RNA sequencing reveals BMP4 as a basis for the dual-target treatment of diabetic retinopathy
Abstract Backgroud: Diabetic retinopathy, currently considered a neurovascular disease, has become the major cause of blindness. Continuously high glucose levels are regarded as a risk factor for DR. Intravitreal injection of anti-VEGF drugs is a classic treatment for DR; however, anti-VEGF drugs can exacerbate fibrosis and eventually lead to retinal detachment.Methods: We explored changes in gene expression in high-glucose-induced vascular endothelial cells using RNA sequencing technology, utilized transcriptome signatures to explore the pathogenesis of DR and identified new treatments that can provide dual-target intervention for angiogenesis and fibrosis. We identified BMP4 and SMAD9 among 449 differentially expressed genes from RNA-seq data and investigated the expression of these two genes in the blood of diabetes patients and in STZ-induced rat retinas. Moreover, considering that DR is a multifactorial and multicellular disease, we used H2O2, AGEs, CoCl2, 4HNE and hypoxia to induce three human retinal cell types (Müller, RPE and HRCECs) to simulate the pathogenesis of DR and then verified the overexpression of these two genes in the cell models. We further tested the effects of BMP4 on retinal cells. Results: The results demonstrated that BMP4 and SMAD9 were highly expressed in both in vivo and in vitro models, while BMP4 could significantly upregulate the expression of SMAD9 and promote the expression of VEGF and fibrosis factors.Conclusions: This study is the first to analyze the mechanism by which high glucose levels affect retinal vascular endothelial cells through RNA transcriptome sequencing and indicates that BMP4 may be a potential target for the dual-target treatment (anti-VEGF and antifibrosis) of DR.