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Activity of HIF-1α in Optic Nerve Head Astrocytes in Response to Cobalt Chloride Treatment
Investigator: Margaret Brown
Mentor: Shahid Husain, PhD
Background: Hypoxia has long been thought to comprise part of the pathophysiology of glaucoma. Evidence for hypoxia in the glaucomatous retina has been provided by studies showing that hypoxia-inducible factor (HIF)-1α expression is increased, with localization demonstrated to both retinal ganglion cells (RGCs) and glia. Although the cellular hypoxic response is certainly broader than just HIF-1α stabilization, examining HIF-1α in isolation may give insight into mechanisms that target it specifically. In particular, δ-opioid receptor (DOR) agonist SNC-121, which has been experimentally shown to preserve RGC function in hypoxic/ischemic models of retinal disease, may accomplish its neuroprotective effects through some process involving HIF-1α regulation.
Methods: We evaluated HIF-1α expression in primary cultures of human optic nerve head astrocytes (ONHA) treated with cobalt chloride (CoCl2), which mimics hypoxic conditions by inhibiting HIF-1α degradation in normoxia. ONHA were treated with 50-200μM CoCl2 over 24 hours; some cells were pre-treated with 1-25μM SNC-121 for 15 minutes before CoCl2 treatment. Evaluation of HIF-1α expression was performed by Western blotting.
Results: CoCl2 treatment resulted in increased expression of HIF-1α over controls. Contrary to expectation, SNC-121 treatment resulted in increased HIF-1α expression in both controls and CoCl2-treated cells. These results, although consistently demonstrating increased HIF-1α expression, were limited by some heterogeneity in dose effect. Previous experiments conducted by this lab have demonstrated a reduction of HIF-1α in ONHA following SNC-121 treatment.
Conclusion: A major difference between these results and those of previous experiments is the use of CoCl2 instead of serum oxygen-glucose deprivation (SOGD)-induced hypoxia, which indicates that SOGD and CoCl2 treatment have differential effects on HIF-1α expression. Additional experiments are needed to elucidate the molecular mechanisms involved in these two processes. Further exploration of the HIF-1α -induced targets and mechanisms of neuroprotection in hypoxic retinal injury could open new horizons in glaucoma therapy.
Last Updated: 2/4/14
Updated on June 19, 2014.