Melatonin suppresses cisplatin-induced nephrotoxicity via activation of Nrf-2/HO-1 pathway

Nutrition & Metabolism

Kazim Sahin²  Fikrettin Sahin⁵  Okkes Yilmaz³  Ibrahim H Ozercan⁶  Mehmet Tuzcu³  Zeynep Tuzcu³  Ertugrul Kilic¹  Ulkan Kilic⁴ 

[1] Department of Physiology, Faculty of Medicine, Medipol University, Istanbul, Turkey;Department of Animal Nutrition, Faculty of Veterinary Science, Firat University, Elazig, Turkey;Department of Biology, Faculty of Science, Firat University, Elazig, Turkey;Department of Medical Biology, Faculty of Medicine, Bezmialem Vakif University, Adnan Menderes Bulvarı Vatan Caddesi, Fatih, TR-34093, Istanbul, Turkey;Department of Genetics and Bioengineering, Yeditepe University, Istanbul, Turkey;Department of Pathology, Faculty of Medicine, Firat University, Elazig, Turkey

关键词: Oxidative stress;    Melatonin;    Nrf2/HO-1 signaling;    Nephrotoxicity;   

Others  :  811351
DOI  :  10.1186/1743-7075-10-7

 received in 2012-08-07, accepted in 2013-01-08,  发布年份 2013

【 摘 要 】

Background

Cisplatin, one of the most effective and potent anticancer drugs, is used in the treatment of a wide variety of both pediatric and adult malignancies. However, the chemotherapeutic use of cisplatin is limited by its serious side-effects such as nephrotoxicity and ototoxicity. Cisplatin chemotherapy induces a reduction in the antioxidant status, leading to a failure of the antioxidant defense against free-radical damage generated by antitumor drugs. Cisplatin-induced oxidative stress in the kidney was partially prevented by antioxidant treatments using superoxide dismutase, glutathione, selenium and flavonoids. Melatonin and its metabolites possess free-radical scavenging activity and it has been shown that they protect against cisplatin toxicity. However, the mechanism of the protective effects of melatonin against cisplatin-induced nephrotoxicity is still essentially unknown. We therefore designed this study to investigate the underlying mechanism of the protective effect of melatonin against cisplatin-induced renal damage in a rat nephrotoxicity model in vivo.

Methods

Twenty eight 8-week-old male Wistar rats were divided into four groups of control, melatonin treatment (4 mg/kg b.w i.p. for 10 days), cisplatin treatment (7 mg/kg b.w., i.p.) and melatonin and cisplatin combination treatment. Serum urea nitrogen (urea-N) and creatinine levels were measured. Histopathological changes were evaluated. In addition, we analyzed the expression levels of HO-1, Nrf2, NF-κB and AP-1 in Western blot analysis.

Results

Both serum creatinine and urea nitrogen increased significantly following cisplatin administration alone; these values decreased significantly with melatonin co-treatment of cisplatin-treated rats. Histological analysis showed that cisplatin caused damage in the proximal tubular cells in the kidneys of cisplatin-treated rats; these changes were reversed by melatonin co-treatment. Upon Western blot analysis, melatonin treatment increased Nrf2 accumulation in the nuclear fraction, and increased the expression of HO-1 in the cytosolic fraction as compared to the cisplatin-treated rats. Expressions of NF-κB p65 and AP-1 were increased significantly in the kidneys of rats treated with cisplatin compared with the expression in the kidneys from the control, melatonin-only-treated and melatonin co-treated rats.

Conclusion

Our present data suggest that melatonin attenuates cisplatin-induced nephrotoxicity possibly by modulating Nrf2/HO-1 signaling.

【 授权许可】

   
2013 Kilic et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

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