Abstract
Purpose: Vascular endothelial growth factor-A (VEGF-A) is an important pathogenic factor in proliferative diabetic retinopathy (PDR), and aflibercept (Eylea) is one of the widely used anti-VEGF agents. This study investigated the microRNA (miRNA) profiles in the vitreous of 5 idiopathic macular hole patients (non-diabetic controls), 5 untreated PDR patients (no-treatment group), and 5 PDR patients treated with intravitreal aflibercept injection (treatment group). Methods: Next-generation sequencing was performed to determine the miRNA profiles. Deregulated miRNAs were validated with quantitative real-time PCR (qRT-PCR) in another cohort. The mRNA profile data (GSE160310) of PDR patients were retrieved from the Gene Expression Omnibus (GEO) database. The function of differentially expressed miRNAs and mRNAs was annotated by bioinformatic analysis and literature study. Results: Twenty-nine miRNAs were significantly dysregulated in the three groups, of which 19,984 target mRNAs were predicted. Hsa-miR-3184-3p, hsa-miR-24-3p, and hsa-miR-197-3p were validated to be remarkably upregulated in no-treatment group versus controls, and significantly downregulated in treatment group versus no-treatment group. In the GSE160310 profile, 204 deregulated protein-coding mRNAs were identified, and finally 179 overlapped mRNAs between the 19,984 target mRNAs and 204 deregulated mRNAs were included for further analysis. Function analysis provided several roles of aflibercept-induced miRNAs, promoting the alternation of drug sensitivity or resistance-related mRNAs, and regulating critical mRNAs involved in angiogenesis and retinal fibrosis. Conclusion: Hsa-miR-3184-3p, hsa-miR-24-3p, and hsa-miR-197-3p were highly expressed in PDR patients, and intravitreal aflibercept injection could reverse this alteration. Intravitreal aflibercept injection may involve in regulating cell sensitivity or resistance to drug, angiogenesis, and retinal fibrosis.
Highlights
Diabetic retinopathy (DR) is a common complication of diabetes mellitus and the leading cause of low vision in working-aged adults (Ogurtsova et al, 2017; Solomon, Chew et al, 2017), which consists of two stages: non-proliferative diabetic retinopathy (NPDR) is the early stage characterized by the developments of microvascular changes; proliferative diabetic retinopathy (PDR) is the later stage, characterized by the formation of neovascularization and fibrous tissue
The excessive release of vascular endothelial growth factor A (VEGF-A) in the retina was a crucial regulator of PDR by promoting the retinal neovascularization
In the screening cohort (15 eyes of 15 patients), five patients diagnosed with idiopathic macular holes were included as control group, five PDR patients who had no history of ophthalmic therapy were included as no-treatment group, and five PDR patients who were at the seventh day after intravitreal aflibercept injection were listed as treatment group
Summary
Diabetic retinopathy (DR) is a common complication of diabetes mellitus and the leading cause of low vision in working-aged adults (Ogurtsova et al, 2017; Solomon, Chew et al, 2017), which consists of two stages: non-proliferative diabetic retinopathy (NPDR) is the early stage characterized by the developments of microvascular changes; proliferative diabetic retinopathy (PDR) is the later stage, characterized by the formation of neovascularization and fibrous tissue. It has been demonstrated that aflibercept reduced the activation of phospholipase A2 (PLA2)/cyclooxygenase-2 (COX-2)/prostaglandin (PG) axis in human retinal pericytes subjected to high glucose to protect it from glucose-induced damage (Giurdanella et al, 2015). All of this suggests anti-VEGF treatment may trigger complex regulatory mechanisms in the intraocular environment. There is an unmet medical need of exploring it to explain different responses and prognosis after anti-VEGF treatment
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