MiR-365 promotes diabetic retinopathy through inhibiting Timp3 and increasing oxidative stress. (March 2018)

• Record Type: Journal Article
• Authors: Wang, Juan; Zhang, Jieping; Chen, Xin; Yang, Yiting; Wang, Fang; Li, Weiye; Awuti, Maihemuti; Sun, Yaping; Lian, Chunpin; Li, Zongyi; Wang, Min; Xu, Jing-Ying; Jin, Caixia; Tian, Haibin; Gao, Furong; Zhang, Jingfa; Sinha, Debasish; Lu, Lixia; Xu, Guo-Tong
• Is Part Of: Experimental eye research. Volume 168(2018)
• Page Start: 89
• Page End: 99
• Publication Date: 2018-03
• Subjects: miR-365 -- Timp3 -- Oxidative stress -- Müller cells -- Diabetic retinopathy; Ophthalmology -- Periodicals; Eye -- Periodicals; Œil -- Périodiques; Ophthalmology; Periodicals; Electronic journals; 612.8405
• DOI: 10.1016/j.exer.2017.11.006
• Languages: English
• ISSNs: 0014-4835

Abstract

Abstract: miRs play critical roles in oxidative stress-related retinopathy pathogenesis. miR-365 was identified in a previously constructed library from glyoxal-treated rat Müller cell. This report explores epigenetic alterations in Müller cells under oxidative stress to develop a novel therapeutic strategy. To examine the miR-365 expression pattern, in situ hybridization and quantitative RT-PCR were performed. Bioinformatical analysis and dual luciferase report assay were applied to identify and confirm target genes. Streptozotocin (STZ)-treated rats were used as the diabetic retinopathy (DR) model. Lentivirus-mediated anti-miR-365 was delivered subretinally and intravitreally into the rats' eyes. The functional and structural changes were evaluated by electroretinogram (ERG), histologically, and through examination of expression levels of metallopeptidase inhibitor 3 ( Timp3 ), glial fibrillary acidic protein ( Gfap ), recoverin ( Rcvrn ) and vascular endothelia growth factor A ( Vegfa ). Oxidative stress factors and pro-inflammatory cytokines were analyzed. miR-365 expression was confirmed in the glyoxal-treated rat Müller cell line (glyoxal-treated rMC-1). In the retina, miR-365 mainly localized in the inner nuclear layer (INL). The increased miR-365 participated in Müller cell gliosis through oxidative stress aggravation, as observed in glyoxal-treated rMC-1 and DR rats before 6 weeks. Timp3 was a target and negatively regulated by miR-365. When miR-365 was inhibited, Timp3 expression was upregulated, Müller cell gliosis was alleviated, and retinal oxidative stress was attenuated. Visual function was also partially rescued as detected by ERG. miR-365 was found to be highly expressed in the retina and the abnormality of miR-365/ Timp3 pathway is closely related to the pathology, like Müller gliosis, and the visual injury in DR. The mechanism might be through oxidative stress, and miR-365/ Timp3 could be a potential therapeutic target for treating DR. Highlights: miR-365 in rat retina is mainly expressed in INL, photoreceptor layer, and RPE layer. Timp3 is the direct target of and negatively regulated by miR-365. The increased miR-365 in Müller cells is involved in DR through miR-365/ Timp3 pathway and oxidative stress mechanism.