Chan C.-M.Huang D.-Y.Huang Y.-P.Hsu S.-H.Kang L.-Y.Shen C.-M.WAN-WAN LIN2021-03-032021-03-032016158218382-s2.0-84982305329https://scholars.lib.ntu.edu.tw/handle/123456789/550433Diabetic retinopathy (DR) and age-related macular degeneration (AMD) are two important leading causes of acquired blindness in developed countries. As accumulation of advanced glycation end products (AGEs) in retinal pigment epithelial (RPE) cells plays an important role in both DR and AMD, and the methylglyoxal (MGO) within the AGEs exerts irreversible effects on protein structure and function, it is crucial to understand the underlying mechanism of MGO-induced RPE cell death. Using ARPE-19 as the cell model, this study revealed that MGO induces RPE cell death through a caspase-independent manner, which relying on reactive oxygen species (ROS) formation, mitochondrial membrane potential (MMP) loss, intracellular calcium elevation and endoplasmic reticulum (ER) stress response. Suppression of ROS generation can reverse the MGO-induced ROS production, MMP loss, intracellular calcium increase and cell death. Moreover, store-operated calcium channel inhibitors MRS1845 and YM-58483, but not the inositol 1,4,5-trisphosphate (IP3) receptor inhibitor xestospongin C, can block MGO-induced ROS production, MMP loss and sustained intracellular calcium increase in ARPE-19 cells. Lastly, inhibition of ER stress by salubrinal and 4-PBA can reduce the MGO-induced intracellular events and cell death. Therefore, our data indicate that MGO can decrease RPE cell viability, resulting from the ER stress-dependent intracellular ROS production, MMP loss and increased intracellular calcium increase. As MGO is one of the components of drusen in AMD and is the AGEs adduct in DR, this study could provide a valuable insight into the molecular pathogenesis and therapeutic intervention of AMD and DR. ? 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.ER stress; intracellular calcium; methylglyoxal; mitochondria; reactive oxygen species; retinal pigment epithelium[SDGs]SDG3activating transcription factor 4; activating transcription factor 6; glucose regulated protein 78; growth arrest and DNA damage inducible protein 153; methylglyoxal; reactive oxygen metabolite; age related macular degeneration; Article; calcium cell level; cell death; cell viability assay; controlled study; diabetic retinopathy; endoplasmic reticulum stress; flow cytometry; human; human cell; mitochondrial membrane potential; MTT assay; pigment epithelium; polyacrylamide gel electrophoresis; priority journal; protein phosphorylation; protein structure; signal transductionjournal article10.1111/jcmm.1289327307396