Abstract
Purpose: Diabetic retinopathy (DR) is one of the most common diabetic microvascular complications. However, the pathogenesis of DR has not yet been fully elucidated. This study aimed to discover novel and key molecules involved in the pathogenesis of DR, which could potentially be targets for therapeutic DR intervention.Methods: To identify potential genes involved in the pathogenesis of DR, we analyzed the public database of neovascular membranes (NVMs) from patients with proliferative diabetic retinopathy (PDR) and healthy controls (HCs) (GSE102485, https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE102485). Further, we compared these findings by performing RNA-sequencing analysis of peripheral blood mononuclear cells (PBMC) from patients with DR, control patients with non-complicated diabetes mellitus (DMC), and HCs. To determine the critical role of candidate genes in DR, knockdown or knockout was performed in human retinal vascular endothelial cells (HRVECs). The oxidative stress pathway, as well as tight junction integrity, was analyzed.Results: Transcriptional profiles showed distinct patterns between the NVMs of patients with DR and those of the HCs. Those genes enriched in either extracellular matrix (ECM)-receptor interaction or focal adhesion pathways were considerably upregulated. Both pathways were important for maintaining the integrity of retinal vascular structure and function. Importantly, the gene encoding the matricellular protein CCN1, a key gene in cell physiology, was differentially expressed in both pathways. Knockdown of CCN1 by small interfering RNA (siRNA) or knockout of CCN1 by the CRISPR-Cas9 technique in HRVECs significantly increased the levels of VE-cadherin, reduced the level of NADPH oxidase 4 (NOX4), and inhibited the generation of reactive oxygen species (ROS).Conclusion: The present study identifies CCN1 as an important regulator in the pathogenesis of DR. Increased expression of CCN1 stimulates oxidative stress and disrupts tight junction integrity in endothelial cells by inducing NOX4. Thus, targeting the CCN1/NOX4 axis provides a therapeutic strategy for treating DR by alleviating endothelial cell injury.
Highlights
Both diabetes [1] and pre-diabetes [2, 3] could lead to microvascular and macrovascular complication
The current study demonstrated that CCN1 affects oxidative stress by modulating NOX4 and provides new insights into the mechanism of Diabetic retinopathy (DR) and a novel target for predicting or treating DR
Our results suggest that CCN1 influenced the tight junction through NOX4induced oxidative stress
Summary
Both diabetes [1] and pre-diabetes [2, 3] could lead to microvascular and macrovascular complication. Diabetic retinopathy (DR) is the most common complication of diabetes mellitus (DM); it has long been recognized as a microvascular disease [4] that affects nearly one-third of all patients with diabetes [5] and is the leading cause of vision loss globally [6]. The condition results in a poor quality of life and increases mortality in patients. Etiological therapy is paramount for the management of DR and improvement of the prognosis. The pathogenesis of DR is not yet thoroughly understood. To date, no specific therapy is available to effectively treat DR
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