title: Febuxostat suppressed renal ischemia-reperfusion injury via reduced oxidative stress.
abstract: Febuxostat is a novel selective inhibitor of xanthine oxidase (XO), approved for treating hyperuricemia. XO inhibits the generation of uric acid (UA) as well as the resulting generation of superoxide. During renal ischemia-reperfusion (I/R) injury, the burst of reactive oxygen species (ROS) can trigger the inflammation and the tubular cell injury. As XO is a critical source of ROS, inhibition of XO could be a therapeutic target for I/R injury. Therefore, we performed this study to test the therapeutic effect of febuxostat on renal I/R injury. Sprague-Dawley rats, received vehicle or febuxostat, were subjected to right nephrectomy and left renal I/R injury. Febuxostat significantly suppressed XO activity, and thereby reduced oxidative stress, assessed by nitrotyrosine, thiobarbituric acid-reactive substances (TBARS) and urine 8-isoprostane. Furthermore, febuxostat reduced the induction of endoplasmic reticulum (ER) stress, assessed by GRP-78, ATF4, and CHOP. Vehicle-treated I/R injured rats exhibited elevated serum creatinine and UN, which were significantly suppressed in febuxostat-treated I/R-injured rats. Histological analysis revealed that fubuxostat-treated rats showed less tubular injury and interstitial fibrosis with reduction in ED1-positive macrophage infiltration, TUNEL positive apoptotic tubular cells, and interstitial smooth muscle α actin (SMαA) expression, compared to vehicle-treated rats. In conclusion; novel XO inhibitor, febuxostat, can protect kidney from renal I/R injury, and may contribute to preserve kidney function.
authors.affiliation: Department of Advanced Technology for Transplantation, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Tsuda
authors.forename: Noritaka
authors.initials: N
authors.lastname: Kawada
authors.forename: Jun-ya
authors.initials: JY
authors.lastname: Kaimori
authors.forename: Harumi
authors.initials: H
authors.lastname: Kitamura
authors.forename: Toshiki
authors.initials: T
authors.lastname: Moriyama
authors.forename: Hiromi
authors.initials: H
authors.lastname: Rakugi
authors.forename: Shiro
authors.initials: S
authors.lastname: Takahara
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Isaka
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D000069465:Febuxostat; D033461:Hyperuricemia / Q000188:drug therapy; D007668:Kidney / Q000098:blood supply* / Q000187:drug effects*; D007684:Kidney Tubules / Q000098:blood supply / Q000187:drug effects; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000517:prevention & control*; D013844:Thiazoles / Q000008:administration & dosage*; D014968:Xanthine Dehydrogenase / Q000037:antagonists & inhibitors; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors*
chemical_list: D013844:Thiazoles; D000069465:Febuxostat; D014968:Xanthine Dehydrogenase; D014969:Xanthine Oxidase