Fenofibrate, a specific agonist of peroxisome proliferator-activated receptor alpha (PPARα), displays robust therapeutic effects on diabetic retinopathy (DR) in type 2 diabetic patients. Our recent studies have shown that PPARα is down-regulated in the diabetic retina, which contributes to the pathogenesis of DR. However, the mechanism for diabetes-induced down-regulation of PPARα remains unknown. We investigated the role of microRNA-21 (miR-21) in regulating PPARα in DR. MiR-21 was over-expressed, while PPARα levels were decreased in the retina of db/db mice, a type 2 diabetic model. Such alterations were also observed in palmitate-treated retinal endothelial cells. MiR-21 targeted PPARα by inhibiting its mRNA translation. Knockout of miR-21 prevented the decrease of PPARα, alleviated microvascular damage, ameliorated inflammation and reduced cell apoptosis in the retina of db/db mice. Intravitreal injection of miR-21 inhibitor attenuated PPARα down-regulation and ameliorated retinal inflammation in db/db mice. Further, retinal miR-21 levels were increased, while PPARα levels were decreased in oxygen-induced retinopathy (OIR). Knockout of miR-21 prevented PPARα down-regulation and ameliorated retinal neovascularization and inflammation in OIR retinas. In conclusion, diabetes-induced over-expression of miR-21 in the retina is responsible, at least in part, for PPARα down-regulation in DR. Targeting miR-21 may represent a novel therapeutic strategy for DR.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db16-1246/-/DC1.
- Received October 12, 2016.
- Accepted February 28, 2017.
- © 2017 by the American Diabetes Association.