Exendin-4 protects retinal cells from early diabetes in Goto-Kakizaki rats by increasing the Bcl-2/Bax and Bcl-xL/Bax ratios and reducing reactive gliosis

Purpose: Exendin-4 (E4), a long-acting agonist of the hormone glucagon-like peptide 1 receptor (GLP-1R), is administered to treat type II diabetes in the clinical setting and also shows a neuroprotective effect. Our previous studies demonstrated its protective effect in early experimental diabetic retinopathy (DR), but the molecular and cellular mechanisms are largely unknown. This study aimed to investigate the protective mechanism of a GLP-1R agonist E4 against early DR in Goto-Kakizaki (GK) rats. Methods: Diabetic GK rats and control animals were randomly assigned to receive E4 or vehicle by intravitreal injection. The retinal function and retinal cell counts were evaluated using an electroretinogram and light microscopy. The expressions of retinal GLP-1R, mitochondria-dependent apoptosis-associated genes, reactive gliosis markers, and endoplasmic reticulum stress-related pathway genes were studied by western blotting and immunohistochemistry in vivo and in vitro. Results: E4 significantly prevented the reduction of the b-wave and oscillatory potential amplitudes and retinal cell loss and maintained the Bcl-2/Bax and Bcl-xL/Bax ratio balances in GK rats. It also downregulated the expression of glial fibrillary acidic protein and reduced retinal reactive gliosis. Similar results were found in primary rat Muller cells under high glucose culture in vitro. Conclusions: E4 may protect retinal cells from diabetic attacks by activating GLP-1R, decreasing retinal cell apoptosis, and reducing retinal reactive gliosis. Thus, E4 treatment may be a novel approach for early DR.