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Hypoxia Inducible Factor-1α (HIF-1α) and Some HIF-1 Target Genes are Elevated in Experimental Glaucoma

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Abstract

Low levels of hypoxia have been suggested to be a mechanism of retinal damage in glaucoma. To test the hypothesis that the activation of the hypoxia-responsive transcription factor hypoxia inducible factor-1α (HIF-1α) is involved in the pathophysiology of glaucoma, we used a rat model of glaucoma to study (1) HIF-1α retinal protein levels by immunoblot analysis, (2) cellular localization of HIF-1α in the retina by immunohistochemistry, and (3) expression of retinal HIF-1 gene targets by quantitative real-time polymerase chain reaction. Glaucoma was unilaterally induced in rats by injecting hypertonic saline in episcleral veins. We find that HIF-1α protein was increased in the retina following elevation of intraocular pressure, specifically in Müller glia and astrocytes but not in activated microglia. Eight established HIF-1 target genes were measured in experimental glaucoma. Retinal Epo, Flt-1, Hsp-27, Pai-1, and Vegfa mRNA levels were increased and Et-1, Igf2, and Tgfβ3 levels were decreased in the glaucomatous retinas. Thus, the increase in HIF-1α levels in Müller glia and astrocytes is accompanied by a marked up regulation of some, but not all, HIF-1 transcriptional targets. These data support the hypothesis that HIF-1α becomes transcriptionally active in astrocytes and Müller cells but not microglia or neurons in glaucoma, arguing against a global hypoxia stimulus to the retina.

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Acknowledgments

The authors thank Hisatomo Kowa and Bradley Hyman at MassGeneral Institute for Neurodegeneration, Charlestown, MA for the discussions and for the equipment used in qRT-PCR. The authors also thank Charles Vanderburg, Rachel Diamond, and Ozge Cagsal-Getkin at the Advanced Tissue Resource Center/MGH, Charlestown, MA for their technical help. This work was supported by R01-EY13399 (CLG), T32-EY07145 (CE), Massachusetts Lions Grant (CLG), and MEEI Vision-Core Grant EY014104.

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Authors and Affiliations

  1. Howe Laboratory of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, 243 Charles Street, Boston, MA, 02114, USA

    Ceren Ergorul, Arjun Ray, Wei Huang, Dan Yi Wang, Yixin Ben & Cynthia L. Grosskreutz

  2. Department of Neurology, Massachusetts General Hospital, 114 16th Street, CNY114-2250, Charlestown, MA, 02129, USA

    Ippolita Cantuti-Castelvetri

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  1. Ceren Ergorul
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  2. Arjun Ray
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Correspondence to Cynthia L. Grosskreutz.

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Ergorul, C., Ray, A., Huang, W. et al. Hypoxia Inducible Factor-1α (HIF-1α) and Some HIF-1 Target Genes are Elevated in Experimental Glaucoma. J Mol Neurosci 42, 183–191 (2010). https://doi.org/10.1007/s12031-010-9343-z

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  • DOI: https://doi.org/10.1007/s12031-010-9343-z

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