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Monika Deshpande, Savalan Babapoor, Gregg L Semenza, Silvia Montaner, Akrit Sodhi; Accumulation of Hypoxia Inducible Factor-1α in Retinal Cells in Response to Acute Hypoglycemia is Necessary for Survival. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):181.
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© ARVO (1962-2015); The Authors (2016-present)
Clinical trials have demonstrated that the progression of diabetic microvascular disease is stabilized with improved glycemic control, motivating clinicians to encourage tight blood sugar control. However, balancing hyperglycemia control with hypoglycemic episodes remains a challenge for insulin-dependent diabetics who have an average of two symptomatic hypoglycemic episodes in a week. While severe hypoglycemic episodes can cause disorientation, loss of consciousness, and death, recent studies have implicated recurrent episodes of hypoglycemia with an increased risk of cardiovascular disease. However, the impact of episodes of acute hypoglycemia on diabetic eye disease remains unclear. In this regard, the transcription factor, hypoxia inducible factor (HIF)-1α, a key regulator of angiogenic genes that promote diabetic eye disease, also plays an important role in regulating glucose metabolism. Here we examine the regulation of HIF-1α during acute glycemic dysregulation.
Immortalized retinal Müller (MIO-M1) cells were exposed to an acute treatment of low (1 mM) to high (50 mM) glucose. Accumulation of HIF-1α was assessed by western blot and immunofluorescence. qPCR and ELISA was performed to examine the mRNA expression of HIF-1α regulated genes. MTS assay was used to examine cell survival. These results were corroborated in primary retinal cells.
Exposure of MIO-M1 cells to hypoglycemia resulted in an increase in the protein stabilization and nuclear localization of HIF-1α, resulting in an increase in the expression of key angiogenic genes. Inhibiting HIF-1α pharmacologically (digoxin, acriflavin) or with RNAi reduced the expression of these angiogenic genes and blocked the angiogenic phenotype promoted by these cells. However, inhibition of HIF-1 also blocked the expression of HIF-1-regulated metabolic genes essential for glucose metabolism, and resulted in a decrease in cell survival.
HIF-1α regulates the expression of key angiogenic genes that promote diabetic eye disease. Our results suggest that hypoglycemic episodes could potentiate these effects. However, we further show that accumulation of HIF-1α in retinal cells exposed to hypoglycemia is necessary for cell survival, suggesting that HIF-1 may not be a suitable target for diabetic eye disease in patients who are insulin-dependent.
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