Hypoxia and the expression of HIF-1α and HIF-2α in the retina of streptozotocin-injected mice and rats

Abstract

Decreases in retinal blood flow in diabetics could render the retina hypoxic. In mouse and rat models of diabetes, a decrease in retinal blood flow occurs early, within 3–4 weeks of the induction of hyperglycemia, although information is scarce on whether this early decrease in flow induces hypoxia. The purpose of the current study was to determine whether hypoxia-inducible factor (HIF) levels increase following 4 and/or 12 weeks of hyperglycemia in streptozotocin (STZ)-injected mouse (C57BL/6) and rat (Wistar) retinas. Additionally, retinal tissue hypoxia was measured with pimonidazole following 12 weeks of hyperglycemia. These aims were accomplished via immunostaining of cross-sections from enucleated eyes. In mice, staining for HIF-1α and HIF-2α showed a contrasting pattern, with HIF-1α higher in the inner retina than outer, but HIF-2α higher in the outer retina than inner. However, in rats, staining for both HIF-1α and HIF-2α was more intense in the inner retina. The HIF-1α staining intensities and patterns were similar between diabetic animals and their non-diabetic counterparts following 4 and 12 weeks of hyperglycemia. The same was true for HIF-2α except for a trend toward an increase following 12 weeks of hyperglycemia in mice. Pimonidazole staining showed significant decreases throughout all layers of the central retina and most layers of the peripheral retina of rats (but not mice), following 12 weeks of hyperglycemia. In summary, despite early decreases in flow in rats and mice, retinal HIF-1α and HIF-2α were not found to be increased, and the extent of hypoxia may even decrease after 12 weeks of hyperglycemia in rats.