English abstract
Background: Cisplatin (CP) is a platinum-based antineoplastic drug that is known to cause nephrotoxicity. The exact mechanism of renal damage is not known, but the imbalance redox status induced by CP is thought to be one of the mechanisms of renal injury. Ellagic acid (EA) is a polyphenolic antioxidant that is found in fruits and nuts. This study aims at investigating the ability of different doses of EA to scavenge reactive oxygen species, and ameliorate CP-induced nephrotoxicity. The study used conventional and recent molecular markers for the assessment of nephrotoxicity. Materials and Methods: Sprague-Dawly rats were randomly divided into eight groups with minimum of six rat in each group: Rats treated with saline (control), or with CP alone, different doses of EA alone (10, 30, and 90mg/Kg) and CP together with different doses of EA (CP+EA10, CP+EA30, CP+EA90). EA was given daily for a period of 10 days, and CP was given by a single intraperitoneal (i.p.) injection (6mg/Kg) on day 5. Urine, blood and kidneys were collected on day 10 for physiological, histpathological, biochemical and molecular analysis. Results: CP treatment was found to reduce body weight (BW), increase relative kidney weight (RKW), reduce water intake and urine output, increase plasma creatinine (Cr) and blood urea nitrogen (BUN) concentrations (p<0.01), and reduce total antioxidant (TAS) and glutathione (GSH) concentrations (p<0.01), EA treatment at 30mg/Kg mitigated the CP-induced loss in BW and RKW. The amount of water intake and urine output in rats treated with CP+EA30, as well as the Cr, BUN, TAS, and GSH concentrations were all restored to near normal levels. However, the results from rats treated with CP+EA10 and CP+EA90 were not significantly different from that seen in rats treated CP alone. Histopathologically, 60% of renal cortical area was damaged with many apoptotic cells in rats treated with CP alone, CP+EA10 and CP+EA90. However, the damage in rats given CP+EA30 was <25%. Molecular analysis showed that clusterin (Clu) protein was expressed in all groups including the controls. However, the : expression levels of Clu mRNA increased by at least 9-fold in rats treated with CP alone or CP+EA. On the other hand, kidney injury molecule-1 (Kim-1) protein was expressed only in rats treated with CP or CP+EA and mRNA expression analysis showed that Kim-1 mRNA levels increased by at least 90-fold in these groups. The high levels of Kim-1 and Clu mRNA caused by CP administration was not affected by any CP+EA combined treatment. Conclusion: It was found that EA (30mg/Kg) ameliorated most of the physiological, histological, and biochemical makers of CP nephrotoxicity. The molecular findings in this work did not tally with the conventional method used.
