期刊
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
卷 60, 期 13, 页码 4215-4223出版社
ASSOC RESEARCH VISION OPHTHALMOLOGY INC
DOI: 10.1167/iovs.19-27825
关键词
miR-590-3p; NLRP1; NOX4/ROS/TXNIP/NLRP3 signaling pathway; pyroptosis; diabetic retinopathy
资金
- National Natural Science Foundation of China [81770947, 81970811]
- National Science and Technology Major Project of China [2017ZX09304010]
- Tibet Natural Science Foundation of China [XZ2017ZR-ZYZ09, XZ2018ZRG-95, XZ2018ZRG-100]
PURPOSE. To elucidate the mechanism whereby miR-590-3p regulates pyroptosis in diabetic retinopathy (DR). METHODS. Human retinal microvascular endothelial cells (HRMECs) incubated with high glucose (HG) were used to establish cell models, and the expression levels of miR-590-3p, caspase-1, IL-1 beta, NLRP1, NOX4, TXNIP, NLRP3, and ROS were determined. Additionally, miR-590-3p was altered using a mimic or an inhibitor, and siRNAs targeting NLRP1 and NOX4 were applied to explore the regulatory mechanism of miR-590-3p in DR. The relationships between miR-590-3p and NLRP1/NOX4 also were investigated using a luciferase reporter assay. Furthermore, vitreous tissue samples were collected to confirm pyroptosis in clinical DR. RESULTS. Downregulated miR-590-3p and upregulated NLRP1/NOX4 levels were observed in a cell culture model of DR. Inhibiting miR-590-3p upregulated NLRP1, the NOX4/ROS/TXNIP/NLRP3 pathway, and caspase-1. NLRP1 and NOX4 were confirmed as direct target genes of miR-590-3p. The overexpression of miR-590-3p or knockdown of NLRP1 and NOX4 increased cell activity and suppressed pyroptosis. Intriguingly, the upregulation of IL-1 beta induced the downregulation of miR-590-3p by lowering the DNA promoter activity of primiR-590. CONCLUSIONS. HG induced pyroptosis in a cell culture model of DR, and the downregulation of miR-590-3p promoted pyroptotic death by targeting NLRP1 and activating the NOX4/ROS/TXNIP/NLRP3 pathway via an IL-1 beta-mediated positive feedback loop.
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