title: Febuxostat exerts dose-dependent renoprotection in rats with cisplatin-induced acute renal injury.
abstract: The aim of the present study was to investigate possible renoprotective effects of febuxostat, a highly potent xanthine oxidase inhibitor, against cisplatin (CIS)-induced acute kidney injury in rats. Male Sprague Dawley rats were randomly assigned into four groups of six rats each, as follows: normal control; CIS, received a single intraperitoneal injection of CIS (7.5 mg/kg); [febuxostat 10 + CIS] and [febuxostat 15 + CIS], received febuxostat (10 and 15 mg/kg/day, respectively, orally) for 14 days, starting 7 days before CIS injection. At the end of experiment, 24-h urine output was collected and serum was separated for biochemical assessments. Kidney tissue homogenate was prepared for determination of oxidative stress-related parameters, nitric oxide (NO), and tumor necrosis factor-α (TNF-α). Moreover, histological alterations of kidney tissues were evaluated. Serum creatinine, blood urea, and urinary total protein were significantly elevated, while serum albumin and creatinine clearance were significantly reduced, in CIS-intoxicated rats, indicating depressed renal function. CIS administration also elicited renal oxidative stress, evidenced by increased malondialdehyde content and depleted levels of reduced glutathione and superoxide dismutase activity. Moreover, enhancement of renal levels of the pro-inflammatory TNF-α indicated renal inflammation. CIS-administered rats also showed increased serum lactate dehydrogenase activity and reduced renal NO bioavailability. Febuxostat dose-dependently improved or restored these changes to near-normal (e.g., mean ± SD of serum creatinine levels in control, CIS, [febuxostat 10 + CIS] and [febuxostat 15 + CIS] groups were 0.78 ± 0.19, 3.28 ± 2.0 (P < 0.01 versus control group), 1.03 ± 0.36 (P < 0.01 versus CIS group), and 0.93 ± 0.21 (P < 0.01 versus CIS group) mg/dl, respectively, and blood urea levels for the different groups were 36.80 ± 4.36, 236.10 ± 89.19 (P < 0.0001 versus control group), 114.50 ± 78.63 (P < 0.05 versus CIS group), and 60.91 ± 14.30 (P < 0.001 versus CIS group) mg/dl, respectively). Histological analysis of renal tissues also demonstrated that febuxostat offered a dose-dependent renoprotection. The present study suggests that antioxidant, anti-inflammatory, and cytoprotective mechanisms potentially mediate the renoprotective effects of febuxostat in CIS-administered rats, presenting febuxostat as a promising combinatorial strategy for cancer patients undergoing CIS chemotherapy.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
authors.forename: Alaa N A
authors.initials: AN
authors.lastname: Fahmi
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt. georgeshehatou@gmail.com.
authors.forename: George S G
authors.initials: GS
authors.lastname: Shehatou
authors.affiliation: Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
authors.forename: Abdelhadi M
authors.initials: AM
authors.lastname: Shebl
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
authors.forename: Hatem A
authors.initials: HA
authors.lastname: Salem
mesh_terms: D058186:Acute Kidney Injury / Q000097:blood / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D015415:Biomarkers / Q000378:metabolism; D002945:Cisplatin; D003404:Creatinine / Q000097:blood; D019610:Cytoprotection; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000069465:Febuxostat / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011507:Proteinuria / Q000139:chemically induced / Q000517:prevention & control; D017207:Rats, Sprague-Dawley; D012709:Serum Albumin / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D064804:Urological Agents / Q000494:pharmacology*; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D015415:Biomarkers; D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; D012709:Serum Albumin; D014409:Tumor Necrosis Factor-alpha; D064804:Urological Agents; D000069465:Febuxostat; D009569:Nitric Oxide; D008315:Malondialdehyde; D003404:Creatinine; D007770:L-Lactate Dehydrogenase; D013482:Superoxide Dismutase; D014969:Xanthine Oxidase; D005978:Glutathione; D002945:Cisplatin
keywords: Cisplatin; Febuxostat; Inflammation; Kidney injury; Oxidative stress; TNF-α