Organophosphate pesticide DEDT promotes diabetic retinopathy progression via AMPK/Nrf2/HO-1 pathway

Abstract Background The impact of environmental toxins, particularly organophosphate pesticides (OPs), on the progression of diabetic retinopathy (DR) remains insufficiently understood. Recent studies have highlighted the potential role of environmental pollutants in exacerbating diabetic complications, but the underlying mechanisms are still unclear. This study aims to explore the effect of diethyldithiophosphate (DEDT), an OP, on DR progression through modulation of the AMPK/Nrf2/HO-1 signaling pathway. Methods Human retinal microvascular endothelial cells (HRMECs) and retinal pigment epithelial cells (ARPE-19) were cultured under high-glucose conditions to simulate diabetic stress. Cells were exposed to various concentrations of DEDT, and their viability, oxidative stress, tight junction integrity, and inflammation were assessed. Western blot, quantitative PCR, and enzyme-linked immunosorbent assay (ELISA) techniques were employed to evaluate the expression of key proteins in the AMPK/Nrf2/HO-1 pathway and inflammatory cytokines. In vivo, diabetic rat models were treated with DEDT to assess retinal damage and oxidative stress. The effects of AMPK activation were also evaluated using AICAR, an AMPK activator, to further explore the mechanistic role of AMPK/Nrf2/HO-1 signaling. Results Our results demonstrated that DEDT exposure significantly reduces retinal cell viability and disrupts tight junction proteins (ZO-1, Occludin, Claudin-5) under high-glucose conditions. Mechanistically, DEDT inhibited the AMPK/Nrf2/HO-1 pathway, leading to increased oxidative stress, enhanced inflammation, and elevated levels of apoptotic markers (Bax and Bcl-2). In vivo, DEDT exposure exacerbated retinal damage and oxidative stress in diabetic rats. Activation of AMPK by AICAR reversed these effects, restoring Nrf2 and HO-1 expression, improving cell viability, and protecting the blood-retinal barrier. These findings indicated that DEDT promotes DR progression by disrupting the AMPK/Nrf2/HO-1 signaling pathway. Conclusion This study provided experimental evidence that DEDT accelerates diabetic retinopathy progression via inhibition of the AMPK/Nrf2/HO-1 pathway, contributing to increased oxidative stress and retinal barrier dysfunction. Our results emphasized the potential health risks associated with pesticide exposure, particularly in diabetic populations, and highlight the importance of regulating environmental toxins to prevent exacerbation of diabetic complications.