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Margaret Brown, Yasir Abdul, Sudha Singh, Melissa Nix, Shahid Husain; Neurodegenerative Role of HIF-1α in Glaucomatous Injury.. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1914.
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This study was designed to determine the neurodegenerative role of hypoxia-inducible transcription factor-1α (HIF-1α) during glaucomatous injury in a chronic glaucoma rat model.
Brown Norway rats were used to elevate intraocular pressure (IOP) by injecting 50 µL of 2 M hypertonic saline into the circumferential limbal veins. IOP was recorded as the average of 6-8 consecutive measurements using a calibrated Tonolab tonometer. Animals were treated with HIF-1α inhibitor (17-DMAG; 2 mg/kg; i.p.) right after injury and subsequently daily for 7 days. The levels of HIF-1α expression was measured by Western blotting and immunohistochemistry. The functional deficiencies were measured by Pattern electroretinograms (PERG). Primary cultures of human optic nerve head (ONH) astrocytes were treated with hypoxia (oxygen, glucose deprivation [OGD]) 24 hours and changes in HIF-1α expression and cytokines were measured by Western blotting.
The mechanisms of retinal ganglion cell (RGC) death in response to glaucomatous injury are not clearly defined, some evidence suggests that tissue hypoxia may adversely affect RGC survival via pro-apoptotic pathways. Immunohistochemistry data show an up-regulation of HIF-1α in rat glaucomatous retina on day 7, post injury, which remained elevated up to 28 days. HIF-1α staining was mainly localized to the nerve fiber layer (NFL) and RGC layer. Additionally, Western blotting data show an up-regulation of HIF-1α by 51±15 and 54 ±14 % at days 7 and 28, respectively, post injury. Pattern-ERGs were not changed at day 7 post injury, while HIF-1α was increased at 7th day. In contrast, pattern-ERG amplitudes were reduced by 25% by day 28 post injury. We measured HIF-1α expression in response to hypoxia-related stress (oxygen, glucose deprivation [OGD]) for 24 hours. OGD increased the expression of HIF-1α (742 ±104%), TNF-α (103 ±19%), and IL-1β (141 ±15%) over the control levels, respectively.
We conclude that hypoxia develops in an early stage of the glaucoma pathology. In addition, data supports an idea that under glaucomatous injury hypoxic microenvironments develop not only in RGCs but also in ONH astrocytes. Such changes during the progression of glaucoma will lead to the production of neurotoxic proteins (e.g., HIF-1α and cytokines) and that will subsequently lead to the RGC death.
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