Retinal hypoxia has been related to the pathogenesis of diabetic retinopathy. This event is mediated by the hypoxia-inducible factors (HIFs), including HIF-1α, HIF-2α, and HIF-3α. Previously, we have demonstrated the protective role of pituitary adenylate cyclase-activating peptide (PACAP) in the early phase of diabetic retinopathy. In the present work, we investigated whether PACAP effect in hyperglycemic retina is mediated through modulation of HIFs' expression. Diabetes was induced with a single injection of streptozotocin (STZ) in rats. After 1 week, a group of diabetic animals was treated with a single intravitreal injection of 100 μM PACAP or saline solution. Then, changes in HIFs' expression levels were evaluated in the retina after 3 weeks of hyperglycemia. The expression of HIF-1α and HIF-2α was significantly (p < 0.001 vs control) increased in diabetic rats as compared to controls. Instead, their expression levels were significantly (p < 0.001 vs STZ) decreased after PACAP intraocular administration, as detected by Western blot analysis. Conversely, the expression of HIF-3α was significantly (p < 0.001 vs control) downregulated in retinas of STZ-injected rats and significantly (p < 0.001 vs control) increased after PACAP treatment. These data were supported by the immunohistochemical analysis. HIFs were localized either in inner and outer retinal layers. Diabetes interferes with their distribution, which is changed following intravitreal injection of PACAP. The present results suggest that the protective effect of the peptide in diabetic retina might be also mediated through modulation of HIFs' expression.
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