Mowat, FM and Luhmann, UFO and Smith, AJ and Lange, C and Duran, Y and Harten, S and Shukla, D and Maxwell, PH and Ali, RR and Bainbridge, JWB (2010) HIF-1alpha and HIF-2alpha Are Differentially Activated in Distinct Cell Populations in Retinal Ischaemia. PLOS ONE , 5 (6) , Article e11103. 10.1371/journal.pone.0011103.
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Background: Hypoxia plays a key role in ischaemic and neovascular disorders of the retina. Cellular responses to oxygen are mediated by hypoxia-inducible transcription factors (HIFs) that are stabilised in hypoxia and induce the expression of a diverse range of genes. The purpose of this study was to define the cellular specificities of HIF-1alpha and HIF-2alpha in retinal ischaemia, and to determine their correlation with the pattern of retinal hypoxia and the expression profiles of induced molecular mediators.Methodology/Principal Findings: We investigated the tissue distribution of retinal hypoxia during oxygen-induced retinopathy (OIR) in mice using the bio-reductive drug pimonidazole. We measured the levels of HIF-1alpha and HIF-2alpha proteins by Western blotting and determined their cellular distribution by immunohistochemistry during the development of OIR. We measured the temporal expression profiles of two downstream mediators, vascular endothelial growth factor (VEGF) and erythropoietin (Epo) by ELISA. Pimonidazole labelling was evident specifically in the inner retina. Labelling peaked at 2 hours after the onset of hypoxia and gradually declined thereafter. Marked binding to Muller glia was evident during the early hypoxic stages of OIR. Both HIF-1alpha and HIF-2alpha protein levels were significantly increased during retinal hypoxia but were evident in distinct cellular distributions; HIF-1alpha stabilisation was evident in neuronal cells throughout the inner retinal layers whereas HIF-2alpha was restricted to Muller glia and astrocytes. Hypoxia and HIF-alpha stabilisation in the retina were closely followed by upregulated expression of the downstream mediators VEGF and EPO.Conclusions/Significance: Both HIF-1alpha and HIF-2alpha are activated in close correlation with retinal hypoxia but have contrasting cell specificities, consistent with differential roles in retinal ischaemia. Our findings suggest that HIF-2alpha activation plays a key role in regulating the response of Muller glia to hypoxia.
|Title:||HIF-1alpha and HIF-2alpha Are Differentially Activated in Distinct Cell Populations in Retinal Ischaemia|
|Open access status:||An open access publication. A version is also available from UCL Discovery.|
|Additional information:||© 2010 Mowat et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This work was supported by Wellcome Trust Grant 074617/Z/04/Z (http://www.wellcome.ac.uk/) and Medical Research Council Grant G03000341 (http://www.mrc.ac.uk/index.htm). JWBB receives financial support from the Department of Health through the award made by the National Institute for Health Research to Moorfields Eye Hospital National Health Service Foundation Trust and University College London Institute of Ophthalmology for a Specialist Biomedical Research Centre for Ophthalmology. The views expressed in this publication are those of the authors and not necessarily those of the Department of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.|
|Keywords:||HYPOXIA-INDUCIBLE FACTOR-1-ALPHA, OXYGEN-INDUCED RETINOPATHY, TUMOR-SUPPRESSOR PROTEIN, FACTOR-ALPHA, TARGET GENE, O-2 HOMEOSTASIS, GANGLION-CELLS, IN-VIVO, ERYTHROPOIETIN, EXPRESSION|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of)|
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