 3.390