Hill Peter, Shukla Deepa, Tran Maxine G B, Aragones Julian, Cook H Terence, Carmeliet Peter, Maxwell Patrick H
Renal Section, Division of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK.
J Am Soc Nephrol. 2008 Jan;19(1):39-46. doi: 10.1681/ASN.2006090998.
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 HIF 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.
由低灌注和缺氧导致的急性肾衰竭是一个重大的临床问题。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存活。为了确定HIF是否可以保护肾脏免受缺血再灌注损伤，我们对hif1a(+/-)和hif2a(+/-)小鼠进行了肾脏缺血再灌注损伤实验。与同窝对照相比，hif(+/-)小鼠的损伤要严重得多，这与HIF的保护作用一致。由于野生型小鼠在无血流缺血时HIF积累未达到最大值，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-含羞草碱和二甲基草酰甘氨酸这两种通过抑制HIF羟化酶来激活HIF的小分子，可以保护小鼠肾脏免受缺血再灌注损伤。因此，HIF的药理学激活可能为保护肾脏免受缺血性损伤提供一种有效的策略。
