Pathogenic Role of <i>microRNA-21</i> in Diabetic Retinopathy Through Downregulation of PPARα

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