title: Luteolin ameliorates cisplatin-induced nephrotoxicity in mice through inhibition of platinum accumulation, inflammation and apoptosis in the kidney.
abstract: The aim of this study was to investigate the effects of flavone luteolin against cisplatin (CP)-induced kidney injury in mice. Luteolin at doses of 10mg/kg was administered intraperitoneally (ip) once daily for 3 days following single CP (10 or 20mg/kg) ip injection. Mice were sacrificed 24h after the last dose of luteolin. The CP treatment significantly increased serum creatinine and blood urea nitrogen and induced pathohistological changes in the kidneys. Renal oxidative/nitrosative stress was evidenced by decreased glutathione (GSH) levels and increased 3-nitrotyrosine (3-NT) and 4-hydroxynonenal (4-HNE) formation as well as cytochrome P450 2E1 (CYP2E1) expression. The CP administration triggered inflammatory response in mice kidneys through activation of nuclear factor-kappaB (NF-κB) and overexpression of tumor necrosis factor-alpha (TNF-α) and cyclooxygenase-2 (COX-2). Simultaneously, the increase in renal p53 and caspase-3 expression indicated apoptosis of tubular cells. The administration of luteolin significantly reduced histological and biochemical changes induced by CP, decreased platinum (Pt) levels and suppressed oxidative/nitrosative stress, inflammation and apoptosis in the kidneys. These results suggest that luteolin is an effective nephroprotective agent, with potential to reduce Pt accumulation in the kidneys and ameliorate CP-induced nephrotoxicity.
authors.affiliation: Department of Chemistry and Biochemistry, Medical Faculty, University of Rijeka, Rijeka, Croatia. robertd@medri.uniri.hr
authors.forename: Robert
authors.initials: R
authors.lastname: Domitrović
authors.forename: Olga
authors.initials: O
authors.lastname: Cvijanović
authors.forename: Ester Pernjak
authors.initials: EP
authors.lastname: Pugel
authors.forename: Gordana Blagojević
authors.initials: GB
authors.lastname: Zagorac
authors.forename: Hana
authors.initials: H
authors.lastname: Mahmutefendić
authors.forename: Marko
authors.initials: M
authors.lastname: Škoda
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D015415:Biomarkers / Q000097:blood; D015153:Blotting, Western; D002945:Cisplatin / Q000493:pharmacokinetics / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D007677:Kidney Function Tests; D047311:Luteolin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018384:Oxidative Stress / Q000187:drug effects; D010984:Platinum / Q000378:metabolism*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D015415:Biomarkers; D010984:Platinum; D047311:Luteolin; D002945:Cisplatin
keywords: Apoptosis; Cisplatin nephrotoxicity; Inflammation; Luteolin; Oxidative/nitrosative stress