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

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 pro...

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Bibliographic Details
Published in:Journal of the American Society of Nephrology 2008, Vol.19 (1), p.39-46
Main Authors: HILL, Peter, SHUKLA, Deepa, TRAN, Maxine G. B, ARAGONES, Julian, COOK, H. Terence, CARMELIET, Peter, MAXWELL, Patrick H
Format: Article
Language:English
Subjects:
Acute Kidney Injury - pathology
Acute Kidney Injury - prevention & control
Animals
Basic Research
Biological and medical sciences
Enzyme Inhibitors - pharmacology
Hypoxia-Inducible Factor 1, alpha Subunit - antagonists & inhibitors
Hypoxia-Inducible Factor 1, alpha Subunit - deficiency
Hypoxia-Inducible Factor 1, alpha Subunit - genetics
Immunohistochemistry
Kidney - drug effects
Kidney - pathology
Male
Medical sciences
Mice
Mice, Inbred C57BL
Mice, Knockout
Mimosine - pharmacology
Mixed Function Oxygenases - metabolism
Nephrology. Urinary tract diseases
Nephropathies. Renovascular diseases. Renal failure
Renovascular diseases
Reperfusion Injury - prevention & control
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Summary: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.
ISSN:1046-6673
1533-3450
DOI:10.1681/asn.2006090998