期刊
INTERNATIONAL IMMUNOPHARMACOLOGY
卷 56, 期 -, 页码 156-167出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.intimp.2018.01.031
关键词
Autophagy; Cisplatin; ER stress; Inflammation; Morin hydrate; ROS
资金
- Daegu University
The present study assessed the possible therapeutic potential of a natural flavonoid morin hydrate (MH), against cisplatin (CP) induced toxicity in HEK-293 cells and mice kidney. Herein, we observed that exposure of HEK-293 cells to CP (20 mu M, 24 h) reduced the cell viability, and increased the intracellular ROS generation, nuclear DNA damage, Ca++ release, and accumulation of acidic vacuoles. Concomitantly, acute exposure of CP (30 mg/kg, 72 h) to male ICR mice induced histopathological changes in kidney tissue, and alterations in serum creatinine and blood urea nitrogen (BUN) levels. Oxidative stress mediated ER-stress was evidenced by the reduced expression of antioxidant enzymes such as SOD-1, SOD-2, GR, and Trx, and increased expression levels of CytP450, IRE1-alpha, PERK, and CHOP. The expression levels of major inflammatory response markers such as NF-kappa B, TNF-alpha, IL-1 beta, COX-2 and iNOS were significantly increased in the HEK-293 cells and mice kidney. Temporal up-regulation of p-AMPK and LC3I/II, and down regulation of mTOR was also noticed after CP treatment. CP-induced DNA damage led to activation of PARP-1, which plays a crucial role in inflammation, apoptosis and autophagy activation. Concurrently, co-treatment of CP-MH and CP-ANI (PARP-1 inhibitor) significantly attenuated the expression level of PARP-1, reduced cellular death, alleviated inflammatory responses, and inhibited autophagy stimulation in HEK-293 cells and mice kidney. On the basis of above findings, we suggest MH as a potential therapeutic agent against CP-induced nephrotoxicity.
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