Pathogenic Role of microRNA-21 in Diabetic Retinopathy Through Downregulation of PPARα

Fenofibrate, a specific agonist of peroxisome proliferator-activated receptor- (PPAR), displays robust therapeutic effects on diabetic retinopathy (DR) in patients with type 2 diabetes. Our recent studies have shown that PPAR is downregulated in the diabetic retina, which contributes to the pathogenesis of DR. However, the mechanism for diabetes-induced downregulation of PPAR remains unknown. We investigated the role of microRNA-21 (miR-21) in regulating PPAR in DR. miR-21 was overexpressed, while PPAR levels were decreased in the retina of db/db mice, a model of type 2 diabetes. Such alterations were also observed in palmitate-treated retinal endothelial cells. miR-21 targeted PPAR by inhibiting its mRNA translation. Knockout of miR-21 prevented the decrease of PPAR, alleviated microvascular damage, ameliorated inflammation, and reduced cell apoptosis in the retina of db/db mice. Intravitreal injection of miR-21 inhibitor attenuated PPAR downregulation and ameliorated retinal inflammation in db/db mice. Further, retinal miR-21 levels were increased, while PPAR levels were decreased in oxygen-induced retinopathy (OIR). Knockout of miR-21 prevented PPAR downregulation and ameliorated retinal neovascularization and inflammation in OIR retinas. In conclusion, diabetes-induced overexpression of miR-21 in the retina is at least partly responsible for PPAR downregulation in DR. Targeting miR-21 may represent a novel therapeutic strategy for DR.