PURPOSE: Diabetic retinopathy (DR) is one of the leading causes of blindness. However, the roles of microRNAs (miRNAs) in DR are still unknown. The aims of this study were to identify miRNAs involved in early DR and to characterize their roles in the pathogenesis of DR. METHODS: miRNA-expression profiling was performed in the retina and retinal endothelial cells (RECs) of streptozotocin (STZ)-induced diabetic rats 3 months after the onset of diabetes and miRNAs differentially expressed in diabetic rats were identified and compared with controls. Subsequently, functional annotation analysis was conducted to identify miRNA signatures of pathologic pathways of DR. In addition, in vitro functional assays were used to dissect interactions of miR-146 and NF-κB activation in a conditionally immortalized retinal capillary endothelial cell line, Tr-iBRB. RESULTS: Approximately 350 and 220 miRNAs were detected in the retinas and RECs, respectively, in both control and diabetic rats. At least 86 and 120 miRNAs were differentially expressed (P < 0.01) in the retinas and RECs of diabetic rats and controls, respectively. Upregulation of NF-κB-, VEGF-, and p53-responsive miRNAs constituted key miRNA signatures, reflecting ongoing pathologic changes of early DR. In addition, it was demonstrated that the negative feedback regulation of miR-146 on NF-κB activation may function in Tr-iBRB endothelial cells, suggesting that miR-146 is a potential therapeutic target for the treatment of DR through its inhibition on NF-κB activation in RECs. CONCLUSIONS: miRNAs are involved in the pathogenesis of DR through the modulation of multiple pathogenetic pathways and may be novel therapeutic targets for the treatment of DR.
PURPOSE:Diabetic retinopathy (DR) is one of the leading causes of blindness. However, the roles of microRNAs (miRNAs) in DR are still unknown. The aims of this study were to identify miRNAs involved in early DR and to characterize their roles in the pathogenesis of DR. METHODS: miRNA-expression profiling was performed in the retina and retinal endothelial cells (RECs) of streptozotocin (STZ)-induced diabeticrats 3 months after the onset of diabetes and miRNAs differentially expressed in diabeticrats were identified and compared with controls. Subsequently, functional annotation analysis was conducted to identify miRNA signatures of pathologic pathways of DR. In addition, in vitro functional assays were used to dissect interactions of miR-146 and NF-κB activation in a conditionally immortalized retinal capillary endothelial cell line, Tr-iBRB. RESULTS: Approximately 350 and 220 miRNAs were detected in the retinas and RECs, respectively, in both control and diabeticrats. At least 86 and 120 miRNAs were differentially expressed (P < 0.01) in the retinas and RECs of diabeticrats and controls, respectively. Upregulation of NF-κB-, VEGF-, and p53-responsive miRNAs constituted key miRNA signatures, reflecting ongoing pathologic changes of early DR. In addition, it was demonstrated that the negative feedback regulation of miR-146 on NF-κB activation may function in Tr-iBRB endothelial cells, suggesting that miR-146 is a potential therapeutic target for the treatment of DR through its inhibition on NF-κB activation in RECs. CONCLUSIONS: miRNAs are involved in the pathogenesis of DR through the modulation of multiple pathogenetic pathways and may be novel therapeutic targets for the treatment of DR.
Authors: Marcelo A Mori; Raissa G Ludwig; Ruben Garcia-Martin; Bruna B Brandão; C Ronald Kahn Journal: Cell Metab Date: 2019-08-22 Impact factor: 27.287
Authors: Nathan G Lambert; Hanan ElShelmani; Malkit K Singh; Fiona C Mansergh; Michael A Wride; Maximilian Padilla; David Keegan; Ruth E Hogg; Balamurali K Ambati Journal: Prog Retin Eye Res Date: 2016-05-06 Impact factor: 21.198