Diabetic retinopathy (DR) is one of the most common microvascular complications of diabetes. In the last years, several in vivo studies have demonstrated the protective role of pituitary adenylate cyclase-activating peptide (PACAP-38) to counteract several alterations occurring during DR. Recently, different studies have demonstrated that some PACAP-38 effects are mediated by EGFR trans-activation, although no data exist regarding the link between this peptide and EGFR in DR. The aim of the present study has been to investigate whether retinal effect of PACAP-38 against high glucose damage is mediated by EGFR phosphorylation. Diabetes was induced by a single injection of streptozotocin (STZ) in rats. After 1 week, a group of animals was treated with a single intravitreal injection of 100 μM PACAP-38 or saline solution. Immunohistochemistry and western blot analysis have demonstrated that intravitreal injection of PACAP-38 induced p-EGFR over-expression in retina of diabetic rats. Several pathogenic mechanisms may contribute to diabetic retinopathy including BRB alteration. To better clarify the relationship between PACAP-38 and EGFR, we have also carried out a study on ARPE-19 cells, representing a model in vitro of outer BRB. Our results have shown that PACAP-38 treatment improved cell viability in ARPE-19 cells exposed to hyperglycemic/hypoxic insult mimicking tissue microenvironment occurring in DR. Binding to PAC1R, peptide induces EGFR phosphorylation via PKA-signaling cascade stimulation. EGFR trans-activation triggers MAPK/ERK signaling pathway involved in cell survival and proliferation. In conclusion, data have suggested that PACAP-38 acts through EGFR phosphorylation in DR and this effect particularly occurs on RPE layer.
Keywords: Cells; Diabetic retinopathy; Epidermal growth factor receptor; Pituitary adenylate cyclase-activating peptide; Retinal pigmented epithelial.
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