Upregulation of Trx alleviated high-glucose-induced Müller cell pyroptosis through ASK-1/Cav-1-mediated endoplasmic reticulum stress and autophagy

TL;DR

This study shows that increasing Trx levels can reduce cell death in retinal cells caused by high glucose, offering a potential new treatment for diabetic retinopathy.

Contribution

The study reveals a novel mechanism where Trx alleviates pyroptosis via ASK-1/Cav-1-mediated ERS and autophagy in Müller cells under high-glucose conditions.

Findings

High glucose increases inflammatory factors and induces pyroptosis in Müller cells.

Trx overexpression reduces ERS and pyroptosis while enhancing autophagy.

Cav-1 inhibition reverses the protective effects of Trx overexpression.

Abstract

Diabetic retinopathy (DR) is a vision-threatening complication of diabetes. A high-glucose state induces endoplasmic reticulum stress (ERS) and autophagy in retinal Müller cells and further triggers pyroptosis, which ultimately promotes the progression of DR. Apoptosis signal-regulating kinase 1 (ASK1) and caveolin-1 (Cav-1) have been found to be closely associated with ERS and autophagy. Thioredoxin (Trx), a small-molecule protein, is essential for regulating cellular function. However, the regulatory mechanisms linking these molecules are not fully understood in DR. In this study, we investigated the role and mechanism of Trx in alleviating high-glucose-induced pyroptosis in Müller cells.

Serum samples from patients with diabetes, diabetic mice, and Müller cells were used in the study.

In vivo and in vitro, high glucose can lead to increased expression of retinal inflammatory factors, morphological damage, and induction of cell pyroptosis. After high-glucose treatment, the expression of ERS- and pyroptosis-related genes increased. This process was reversed after Trx overexpression. Furthermore, autophagy was activated, and the number of TUNEL-positive cells decreased. These effects were reversed by Cav-1 inhibitor treatment.

Trx overexpression could delay high-glucose-induced Müller cell pyroptosis by regulating ERS and autophagy via ASK-1/Cav-1, providing a new therapeutic target for DR treatment.

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