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

Kaimin Bao¹Xuebin Yu¹Limin Wei¹Yang Yu¹Shiwen Zhong²Zhiyi Ren¹Hongyang Chen¹Li Kong¹Hui Kong²Xiang Ren^1*

• ¹Department of Histology and Embryology, College of Basic Medical Sciences, Dalian Medical University, Dalian, China
• ²The Second Hospital of Dalian Medical University, Dalian, China

Objectives: Diabetic retinopathy (DR) is a vision-threatening diabetic complication. High glucose state leads to endoplasmic reticulum stress (ERS) and autophagy in retinal Müller cells and further induces the onset of pyroptosis, which ultimately promotes the development of DR. It has been found that apoptosis signal-regulating kinase 1 (ASK1) and Caveolin-1 (Cav-1) is closely related to ERS and autophagy. Thioredoxin (Trx), a small molecule protein, is essential for regulating the cellular function. However, the regulatory mechanisms between them were 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. Study design: Diabetes patients serum sample, diabetic mice and Müller cells were used in the study. Results: in vivo and in vitro, high glucose can lead to increased expression of retinal inflammatory factors, morphology damage, and induce cell pyroptosis. After high glucose treatment, the expression of ERS-related and pyroptosis-related proteins was increased. However, this process was reversed after Trx overexpression. Besides, the autophagy was activated. The number of TUNEL-stained positive cells decreased. However, it could be reversed after Cav-1 inhibitor treatment. Conclusions: Trx overexpression could delay high glucose-induced Müller cell pyroptosis by regulating ERS and autophagy via ASK-1/Cav-1, which provided a new therapeutic target for DR treatment.