Journal
TOXICOLOGY AND APPLIED PHARMACOLOGY
Volume 329, Issue -, Pages 128-139Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.taap.2017.05.034
Keywords
Cisplatin nephrotoxicity; ERK; Galangin; Inflammation; NF-kappa B; Oxidative stress
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Funding
- Ministry of Science and Technology of Taiwan [NSC104-2320-B-040-015]
- Chung Shan Medical University [CSMU-INT-105-10]
- Tao Yuan General Hospital, Ministry of Welfare and Health [10610]
- Ministry of Science and Technology
- Ministry of Education
- Chung Shan Medical University
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Cisplatin is a chemotherapeutic agent widely used in the treatment of various cancers. However, cisplatin can induce nephrotoxicity and neurotoxicity, limiting its dosage and usage. Galangin, a natural flavonol, has been found to exhibit anti-oxidant and anti-inflammatory effects in vivo. Here, we investigated the effects of galangin on cisplatin-induced acute kidney injury (AKI) and its molecular mechanisms in mice. Galangin administration reduced the cisplatin-induced oxidative stress by decreasing renal MDA and 3-NT formations. Galangin administration also increased renal anti-oxidative enzyme activities (SOD, GPx, and CAT) and GSH levels depleted by cisplatin. Furthermore, galangin administration inactivated stress-induced Nrf2 protein and its downstream products, HO-1 and GCLC. In terms of the inflammatory response, galangin administration reduced I kappa B alpha phosphorylation, NF-kappa B phosphorylation and nuclear translocation, and then inhibited cisplatin-induced secretions of pro-inflammatory TNF-alpha, IL-1 beta and IL-6. In addition, cisplatin-induced ERR and p38 phosphorylations were inhibited by galangin administration. In terms of cell death, galangin administration reduced levels of p53, pro-apoptotic Bax and activated caspase-3 to inhibit the cisplatin-induced apoptosis. Galangin administration also reduced the expression levels of RIP1 and RIP3 to inhibit cisplatin-induced RIP1/RIP3-dependent necroptosis. Therefore, galangin administration significantly ameliorates cisplatin-induced nephrotoxicity by attenuating oxidative stress, inflammation, and cell death through inhibitions of ERR and NF-kappa B signaling pathways. Galangin might be a potential adjuvant for clinical cisplatin therapy. (C) 2017 Elsevier Inc. All rights reserved.
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