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

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.

Metabolic adaptation and neuroprotection differ in the retina and choroid in a piglet model of acute postnatal hypoxia

“…HIF-1α plays a role in several retinal disorders (16,17). Nevertheless, our results do not substantiate a role for HIF-1α after hypoxia supported by several lines of evidence: (i) lack of HIF-1α stabilization, (ii) signaling events that trigger HIF-1α activation were not activated in choroid and even repressed in retina (10)(11)(12)(13).…”

“…HIF-1α, which plays a major role during acute episodes of hypoxia (14) and its canonical target vascular endothelial growth factor alpha (VEGFA), involved in angiogenesis and vascular remodeling, exert neuroprotection during cerebral hypoxia-ischemia (8,15). Both HIF-1α and VEGF-α levels are altered in a number of retinal disorders, such as hypoxia/ischemia and retinopathy of prematurity and experimental evidence supports its role in promoting pathological angiogenesis (16,17). Intriguingly, at present it is unclear if a pathological state is favored by HIF-1α itself or by one of its target genes, like VEGFA.…”

The Role of Inflammation in the Pathogenesis of Glaucoma

“…The inflammatory mediators TNF-a, IL-1b, and VEGF have been shown to decrease efficacy of the BRB. 45 VEGF is up-regulated during hypoxia 18 and enhances the adhesion of leukocytes to vascular walls and increases intercellular adhesion molecule-1 expression in the brain and retina, eliciting inflammation. 44 In addition, overexposure of VEGF in neural tissue has been shown to increase majorhistocompatibility complex class I and II, consequently initiating an inflammatory immune response and thereby a disruption of the BBB.…”

“…75 Moreover, increased levels of NO occur in response to up-regulation of the transcriptional hypoxia-inducible-factor-1alpha (HIF-a), which is induced in ischemia-associated hypoxia in the retina and ONH. 18,79 Several other inflammatory molecules such as vascular endothelial growth factor (VEGF), tumor necrosis factor alpha (TNF-a), interleukins (IL), C-reactive protein (CRP) and serum amyloid A (SAA) have been shown to be up-regulated in glaucoma. 41,49,78,80,81,85 We aim to summarize the current evidence on the possible involvement of inflammatory responses in the pathogenesis of glaucoma (Table 1).…”

HIF-1 expression in retinal ganglion cells and optic nerve axons in glaucoma

“…In normoxic conditions, HIF-alpha is bound to von Hippel-Lindau protein and is damaged by ubiquitination and proteosomal degradation. Specifically, recent results have shown that the HIF pathway can be used as a therapeutic target, although there is still a long way to go from bench to clinic [3][4][5].…”