Oxidative and endoplasmic reticulum stress in diabetes-related hearing loss: Protective effects of thioredoxin

Abstract

Diabetes mellitus (DM) induces complex physiological changes in the inner ear environment. This study investigates the roles of oxidative stress (OS) and endoplasmic reticulum stress (ERS) in diabetic hearing loss and explores the potential of thioredoxin (Trx) in regulating OS, ERS, and apoptosis-related factors to mitigate the progression of hearing impairment. We conducted auditory and serological assessments in 63 patients with type 2 diabetes and 30 healthy controls. Type 2 diabetes models were induced in wild-type and Trx transgenic (Tg) mice, with auditory brainstem response (ABR) used to evaluate hearing changes. Cochlear tissues were isolated to analyse markers of apoptosis, OS, and ERS. Both patients with diabetes and mouse models exhibited hearing loss, alongside increased serum levels of Trx1, TXNIP, and AOPP, indicating oxidative damage. H&E and succinate dehydrogenase (SDH) staining revealed varying degrees of hair cell loss from the base to the apex of the cochlea in diabetic mice, with decreased expression of the hair cell protein prestin gene. Notably, Tg mice showed significant delay in hearing loss progression. In vitro, advanced glycation end-products (AGEs) induced OS and ERS in cochlear-like HEI-OC1 cells, while Trx overexpression enhanced Nrf2 activity, alleviating AGE-induced cellular stress. In conclusion, Trx exhibits protective effects against diabetes-related hearing loss, potentially by enhancing Nrf2/HO-1/SOD2 function to reduce OS and ERS.