microRNAs in Early Diabetic Retinopathy in Streptozotocin-Induced Diabetic Rats
microRNAs in Early Diabetic Retinopathy in Streptozotocin-Induced Diabetic Rats
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DOI：
10.1167/iovs.10-6879
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发表时间：
2011-06-01
影响因子：
4.4
通讯作者：
Xu, Shunbin
中科院分区：
文献类型：
--
作者：
Kovacs, Beatrix;Lumayag, Stephen;Xu, Shunbin
目的.糖尿病视网膜病变（DR）是导致失明的主要原因之一。然而，microRNA（miRNAs）在DR中的作用仍然未知。本研究的目的是鉴定参与早期DR的miRNAs，并分析其在DR发病机制中的作用。在糖尿病发病3个月后，在链脲佐菌素（STZ）诱导的糖尿病大鼠的视网膜和视网膜内皮细胞（RECs）中进行miRNA表达谱分析，鉴定糖尿病大鼠中差异表达的miRNA，并与对照组进行比较。随后，进行功能注释分析以鉴定DR病理途径的miRNA特征。此外，使用体外功能测定来剖析条件永生化视网膜毛细血管内皮细胞系Tr-iBRB. MTS中miR-146和NF-κ B活化的相互作用。在对照组和糖尿病大鼠的视网膜和RECs中分别检测到约350和220个miRNA。在糖尿病大鼠和对照组的视网膜和RECs中，分别有至少86和120个miRNAs差异表达（P < 0.01）。NF-κ B-、VEGF-和p53-应答性miRNA的上调构成了关键的miRNA特征，反映了早期DR的持续病理变化。此外，证明了miR 146对NF-κ B活化的负反馈调节可能在Tr-iBR B内皮细胞中起作用，提示miR-146是通过抑制REC中NF-κ B活化治疗DR的潜在治疗靶点。miRNA通过调节多种发病途径参与DR的发病机制，并且可能是用于治疗DR的新的治疗靶标（Invest Ophthalmol维斯Sci. 2011;52：4402-4409）DOI：10.1167/iovs.10-6879
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-kappa B 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-kappa B-, 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 miR146 on NF-kappa B 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-kappa B 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. (Invest Ophthalmol Vis Sci. 2011;52:4402-4409) DOI:10.1167/iovs.10-6879