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.