A protective role of unfolded protein response in mouse ischemic acute kidney injury
A protective role of unfolded protein response in mouse ischemic acute kidney injury
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DOI：
10.1016/j.ejphar.2008.06.108
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发表时间：
2008-09-11
影响因子：
5
通讯作者：
Ikeda, Masahiro
中科院分区：
文献类型：
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作者：
Prachasilchai, Worapat;Sonoda, Hiroko;Ikeda, Masahiro
虽然已知肾缺血-再灌注可激活未折叠蛋白反应，但在体内损伤后，肾脏部位和激活该反应的作用仍然很大程度上未知。本研究研究了未折叠蛋白反应网络的核心调节因子葡萄糖调节蛋白（GRP） 78在肾缺血再灌注后的肾脏时空表达模式，以及特异性化学未折叠蛋白反应诱导剂tunicamycin和thapsigarin对小鼠肾缺血再灌注损伤的影响。肾缺血再灌注导致X-box结合蛋白-1 （xbp -1）转录物的剪接形式表达，这是一种未折叠的蛋白反应靶点，在损伤后1和2小时。这种反应之后是GRP78转录物和蛋白的增加。缺血再灌注后GRP78蛋白量的增加主要局限于近端小管细胞。tunicamycin或thapsigarin预处理可显著改善缺血再灌注后的肾功能和损伤。综上所述，未折叠蛋白反应在肾缺血-再灌注后在易受缺血-再灌注损伤的部位被激活，这种激活在体内对肾缺血-再灌注损伤具有保护作用。参与未折叠蛋白反应的分子可能为药物干预肾缺血-再灌注损伤提供新的机会，肾缺血-再灌注损伤是急性肾损伤的重要原因。(C) 2008 Elsevier B.V.版权所有
Although renal ischemia-reperfusion is known to activate the unfolded protein response, the renal site and role of activation of this response following the insult in vivo remains largely unknown. Here we studied the renal spatio-temporal expression pattern of glucose-regulated protein (GRP) 78, a central regulator of the unfolded protein response network, following renal ischemia-reperfusion and the effects of the specific chemical unfolded protein response inducers, tunicamycin and thapsigargin, on renal ischemia-reperfusion injury in mice. Renal ischemia-reperfusion resulted in expression of the spliced form of the X-box binding protein-1 (XBP-1s) transcript, an unfolded protein response target, at I and 2 h after the insult. This response was followed by an increase in the GRP78 transcript and protein. The increased amount of GRP78 protein after ischemia-reperfusion was largely localized in proximal tubule cells. Pretreatment with tunicamycin or thapsigargin significantly ameliorated renal dysfunction and injury after ischemia-reperfusion. Taken together with these results, the unfolded protein response was activated following renal ischemia-reperfusion at sites that are susceptible to ischemia-reperfusion injury, and this activation had a protective effect against renal ischemia-reperfusion injury in vivo. Molecules involved in the unfolded protein response may offer new opportunities for pharmacological intervention against renal ischemia-reperfusion injury, which is an important cause of acute kidney injury. (C) 2008 Elsevier B.V. All rights reserved.