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Inhibition of Hypoxia Inducible Factor Hydroxylases Protects Against Renal Ischemia-Reperfusion Injury

Peter Hill^*, Deepa Shukla^*, Maxine G.B. Tran^*, Julian Aragones, H. Terence Cook, Peter Carmeliet and Patrick H. Maxwell^*

^* Renal Section, Division of Medicine, and Department of Histopathology, Imperial College London, Hammersmith Campus, London, United Kingdom; and Center of Transgene Technology and Gene Therapy, University of Leuven, Flanders Interuniversity Institute for Biotechnology, Leuven, Belgium

Correspondence: Prof. Patrick Maxwell, Renal Section, Division of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK. Phone: +44-0-2083838594; Fax: +44-0-2083832062; E-mail: p.maxwell{at}imperial.ac.uk

Received for publication September 12, 2006. Accepted for publication July 18, 2007.

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.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673