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

Author:

Chen Qian12,Qiu Fangfang1,Zhou Kelu1,Matlock H. Greg1,Takahashi Yusuke23,Rajala Raju V.S.14,Yang Yanhui15,Moran Elizabeth26,Ma Jian-xing12

Affiliation:

1. Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK

2. Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK

3. Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK

4. Dean A. McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK

5. Tianjin Metabolic Diseases Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China

6. Department of Ophthalmology, Boston Children’s Hospital, Boston, MA

Abstract

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 microRNA-21 (miR-21) in regulating PPARα in DR. miR-21 was overexpressed, while PPARα 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 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 downregulation 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 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 PPARα downregulation in DR. Targeting miR-21 may represent a novel therapeutic strategy for DR.

Funder

Foundation for the National Institutes of Health

Oklahoma Center for the Advancement of Science & Technology

Harold Hamm Diabetes Center

American Heart Association

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

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