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J. Biol. Chem., Vol. 282, Issue 50, 36330-36340, December 14, 2007

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Hypoxia-inducible Factor-1 Mediates Neuronal Expression of the Receptor for Advanced Glycation End Products following Hypoxia/Ischemia^*

Paola Pichiule¹, Juan Carlos Chavez^¶2, Ann Marie Schmidt^||, and Susan J. Vannucci³

From the Departments of Pediatrics and Surgery, Columbia University, New York, New York 10032, the ^¶Burke Medical Research Institute, White Plains, New York 10605, and the ^||Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York 10021

Activation of the receptor for advanced glycation endproducts (RAGE) by its multiple ligands can trigger diverse signaling pathways with injurious or pro-survival consequences. In this study, we show that Rage mRNA and protein levels were stimulated in the mouse brain after experimental stroke and systemic hypoxia. In both cases, RAGE expression was primarily associated with neurons. Activation of RAGE-dependent pathway(s) post-ischemia appears to have a neuroprotective role because mice genetically deficient for RAGE exhibited increased infarct size 24 h after injury. Up-regulation of RAGE expression was also observed in primary neurons subjected to hypoxia or oxygen-glucose deprivation, an in vitro model of ischemia. Treatment of neurons with low concentrations of S100B decreased neuronal death after oxygen-glucose deprivation, and this effect was abolished by a neutralizing antibody against RAGE. Conversely, high concentrations of exogenous S100B had a cytotoxic effect that seems to be RAGE-independent. As an important novel finding, we demonstrate that hypoxic stimulation of RAGE expression is mediated by the transcription factor hypoxia-inducible factor-1. This conclusion is supported by the finding that HIF-1 down-regulation by Cre-mediated excision drastically decreased RAGE induction by hypoxia or desferrioxamine. In addition, we showed that the mouse RAGE promoter region contains at least one functional HIF-1 binding site, located upstream of the proposed transcription start site. A luciferase reporter construct containing this RAGE promoter fragment was activated by hypoxia, and mutation at the potential HIF-1 binding site decreased hypoxia-dependent promoter activation. Specific binding of HIF-1 to this putative HRE in hypoxic cells was detected by chromatin immunoprecipitation assay.

Received for publication, August 2, 2007 , and in revised form, October 15, 2007.

^* This work was supported in part by American Diabetes Association Research Grant 1-05-RA-139 (to S. J. V.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Recipient of Post-doctoral Fellowship 0525870T from the Heritage Affiliate of the American Heart Association.

² Recipient of a Scientist Developing Grant 0635556T from the NE Affiliate of the American Heart Association.

³ To whom correspondence should be addressed: Morgan Stanley Children's Hospital of New York, Columbia University, 3959 Broadway, CHN 10-24, New York, NY 10032. Tel.: 212-305-8458; Fax: 212-342-2293; E-mail: sv2020{at}columbia.edu.

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