Hypoxia inducible factor-1α (HIF-1α) and some HIF-1 target genes are elevated in experimental glaucoma.
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-1alpha (HIF-1alpha) is involved in the pathophysiology of glaucoma, we used a rat model of glaucoma to study (1) HIF-1alpha retinal protein levels by immunoblot analysis, (2) cellular localization of HIF-1alpha 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-1alpha 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 Tgfbeta3 levels were decreased in the glaucomatous retinas. Thus, the increase in HIF-1alpha 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-1alpha becomes transcriptionally active in astrocytes and Müller cells but not microglia or neurons in glaucoma, arguing against a global hypoxia stimulus to the retina.
Howe Laboratory of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, 243 Charles Street, Boston, MA 02114, USA.
Ceren
C
Ergorul
Arjun
A
Ray
Wei
W
Huang
Dan Yi
DY
Wang
Yixin
Y
Ben
Ippolita
I
Cantuti-Castelvetri
Cynthia L
CL
Grosskreutz
D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology* / Q000502:physiology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000502:physiology; D005901:Glaucoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000235:genetics*; D008297:Male; D051381:Rats; D011914:Rats, Inbred BN; D012165:Retinal Ganglion Cells / Q000378:metabolism / Q000473:pathology*
C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit