Epigallocatechin-3-gallate activates Nrf2/HO-1 signaling pathway in cisplatin-induced nephrotoxicity in rats

• Published in: Life sciences (1973) 2010-08, Vol.87 (7), p.240-245
• Main Authors: Sahin, Kazim, Tuzcu, Mehmet, Gencoglu, Hasan, Dogukan, Ayhan, Timurkan, Mustafa, Sahin, Nurhan, Aslan, Abdullah, Kucuk, Omer
• Format: Article
• Language: English
• Subjects: 4-Hydroxynonenal; Aldehydes - metabolism; Animals; Antineoplastic Agents - adverse effects; Antioxidants - pharmacology; Antioxidants - therapeutic use; Catalase - metabolism; Catechin - analogs & derivatives; Catechin - pharmacology; Catechin - therapeutic use; Cisplatin; Cisplatin - adverse effects; Epigallocatechin-3-gallate; Glutathione - metabolism; Glutathione Peroxidase - metabolism; Heme Oxygenase-1 - metabolism; HO-1; Kidney - drug effects; Kidney - metabolism; Kidney - pathology; Male; Neoplasms - drug therapy; Nephrotoxicity; NF-E2-Related Factor 2 - metabolism; NF-kappa B - metabolism; Nrf2; Rats; Rats, Wistar; Signal Transduction; Superoxide Dismutase - metabolism; Tea - chemistry
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2010.06.014

Cisplatin-induced nephrotoxicity is associated with increased oxidative stress and inflammatory cytokines in the kidney. Epigallocatechin-3-gallate (EGCG) has anti-oxidant, anti-inflammatory, and anti-tumorigenic properties. In this study, we investigated the effects of EGCG on cisplatin-induced nephrotoxicity and potential mechanisms by which it enhances antioxidant activities and resolves inflammation after EGCG treatment during cisplatin-induced nephrotoxicity. Twenty-eight rats were divided into four groups as control (group 1; no treatment; n = 7), EGCG (group 2; n = 7), cisplatin (group 3; n = 7) or cisplatin and EGCG (group 4; n = 7). After 2 days of EGCG treatment at a dose of l00 mg/kg BW, rats were treated with a single i.p. injection of cisplatin (7 mg/kg BW). On day 12 (10 days after the cisplatin treatment), all rats were sacrificed by cervical dislocation. The level of protein was examined by Western blotting. Cisplatin caused a significant decrease in the expression nuclear levels of NF-E2-related factor-2 (Nrf2), heme oxygenase-1(HO-1), and an increase in the levels of nuclear factor-kappa B (NF-κB p65) and 4-hydroxynonenal (HNE) an oxidative stress marker. EGCG supplementation significantly improved the changes associated with cisplatin nephrotoxicity by increasing levels of Nrf-2 and HO-1, and decreasing levels of NF-κB and HNE. Renal activities of antioxidant enzymes (catalase, superoxide dismutase, glutathione peroxidase) and glutathione were significantly lower in cisplatin-treated rats compared with control rats, and EGCG treatment significantly increased the activities of antioxidant enzymes and glutathione ( P < 0.001). The results suggest that Nrf2/HO-1 signaling pathway may be the primary target for prevention of cisplatin-induced nephrotoxicity by EGCG, and that reduces it inflammation by inhibiting NF-κB.