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Inhibition of hypoxia inducible factor hydroxylases protects against renal ischemia-reperfusion injury

Hill, P; Shukla, D; Tran, MGB; Aragones, J; Cook, HT; Carmeliet, P; Maxwell, PH; (2008) Inhibition of hypoxia inducible factor hydroxylases protects against renal ischemia-reperfusion injury. J AM SOC NEPHROL , 19 (1) 39 - 46. 10.1681/ASN.2006090998.

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Abstract

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.

Type:Article
Title:Inhibition of hypoxia inducible factor hydroxylases protects against renal ischemia-reperfusion injury
DOI:10.1681/ASN.2006090998
Keywords:TRANSCRIPTIONAL ACTIVATION, GENE-EXPRESSION, HIF-ALPHA, FACTOR-I, MICE, HIF-1-ALPHA, FAILURE, KIDNEY, ERYTHROPOIETIN, HOMEOSTASIS
UCL classification:UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of)

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