Abstract：
Diabetic retinopathy is one of the most characteristic complications of diabetes mellitus, and pyroptosis plays acrucial role in the onset and development of diabetic retinopathy. Although microRNA-192 (miR-192) has been demonstrated to be involved in diabetic retinopathy progression, to the best of our knowledge, its potential and mechanism in cell pyroptosis in diabetic retinopathy have not been studied. The present study demonstrated that high glucose (HG) contributes to the pyroptosis of retinal pigment epithelial (RPE) cells in a dose-dependent manner. The results revealed that miR-192 was weakly expressed in HG-induced RPE cells. Furthermore, overexpression of miR-192 abrogated the role of HG in RPE cell pyroptosis. Based on the bioinformatics analysis, a dual-luciferase reporter assay, and an RNA pull-down assay, FTO α-ketoglutarate-dependent dioxygenase (FTO) was demonstrated to be a direct target of miR-192. Additionally, upregulation of FTO abolished the effects of miR-192 on RPE cells treated with HG. Nucleotide-binding domain leucine-rich repeat family protein 3 (NLRP3) inflammasome activation is vital for cell pyroptosis, and FTO functions as a pivotal modulator in the N6-methyladenosine modifications of various genes. Mechanistically, FTO enhanced NLRP3 expression by facilitating demethylation of NLRP3. In conclusion, the present results demonstrate that miR-192 represses RPE cell pyroptosis triggered by HG via regulation of the FTO/NLRP3 signaling pathway.
摘要：
糖尿病视网膜病变是糖尿病最常见的并发症之一,焦亡在糖尿病视网膜病变的发生和发展中起着决定性的作用。尽管microRNA-192（miR-192）已被证明与糖尿病视网膜病变的进展有关，据我们所知,其在糖尿病性视网膜病变细胞焦亡中的潜力和机制尚未被研究。本研究表明，高葡萄糖（HG）以剂量依赖性方式促进视网膜色素上皮（RPE）细胞的焦亡。结果显示miR-192在HG诱导的RPE细胞中弱表达。此外，miR-192的过表达废除了HG在RPE细胞焦亡中的作用。基于生物信息学分析,双荧光素酶报告分析，和RNA下拉法，FTOα-酮戊二酸依赖性双加氧酶(FTO)被证明是miR-192的直接靶标。此外,FTO的上调消除了miR-192对用HG处理的RPE细胞的影响。核苷酸结合域富含亮氨酸的重复家族蛋白3（NLRP3）炎性体激活对于细胞焦亡至关重要，和FTO在各种基因的N6-甲基腺苷修饰中起关键调节剂的作用。机械上,FTO通过促进NLRP3的去甲基化来增强NLRP3的表达。总之,本研究结果表明,miR-192可通过调节FTO/NLRP3信号通路抑制HG引发的RPE细胞凋亡.
