title: Pathogenic Role ofmicroRNA-21in Diabetic Retinopathy Through Downregulation of PPARα.
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 ofmicroRNA-21(miR-21) in regulating PPARα in DR.miR-21was overexpressed, while PPARα levels were decreased in the retina ofdb/dbmice, a model of type 2 diabetes. Such alterations were also observed in palmitate-treated retinal endothelial cells.miR-21targeted PPARα by inhibiting its mRNA translation. Knockout ofmiR-21prevented the decrease of PPARα, alleviated microvascular damage, ameliorated inflammation, and reduced cell apoptosis in the retina ofdb/dbmice. Intravitreal injection ofmiR-21inhibitor attenuated PPARα downregulation and ameliorated retinal inflammation indb/dbmice. Further, retinalmiR-21levels were increased, while PPARα levels were decreased in oxygen-induced retinopathy (OIR). Knockout ofmiR-21prevented PPARα downregulation and ameliorated retinal neovascularization and inflammation in OIR retinas. In conclusion, diabetes-induced overexpression ofmiR-21in the retina is at least partly responsible for PPARα downregulation in DR. TargetingmiR-21may represent a novel therapeutic strategy for DR.
authors.affiliation: Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK.|Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK.
authors.forename: Qian
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Qiu
authors.affiliation: Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK.
authors.forename: Kelu
authors.initials: K
authors.lastname: Zhou
authors.affiliation: Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK.
authors.forename: H Greg
authors.initials: HG
authors.lastname: Matlock
authors.affiliation: Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK yusuke-takahashi@ouhsc.edu.|Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK.|Dean A. McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK.
authors.forename: Raju V S
authors.initials: RVS
authors.lastname: Rajala
authors.affiliation: Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK.|Tianjin Metabolic Diseases Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China.
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK.|Department of Ophthalmology, Boston Children's Hospital, Boston, MA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Moran
authors.affiliation: Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK.|Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK.
authors.forename: Jian-Xing
authors.initials: JX
authors.lastname: Ma
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D003930:Diabetic Retinopathy / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D006801:Humans; D007249:Inflammation; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D047493:PPAR alpha / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D012160:Retina / Q000378:metabolism; D015861:Retinal Neovascularization / Q000235:genetics; D055213:Retinal Pigment Epithelium / Q000166:cytology; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C524940:MIRN21 microRNA, human; C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs; D047493:PPAR alpha