Long noncoding RNA PPT2-EGFL8 regulates pathological retinal neovascularization in PDR by functioning as a competing endogenous RNA

Diabetic retinopathy (DR) is a common complication in patients with diabetes, and PDR has become an important cause of blindness; however, the mechanisms involved have not been fully elucidated. Long noncoding RNAs (lncRNAs) and microRNAs can play an important role in DR, and they can accurately regulate the expression of target genes through a new regulatory model: competing endogenous RNAs (ceRNAs). We isolated total RNA of extracellular vesicles (EVs) in the serum of healthy individuals (Con) and individuals with diabetes mellitus without DR (DM-NDR), non-proliferative DR (NPDR), or proliferative DR (PDR), and subjected them to deep sequencing. We found aberrantly low expression of PPT2-EGFL8, and significantly increased level of miR-423-5p. PPT2-EGFL8 adsorbs miR-423-5p as a molecular sponge, and inhibits hypoxia-induced hRMEC proliferation. In an oxygen-induced retinopathy (OIR) model and a streptozotocin (STZ)-induced diabetic model, Egfl8-OE treatment reduces diabetes-related reactive gliosis, inflammation and acellular capillaries, attenuates the development of pathological neovascularization. In addition, PPT2-EGFL8 targeting miR-423-5p plays an important role in hypoxia-induced PPARD/ANGPTL4 signaling activation, especially the expression of C-terminal (cANGPTL4) fragment. Finally, ANGPTL4 significantly induces retinal vessel breakage in the inner limiting membrane (ILM) and facilitate retinal vessel sprouting into the vitreous in the OIR mice. Thus, either new biomarkers or new therapeutic targets may be identified with translation of these findings.