The Effect of Melatonin on Cisplatin Induced-Kidney Injury in Rats: Possible Role of Autophagy

Background: Acute kidney injury by nephrotoxin; the chemotherapeutic cisplatin is a typical condition of renal stress, leading to cell death, tissue damage, and loss of renal function or renal failure. Melatonin hormone possess freeradical scavenging activity and it has been shown that it protects against cisplatin toxicity. Autophagy which is a cellular process of bulk degradation of damaged macromolecules in the cytoplasm, is thought to be contributing to cell death, or it might act as a cytoprotective mechanism. However, the mechanism of the protective effects of melatonin against cisplatin-induced nephrotoxicity and its relation to autophagy is still essentially unknown. Aim: The present study was designed to investigate the effects of acute kidney injury induced by cisplatin in adult male rats on autophagy and apoptosis after 19 days of its administration and to clarify the possible protective mechanisms of melatonin against acute kidney injury and its relation to both autophagy and apoptosis. Material and Methods: The study was conducted on 24 male adult albino rats. The experimental animals were divided into 3 groups, 8 rats each. Group I: Control treated with vehicle, Group II: Cisplatin treated (7mg/kg b.w., i.p.once), Group III: Melatonin+cisplatin co-treatment, melatonin (4mg/kgb.w., i.p. at 17:00hr. for 3 weeks 5 days/week) and cisplatin (7mg/kg b.w., i.p. once). Melatonin administration was started two days before the single i.p. injection of cisplatin. At the end of the experimental period, Blood samples were taken for the determination of serum urea nitrogen and creatinine then all rats were sacrificed and kidneys were excised for the determination of Tumor necrosis factor α (TNFα), Hemeoxygenase-1 (HO-1), LC3-II (an autophagic marker) and Bcl2 (antiapoptotic marker) in the kidney tissues, in addition to examine histological changes in the kidney. Results: It was observed that melatonin co-treated group showed a significant low extent and severity of the histological and biochemical signs of kidney injury than untreated one. The main significant biochemical changes between melatonin co-treated and cisplatin treated rats were (i) significant decrease in the elevated inflammatory marker (TNF α), (ii) significant Correspondence to: Dr. Ola M. Tork, E-mail: ola_tork@yahoo-com decease in HO-1 activity which indicate reduction of the oxidative stress, as well as (iii) significant increase of LC3II and Bcl2 gene expression in the kidney. Conclusion: Melatonin may be one of the future therapeutic possibilities to overcome the side effects of anti-cancer drugs induced acute renal injury through various mechanisms including stimulation of autophagy in addition to its antiinflammatory, antioxidant and antiapoptotic effects.