Transient ureteral obstruction prevents against kidney ischemia/reperfusion injury via hypoxia-inducible factor (HIF)-2α activation.
Transient ureteral obstruction prevents against kidney ischemia/reperfusion injury via hypoxia-inducible factor (HIF)-2α activation.
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DOI：
10.1371/journal.pone.0029876
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Xia Q
中科院分区：
文献类型：
--
作者：
Zhang S;Han CH;Chen XS;Zhang M;Xu LM;Zhang JJ;Xia Q
虽然缺血前短暂性输尿管梗阻（UO）对随后的肾缺血/再灌注（I/R）损伤的保护作用已被证明，但其潜在的分子机制仍有待了解。我们在当前的研究中发现，24 h的UO导致小鼠同侧肾脏肾小管缺氧，缺氧诱导因子（HIF）-2α蓄积，并在UO释放后持续一周。为了研究HIF-2α在UO介导的肾IRI保护中的作用，我们利用Mx-Cre/loxP重组系统敲除靶基因。HIF-2α的失活而非HIF-1α的失活削弱了UO的肾保护作用，这一点通过更高的血清肌酐水平和更严重的组织学损伤来证明。UO不能阻止HIF-2α基因敲除小鼠缺血后中性粒细胞浸润和凋亡诱导，这也减少了保护性分子热休克蛋白（HSP）-27的阻塞后上调。UO的肾脏保护作用与其促进缺血后肾内微血管血流恢复有关，并依赖于HIF-2α的激活。我们的结果表明UO通过激活HIF-2α保护肾脏，HIF-2α通过在缺血后保持足够的肾脏微血管灌注来减少肾小管损伤。因此，预处理HIF-2α激活可能成为治疗缺血性急性肾功能衰竭的新策略。
Although the protective effect of transient ureteral obstruction (UO) prior to ischemia on subsequent renal ischemia/reperfusion (I/R) injury has been documented, the underlying molecular mechanism remains to be understood. We showed in the current study that 24 h of UO led to renal tubular hypoxia in the ipsilateral kidney in mice, with the accumulation of hypoxia-inducible factor (HIF)-2α, which lasted for a week after the release of UO. To address the functions of HIF-2α in UO-mediated protection of renal IRI, we utilized the Mx-Cre/loxP recombination system to knock out target genes. Inactivation of HIF-2α, but not HIF-1α blunted the renal protective effects of UO, as demonstrated by much higher serum creatinine level and severer histological damage. UO failed to prevent postischemic neutrophil infiltration and apoptosis induction in HIF-2α knockout mice, which also diminished the postobstructive up-regulation of the protective molecule, heat shock protein (HSP)-27. The renal protective effects of UO were associated with the improvement of the postischemic recovery of intra-renal microvascular blood flow, which was also dependent on the activation of HIF-2α. Our results demonstrated that UO protected the kidney via activation of HIF-2α, which reduced tubular damages via preservation of adequate renal microvascular perfusion after ischemia. Thus, preconditional HIF-2α activation might serve as a novel therapeutic strategy for the treatment of ischemic acute renal failure.
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