The purpose of this study was to explore the role of microRNA-451a (miR-451a) in diabetic retinopathy through activating transcription factor 2 (ATF2). The epiretinal membrane samples from patients with proliferative diabetic retinopathy (PDR) were immunolabeled with an antibody for Ki-67 to identify the proliferative cells. The expression of miR-451a was measured by qRT-PCR in the retina of Akita mice and in RPE cells under diabetic conditions. The potential downstream targets of miR-451a were predicted by bioinformatics and confirmed by dual luciferase assay, qRT-PCR, and Western blotting. Mitochondrial function, cell proliferation, and migration assays were used to detect the functional change after transfection of miR-451a mimic and inhibitor. Proliferative RPE cells were identified in the epiretinal membrane from PDR patients. The expression of miR-451a was downregulated both in the retina of Akita mice and 4-hydroxynonenal (4-HNE)-treated RPE cells. Bioinformatic analysis and luciferase assay identified ATF2 as a potential target of miR-451a. miR-451a inhibited proliferation and migration of RPE cells. The mitochondrial function was enhanced by miR-451a mimic, but suppressed by miR-451a inhibitor. In diabetic conditions, miR-451a showed a protective effect on mitochondrial function. The results of qRT-PCR and Western blotting revealed that overexpression of miR-451a downregulated the expression of ATF2 and its downstream target genes CyclinA1, CyclinD1, and MMP2. In conclusion, miR-451a/ATF2 plays a vital role in the regulation of proliferation and migration in RPE cells through regulation of mitochondrial function, which may provide new perspectives for developing effective therapies for PDR.
Keywords: ATF2; cell proliferation; diabetic retinopathy; miRNA-451a; mitochondrial function.