As one of the common and serious chronic complications of diabetes mellitus (DM), the related mechanism of diabetic retinopathy (DR) has not been fully understood. Müller cell reactive gliosis is one of the early pathophysiological features of DR. Therefore, exploring the manner to reduce diabetes‐induced Müller cell damage is essential to delay DR. Thioredoxin 1 (Trx1), one of the ubiquitous redox enzymes, plays a vital role in redox homeostasis via protein–protein interactions, including apoptosis signal‐regulating kinase 1 (ASK1). Previous studies have shown that upregulation of Trx by some drugs can attenuate endoplasmic reticulum stress (ERS) in DR, but the related mechanism was unclear. In this study, we used DM mouse and high glucose (HG)‐cultured human Müller cells as models to clarify the effect of Trx1 on ERS and the underlying mechanism. The data showed that the diabetes‐induced Müller cell damage was increased significantly. Moreover, the expression of ERS and reactive gliosis was also upregulated in diabetes in vivo and in vitro. However, it was reversed after Trx1 overexpression. Besides, ERS‐related protein expression, reactive gliosis, and apoptosis were decreased after transfection with ASK1 small‐interfering RNA in stable Trx1 overexpression Müller cells after HG treatment. Taken together, Trx1 could protect Müller cells from diabetes‐induced damage, and the underlying mechanism was related to inhibited ERS via ASK1.
Diabetes-induced cell dysfunction of the retinal pigment epithelium (RPE) contributes to the initiation and progression of diabetic retinopathy (DR). Thioredoxin 1 (Trx1) plays a key role in DR. However, the effect and mechanism of Trx1 on diabetes-induced cell dysfunction of the RPE is not fully understood during DR. In the present study, the effect of Trx1 on this process and its related mechanism were investigated. A Trx1 overexpression cell line, ARPE19-Trx1/LacZ, was constructed and treated with or without high glucose (HG). Flow cytometry was used to analyze apoptosis of these cells and the mitochondrial membrane potential was analyzed using JC-1 staining solution. A DCFH-DA probe was also used to detect the reactive oxygen species (ROS) generation. Western blotting was used to examine the expression of related proteins in ARPE-19 cells after HG treatment. The results demonstrated that the RPE layer was damaged in clinical samples. ROS formation and RPE cell dysfunction increased after HG treatment
in vitro
. Besides, the expression of mitochondrial-mediated apoptosis related proteins (Bax, apoptosis-inducing factor, cytochrome C, Caspase3 and Caspase9) also increased; however, overexpression of Trx1 attenuated these changes and improved the function of ARPE19 cells. These results indicated that overexpression of Trx1 alleviated diabetes-induced RPE cell dysfunction in DR by attenuating oxidative stress.
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