Inhibition of hypoxia inducible factor hydroxylases protects against renal ischemia-reperfusion injury
Inhibition of hypoxia inducible factor hydroxylases protects against renal ischemia-reperfusion injury
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DOI：
10.1681/asn.2006090998
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发表时间：
2008-01-01
影响因子：
13.6
通讯作者：
Maxwell, Patrick H.
中科院分区：
文献类型：
--
作者：
Hill, Peter;Shukla, Deepa;Maxwell, Patrick H.
由低灌注和缺氧引起的急性肾衰竭是一个重要的临床问题。缺氧会激活异二聚体转录因子缺氧诱导因子（HIF），导致基因表达发生变化，从而促进组织适应和生存。为了确定 H IF 是否可以保护肾脏免受缺血再灌注损伤，我们对 hif1a(+/-) 和 hif2a(+/-) 小鼠进行肾缺血再灌注损伤。 hif(+/-) 的损伤比同窝对照的损伤严重得多，这与 HIF 的保护作用一致。由于野生型小鼠在无血流缺血时表现出次最大 HIF 积累，因此我们测试了可能增强这些动物缺血再灌注后保护性 HIF 反应的化合物。我们发现 L-Mimosine 和二甲基乙二酰甘氨酸这两种小分子通过抑制 HIF 羟化酶来激活 HIF，从而保护小鼠肾脏免受缺血再灌注损伤。因此，HIF 的药理激活可能提供一种有效的策略来保护肾脏免受缺血性损伤。
Acute renal failure resulting from hypoperfusion and hypoxia is a significant clinical problem. Hypoxia activates the heterodimeric transcription factor hypoxia inducible factor (HIF), leading to changes in gene expression that promote tissue adaptation and survival. To determine whether H IF may protect the kidney from ischemia-reperfusion injury, we subjected hif1a(+/-) and hif2a(+/-) mice to renal ischemia-reperfusion injury. Injury was substantially more severe in hif(+/-) than in littermate controls, consistent with a protective role for HIF. Because wild-type mice exhibited submaximal HIF accumulation in response to no-flow ischemia, we tested compounds that might augment the protective HIF response following ischemia-reperfusion in these animals. We found that L-Mimosine and dimethyloxalylglycine, two small molecules that activate HIF by inhibiting HIF hydroxylases, protected mouse kidneys from ischemia-reperfusion injury. Therefore, pharmacological activation of HIF may offer an effective strategy to protect the kidney from ischemic injury.