Exendin-4 alleviates diabetic retinopathy by activating autophagy via regulation of the adenosine monophosphate-activated protein kinase/sirtuin 1 pathway.

Exendin-4 has been implicated to impact diabetic retinopathy (DR), a serious ocular complication of glycosuria that can cause blindness; therefore, we aimed to investigate mechanisms of therapeutic effects of Exendin-4 in DR via autophagy activation. High glucose-induced human retinal microvascular endothelial cells were used to detect Exendin-4 to protect cells from damage and activate autophagy in vitro. Additionally, twenty Sprague Dawley rats were divided into control, DR, Exendin-4, and Exendin-4 + ex-527 groups. The pathological changes and activation of autophagy were observed in each group after treatment. Furthermore, the involvement of the adenosine monophosphate-activated protein kinase (AMPK)/sirtuin (SIRT)1 pathway in the Exendin-4 activation of autophagy was investigated. Exendin-4 inhibited apoptosis, angiogenesis, and inflammation, and upregulated the expression of autophagy biomarkers. Moreover, histological staining revealed that after Exendin-4 treatment, the disorder of retinal ganglion cell arrangement and the reduction or loss of cells in DR rats were relieved. Autophagy biomarkers were upregulated in the retinal tissue of DR rats after Exendin-4 treatment. Western blotting showed that the protein expression levels of AMPK/SIRT1 pathway increased significantly after Exendin-4 administration. However, SIRT1 inhibitor reversed the therapeutic effects of Exendin-4. Our results suggest that the efficacy of Exendin-4 in the treatment of DR is achieved by activating autophagy; this therapeutic mechanism may involve regulation of the AMPK/SIRT1 pathway.