circKIAA1462 impaires autophagy and promotes pyroptosis in retinal pigment epithelium via the miR-183-5p/HMGB1 axis in diabetic retinopathy.
TL;DR
The cKIAA1462/miR-183-5p/HMGB1 axis plays a critical role in diabetic RPE injury by dual regulation of autophagy and pyroptosis by targeting this pathway may offer a novel therapeutic strategy for early diabetic retinopathy.
Abstract
Background
Diabetic retinopathy (DR) is one of the most prevalent complications of diabetes which could lead to vision impairment. Dysfunction of the retinal pigment epithelium (RPE) is an early pathogenic event, where various mechanisms may contribute to the disease progression. circular RNAs (circRNAs) have been reported to be important regulators in diabetic complications, acting as miRNA sponge, participating in the regulation of gene transcription or coding short peptides.
Methods
Circular RNA microarray and RNA-seq were used to identify differentially expressed circRNAs in ARPE-19 cells in normal and high glucose treatments. The expression of cKIAA1462, miR-183-5p, and high mobility group box 1 (HMGB1) were determined using quantitative real-time polymerase chain reaction and Western blot. In vitro experiments, such as flow cytometry, Western blot, and Electron microscope (TEM) were conducted. The binding interaction was confirmed using dual-luciferase reporter and overexpression/inhibition experiments. cKIAA1462 was knocked down via intravitreal lentiviral injection in diabetic mice, followed by expression level detection, functional analysis and histological assessments.
Results
cKIAA1462 was significantly upregulated under high glucose conditions both in vitro and in vivo (in retinas of diabetic mice). It acted as a molecular sponge for miR-183-5p, increasing the expression of HMGB1. Elevated HMGB1 concurrently impaired autophagic flux (increased p62, decreased autophagosomes) and activated the NLRP3 inflammasome (upregulated NLRP3, ASC, caspase-1), promoting pyroptosis. Silencing cKIAA1462 in vivo restored autophagy, suppressed pyroptosis, improved retinal structure, and enhanced electroretinogram responses in diabetic mice.
Conclusion
The cKIAA1462/miR-183-5p/HMGB1 axis plays a critical role in diabetic RPE injury by dual regulation of autophagy and pyroptosis. Targeting this pathway may offer a novel therapeutic strategy for early diabetic retinopathy.