Disruption of xanthine oxidoreductase gene attenuates renal ischemia reperfusion injury in mice
Disruption of xanthine oxidoreductase gene attenuates renal ischemia reperfusion injury in mice
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DOI：
10.1016/j.lfs.2017.06.011
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发表时间：
2017-08-01
期刊：
影响因子：
6.1
通讯作者：
Kitazono, Takanari
中科院分区：
文献类型：
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作者：
Haga, Yoshie;Ohtsubo, Toshio;Kitazono, Takanari
目的：本研究旨在探讨黄嘌呤氧化还原酶（xanthine oxidoreductase，XOR）在肾缺血再灌注（ischemia reperfusion，IR）损伤中的作用。以血尿素氮（BUN）、血清肌酐（Cr）为指标评价肾损害程度，PAS染色观察肾组织学改变。检测黄嘌呤脱氢酶（Xanthine dehydrogenase，XO）、氧化酶（oxidase，XOR）活性、血、尿8-OHdG含量、TNF-α和MCP-1 mRNA表达。F4/80和硝基酪氨酸阳性细胞通过免疫组化染色进行评估。关键发现：与XOR+/- IR和别嘌呤醇治疗的XOR +/+ IR小鼠相比，XOR+/+ IR小鼠的BUN和Cr浓度显著增加。与XOR+/+ IR小鼠相比，别嘌呤醇处理的XOR+/+ IR和XOR+/-IR小鼠的XO和XOR活性在IR小鼠中增加，但在XOR+/+ IR小鼠中减少。与XOR+/-IR小鼠相比，XOR+/+ IR小鼠血、尿8-OHdG浓度及MCP-1、TNF-α mRNA表达均显著升高。组织学分析显示，XOR+/-IR和别嘌呤醇处理的XOR+/+ IR小鼠在皮质区域中显示出比XOR+/+ IR小鼠更少的肾小管损伤，通过F4/80和硝基酪氨酸的免疫组织学染色评估炎症和氧化应激的减少。XOR+/-小鼠中XOR基因的破坏和别嘌呤醇处理的XOR+/+ IR小鼠中XOR活性的降低都减轻了该IR模型中的肾组织损伤。肾IR期间XOR活性降低可能是有益的治疗目标。(C)2017爱思唯尔公司All rights reserved.
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-alpha 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-alpha 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. (C) 2017 Elsevier Inc. All rights reserved.