Protective role of hypoxia-inducible factor-2α against ischemic damage and oxidative stress in the kidney
Protective role of hypoxia-inducible factor-2α against ischemic damage and oxidative stress in the kidney
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DOI：
10.1681/asn.2006060639
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发表时间：
2007-04-01
影响因子：
13.6
通讯作者：
Nangaku, Masaomi
中科院分区：
文献类型：
--
作者：
Kojima, Ichiro;Tanaka, Tetsuhiro;Nangaku, Masaomi
细胞对低氧环境的反应的中心是低氧诱导因子（HIF）转录控制系统。在与氧化应激相关的肾缺血-再灌注损伤（IRI）模型中，使用HIF-2 α敲低小鼠研究HIF-2 α的作用。在这些小鼠中，HIF-2 α表达约为野生型小鼠的一半，而HIF-1 α表达相当。HIF-2 α基因敲除小鼠对肾IRI更敏感，如升高的血尿素氮水平和半定量组织学分析所示。氧化应激标记物的免疫染色显示HIF-2 α敲低小鼠肾脏中的氧化应激增强，这与肾小管周围毛细血管损失有关。实时定量PCR分析显示HIF-2 α敲低肾脏中抗氧化应激基因的表达降低。使用小干扰RNA的研究证实了培养的内皮细胞中抗氧化应激基因的调节。尽管HIF-2 α敲低小鼠贫血，但血清促红细胞生成素水平没有显著增加，反映了HIF-2 α敲低导致的对贫血的不适当反应。使用血液稀释的肾缺血小鼠进行的实验表明，这种程度的贫血并不影响对缺血的敏感性。通过骨髓移植实验敲低炎性细胞中的HIF-2 α表明，炎性细胞中的HIF-2 α并不有助于对肾IRL的易感性。通过与Tie 1-Cre小鼠杂交恢复内皮中的HIF-2 α改善了IRI引起的肾损伤，证明了内皮HIF-2 α的特异性作用。这些结果表明，内皮细胞中的HIF-2 α通过改善氧化应激对肾脏缺血具有保护作用。
Central to cellular responses to hypoxic environment is the hypoxia-inducible factor (HIF) transcriptional control system. A role for HIF-2 alpha was investigated in a model of renal ischemia-reperfusion injury (IRI) associated with oxidative stress using HIF-2 alpha knockdown mice. In these mice, HIF-2 alpha expression was approximately one half that of wild-type mice, whereas HIF-1 alpha expression was equivalent. HIF-2 alpha knockdown mice were more susceptible to renal IRI, as indicated by elevated blood urea nitrogen levels and semiquantitative histologic analysis. Immunostaining with markers of oxidative stress showed enhanced oxidative stress in the kidney of HIF-2 alpha knockdown mice, which was associated with peritubular capillary loss. Real-time quantitative PCR analysis showed decreased expression of antioxidative stress genes in the HIF-2 alpha knockdown kidneys. Studies that used small interference RNA confirmed regulation of the antioxidative stress genes in cultured endothelial cells. Although HIF-2 alpha knockdown mice were anemic, serum erythropoietin levels were not significantly increased, reflecting inappropriate response to anemia as a result of HIF-2 alpha knockdown. Experiments that used hemodiluted mice with renal ischemia demonstrated that anemia of this degree did not affect susceptibility to ischemia. Knockdown of HIF-2 alpha in inflammatory cells by bone marrow transplantation experiments demonstrated that HIF-2 alpha in inflammatory cells did not contribute to susceptibility to renal IRL Restoration of HIF-2 alpha in endothelium by intercrossing with Tie1-Cre mice ameliorated renal injury by IRI, demonstrating a specific role of endothelial HIF-2 alpha. These results suggest that HIF-2 alpha in the endotheliunt has a protective role against ischemia of the kidney via amelioration of oxidative stress.