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miR-590-3p Inhibits Pyroptosis in Diabetic Retinopathy by Targeting NLRP1 and Inactivating the NOX4 Signaling Pathway
- Source :
- Investigative ophthalmologyvisual science. 60(13)
- Publication Year :
- 2019
-
Abstract
- 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-1β, 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-1β induced the downregulation of miR-590-3p by lowering the DNA promoter activity of pri-miR-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-1β-mediated positive feedback loop.
- Subjects :
- 0301 basic medicine
Small interfering RNA
Cell
Caspase 1
NLR Proteins
03 medical and health sciences
0302 clinical medicine
Downregulation and upregulation
medicine
Pyroptosis
Humans
Cells, Cultured
Adaptor Proteins, Signal Transducing
Gene knockdown
Diabetic Retinopathy
Chemistry
Endothelial Cells
Cell biology
MicroRNAs
030104 developmental biology
medicine.anatomical_structure
NADPH Oxidase 4
030220 oncology & carcinogenesis
cardiovascular system
Signal transduction
Apoptosis Regulatory Proteins
Reactive Oxygen Species
TXNIP
Signal Transduction
Subjects
Details
- ISSN :
- 15525783
- Volume :
- 60
- Issue :
- 13
- Database :
- OpenAIRE
- Journal :
- Investigative ophthalmologyvisual science
- Accession number :
- edsair.doi.dedup.....751451bb838924692937c844650f9f4b