Journal
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
Volume 320, Issue 3, Pages E598-E608Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpendo.00089.2020
Keywords
diabetic retinopathy; endothelial-mesenchymal transition; DNA methyltransferase 1; long non-coding RNA MEG3; methylation
Categories
Funding
- project of Youth Innovation in Medical Research in Sichuan Province [Q15014]
- Luzhou Municipal Government-Sichuan Medical University Science and Technology Strategic Cooperation Project [2015LZCYD-S06(1/11)]
- Scientific Research Topics of Sichuan Health and Family Planning Commission [16PJ560]
- Affiliated Hospital of Luzhou Medical College Scientific Research Project [2015-PT-017]
- Doctoral Research Initiation Fund of Affiliated Hospital of Southwest Medical University
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Diabetic retinopathy (DR) is one of the serious complications that occurs in diabetic patients that frequently causes blindness. Long noncoding RNAs (lncRNAs) have been associated with DR pathology. This study aimed to determine the underlying mecha-nism of lncRNA maternally expressed gene 3 (MEG3) in association with DNA methyltransferase 1 (DNMT1) in the endothelial-mesenchymal transition (endMT) that occurs in DR. A rat model of DR was induced by streptozotocin (STZ) injection, and a high-glucose (HG)-induced cell model was established by exposing microvascular endothelial cells obtained from retina of rats to HG. Subsequently, MEG3 was overexpressed in rat and cell models to characterize its impact on endMT in DR and the involvement of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway. Furthermore, the meth-ylation level of MEG3 promoter region was determined with the application of methylation-specific polymerase chain reaction, followed by chromatin immunoprecipitation assay for methyltransferase enrichment. Finally, we examined the regulation of DNMT1 on MEG3 methylation and endMT in the HG-induced cell model. The results obtained revealed downregulated MEG3 expression in DR rat and cell models. Overexpressed MEG3 was shown to suppress endMT in DR rat and cell models through the inhibition of the PI3K/Akt/mTOR signaling pathway. Notably, DNMT1 could promote MEG3 promoter methylation to inhibit MEG3 expression by recruiting methyltransferase, which activated the PI3K/Akt/mTOR signaling pathway to accelerate endMT in DR. These findings further highlighted the inhibitory effect of MEG3 on endMT in DR, thus presenting a novel therapeutic target candidate for DR treatment.
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