Yoshie Haga1, Toshio Ohtsubo2, Noboru Murakami1, Hideko Noguchi1, Yasuo Kansui3, Kenichi Goto1, Kiyoshi Matsumura1, Takanari Kitazono1. 1. Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. 2. Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address: tohtsubo@intmed2.med.kyushu-u.ac.jp. 3. Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Internal Medicine, Fukuoka Dental College, Fukuoka, Japan.
Abstract
AIMS: We examined the roles of xanthine oxidoreductase (XOR) in renal ischemia reperfusion (IR) injury. MAIN METHODS: XOR+/+ and XOR+/- mice were subjected to 24-h reperfusion after a 45-min bilateral renal artery occlusion or sham operation. We evaluated the renal damage based on the concentrations of blood urea nitrogen (BUN) and serum creatinine (Cr), and histological changes were detected by PAS staining. Xanthine dehydrogenase, oxidase (XO) and XOR activities, amounts of blood and urine 8-OHdG, and expressions of TNF-α and MCP-1 mRNA were examined. F4/80 and nitrotyrosine-positive cells were assessed by immunohistochemical staining. KEY FINDINGS: The BUN and Cr concentrations in the XOR+/+IR mice were increased significantly compared to those in XOR+/-IR and allopurinol-treated XOR+/+IR mice. XO and XOR activity, which were increased in IR mice, were reduced in the allopurinol-treated XOR+/+IR and XOR+/-IR mice compared to the XOR+/+IR mice. The concentrations of blood and urine 8-OHdG, and the expressions of MCP-1 and TNF-α mRNA were increased significantly in the XOR+/+IR mice compared to those in the XOR+/-IR mice. The histological analysis revealed that the XOR+/-IR and allopurinol-treated XOR+/+IR mice showed less tubular injury than the XOR+/+IR mice in the cortex regions, with the reduction of inflammation and oxidative stress assessed by the immunohistological staining for F4/80 and nitrotyrosine. SIGNIFICANCE: Both the disruption of XOR gene in XOR+/- mice and the reduction of XOR activity in allopurinol-treated XOR+/+IR mice attenuated renal tissue injury in this IR model. Reduced XOR activity during renal IR could be a beneficial treatment target.
AIMS: We examined the roles of xanthine oxidoreductase (XOR) in renal ischemia reperfusion (IR) injury. MAIN METHODS:XOR+/+ and XOR+/- mice were subjected to 24-h reperfusion after a 45-min bilateral renal artery occlusion or sham operation. We evaluated the renal damage based on the concentrations of blood ureanitrogen (BUN) and serum creatinine (Cr), and histological changes were detected by PAS staining. Xanthine dehydrogenase, oxidase (XO) and XOR activities, amounts of blood and urine 8-OHdG, and expressions of TNF-α and MCP-1 mRNA were examined. F4/80 and nitrotyrosine-positive cells were assessed by immunohistochemical staining. KEY FINDINGS: The BUN and Cr concentrations in the XOR+/+IR mice were increased significantly compared to those in XOR+/-IR and allopurinol-treated XOR+/+IR mice. XO and XOR activity, which were increased in IR mice, were reduced in the allopurinol-treated XOR+/+IR and XOR+/-IR mice compared to the XOR+/+IR mice. The concentrations of blood and urine 8-OHdG, and the expressions of MCP-1 and TNF-α mRNA were increased significantly in the XOR+/+IR mice compared to those in the XOR+/-IR mice. The histological analysis revealed that the XOR+/-IR and allopurinol-treated XOR+/+IR mice showed less tubular injury than the XOR+/+IR mice in the cortex regions, with the reduction of inflammation and oxidative stress assessed by the immunohistological staining for F4/80 and nitrotyrosine. SIGNIFICANCE: Both the disruption of XOR gene in XOR+/- mice and the reduction of XOR activity in allopurinol-treated XOR+/+IR miceattenuated renal tissue injury in this IR model. Reduced XOR activity during renal IR could be a beneficial treatment target.