Hypoxia Inducible Factors and Hypoglycemia in Early Diabetic Eye Disease

PROJECT SUMMARY: Diabetes accounts for 10% of healthcare spending in the United States. A growing portion of this cost is spent on treatments for diabetic eye disease, the leading cause of blindness among working-age adults in the developed world. Early nonproliferative diabetic retinopathy (NPDR) is driven by hyperglycemia that promotes injury to the retina microvasculature. On the other hand, proliferative diabetic retinopathy (PDR) develops after progressive microvascular damage ultimately results in retinal ischemia and subsequent hypoxia, driving the expression of factors that promote angiogenesis. Several labs have demonstrated that the regulation of angiogenic genes in late stages of diabetic eye disease is mediated by the transcription factor, hypoxia-inducible factor (HIF) in patients with retinal ischemia and PDR. However, a role for HIF in early stages of diabetic retinopathy (DR) is unclear. We recently demonstrated that transient episodes of hypoglycemia promotes the nuclear accumulation of HIF-1α, independent of hypoxia. This, in turn, results in an increase in expression of the angiogenic mediators that promote the growth of abnormal, leaky vessels in patients with DR. More recently, we have observed that activation of the p38 signaling pathway is necessary for HIF-1α accumulation in response to transient hypoglycemia. These observations implicate the p38/HIF-1 pathway in early. Events in the promotion of DR progression, independent of retinal ischemia. Based on these observations, we propose that inhibiting the p38/HIF-1α pathway will be an effective approach to prevent the progression of DR. In this proposal, we use a combination of genetic and pharmacologic approaches to evaluate the safety and efficacy of therapies that target HIF-1 (SA1) or p38 (SA2) to prevent the progression of DR.