Hypoglycemia Promotes Pathological Angiogenesis by a p38-Dependent Increase in Hypoxia Inducible Factor-1α Nuclear Accumulation

Abstract

Purpose : Glycemic variability (i.e., oscillations in serum glucose) has been reported to be a risk factor for diabetic retinopathy (DR) independent of glycosylated hemoglobin (HbA1c). However, the molecular mechanism whereby transient changes in serum glucose levels influence the development of DR is not known. In the current study, we set out to examine the contribution of acute episodes of glucose dysregulation to the development and progression of diabetic eye disease.

Methods : Immortalized (MIO-M1) and primary retinal Müller cells were exposed to low (1-4 mM), normal (5 mM) or high (25-50 mM) glucose. These results were corroborated in vivo using the insulin-induced hypoglycemia mouse model. The angiogenic potential of media conditioned from these cells was evaluated by tubule formation assay and directed in vivo angiogenesis. The contribution of the hypoxia-inducible factor (HIF)-1α was assessed by western blot and immunofluorescence. HIF-1 target gene expression was examined by qPCR and ELISA. The role of the p38 signaling pathway was assessed using pharmacologic inhibitors.

Results : We demonstrate that transient hypoglycemia promotes the HIF-dependent angiogenic phenotype of retinal Müller glial cells. Hypoglycemia increased HIF-1α nuclear accumulation independent of its canonical post-translational modification by HIF prolyl hydroxylases. Instead, we identify a previously unrecognized mechanism whereby hypoglycemia independently promotes HIF-1α translation and nuclear translocation. In the setting of hypoxia, this leads to a synergistic increase in the expression of the HIF-regulated angiogenic gene products. We further demonstrate that regulation of HIF-1α translation by hypoglycemia was mediated through the p38 signaling pathway.

Conclusions : Our results provide a molecular explanation for how glycemic variability can promote the progression of DR independent of HbA1c and suggest that inhibition of HIF-1 or the p38 signaling pathway may be effective approaches to mitigate the impact of hypoglycemia on DR. These observations have important clinical implications for optimizing glucose management in diabetic patients.

This is a 2020 ARVO Annual Meeting abstract.