Abstract
Cisplatin is a widely used chemotherapeutic drug in the treatment of various solid tumors. However, the cisplatin-induced acute kidney injury remains a disturbing complication, which still lacks effective prevention. Cisplatin-induced oxidative damage and mitochondrial dysfunction are anticipated to be crucial in the occurrence of kidney injury. Astragalus polysaccharide (APS) has been reported to possess multiple biological activities including anti-inflammatory, antioxidant, and mitochondria protection. In this study, we investigated the potentially protective effect of APS against cisplatin-induced kidney injury both in vivo and in vitro. We found that APS pretreatment attenuated the cisplatin-induced renal dysfunction and histopathological damage in mice; in addition, it also protected the viability of HK-2 cells upon cisplatin exposure. APS attenuated the cisplatin-induced oxidative damage by reducing reactive oxygen species (ROS) generation and recovering the activities of total superoxide dismutase and glutathione peroxidase in mice kidney. In addition, electron microscope analysis indicated that cisplatin induced extensive mitochondrial vacuolization in mice kidney. However, APS administration reversed these mitochondrial morphology changes. In HK-2 cells, APS reduced the cisplatin-induced mitochondrial and intracellular ROS generation. Furthermore, APS protected the normal morphology of mitochondria, blocked the cisplatin-induced mitochondrial permeability transition pore opening, and reduced the cytochrome c leakage. Subsequently, APS reduced the cisplatin-induced apoptosis in mice renal and HK-2 cells. In conclusion, our data suggested that APS pretreatment might prevent cisplatin-induced kidney injury through attenuating oxidative damage, protecting mitochondria, and ameliorating mitochondrial-mediated apoptosis.
Highlights
Cisplatin is a chemotherapeutic drug which is widely used in a variety of solid tumors [1]
HK-2 cells were purchased from American Type Culture Collection (ATCC, Manassas, VA) and cultured in DMEM/F12 (Gibco, America) containing 10% FBS at 37°C with 5% CO2. e cells were treated with four different drug strategies: the control group was treated with DMSO; the Astragalus polysaccharide (APS) group was treated with APS (100 μg/mL, MedChem Express) for 24 h; the cisplatin group was treated with cisplatin (20 μmol/L, Hospira, Australia, Pty Ltd) for 24 h; and the APS and cisplatin group was pretreated with APS (100 μg/mL, MedChem Express) for 24 h and stimulated with cisplatin for 24 h
Activation of apoptosis in renal tubular epithelial cells has been demonstrated in cisplatininduced acute kidney injury (AKI) [2]. erefore, we explored whether APS could ameliorate cisplatin-induced apoptosis in mice kidney and HK-2 cells using transferase dUTP nick end-labeling (TUNEL) staining
Summary
Cisplatin is a chemotherapeutic drug which is widely used in a variety of solid tumors [1]. About 30% of patients who received highdose cisplatin suffered renal dysfunction, and the proportion was reported over 70% in pediatric patients [2]. Many studies have made efforts to understand the potential mechanism of cisplatin-induced kidney injury, which may be helpful in exploring effective prevention [3,4,5,6,7,8,9,10]. E mechanism of cisplatin-induced nephrotoxicity is complex and involves many factors, including mitochondrial dysfunction, oxidative damage, and activation of apoptosis in renal tubular epithelial cells [6,7,8,9,10]. It is suggested that cisplatin can accumulate in mitochondria and cause mitochondrial damage, leading to reactive oxygen species (ROS) enrichment and kidney tubular cell death [6, 7].
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