ORIGINAL PAPER Potential Role of Endoplasmic Reticulum Stress in Pathogenesis of Diabetic Retinopathy Gustavo Sa´nchez-Cha´vez 1 • Ernesto Herna´ndez-Ramı ´rez 1 • Ixchel Osorio-Paz 1 • Claudia Herna´ndez-Espinosa 1 • Rocı ´o Salceda 1 Received: 9 July 2015 / Revised: 9 December 2015 / Accepted: 9 December 2015 Ó Springer Science+Business Media New York 2015 Abstract Diabetes mellitus is a metabolic disease that leads to several complications which include retinopathy. Multiple biochemical abnormalities have been proposed to explain the development of retinopathy, including oxida- tive stress. Although the existence of oxidative stress has been established in the retina from long standing diabetic animals, pathogenesis and progression of retinopathy remain unclear. In order to gain insight into the patho- genesis of diabetic retinopathy, we analyzed the levels of different oxidative stress biomarkers in the retina at early stages during the progress of streptozotocin-induced dia- betes. No significant changes in glutathione content, expression of NADPH-oxidase, levels of lipid peroxida- tion, nor production of free radicals were observed in the retina up to 45 days of diabetes induction. Likewise, a transient decrease in aconitase activity, parallel to an increase in the superoxide dismutase activity was observed at 20 days of hyperglycemia, suggesting a high capacity of retina to maintain its redox homeostasis, at least at early stages of diabetes. Nonetheless, we found an early and time-dependent increase in the levels of oxidized proteins, which was not affected by the administration of the antioxidant quercetin. Also, positive immunoreactivity to the reticulum stress protein CHOP was found in glial Mu¨ller cells of diabetic rat retinas. These findings suggest the occurrence of endoplasmic reticulum stress as a pri- mary event in retina pathogenesis in diabetes. Keywords Diabetes Á Retina Á Endoplasmic reticulum stress Á Carbonylation Á Glutathione Á Superoxide dismutase Á NOX Á Quercetin Introduction Diabetes is a metabolic disorder characterized by high blood glucose concentrations resulting from defective insulin secretion or resistance to insulin action. Diabetes leads to several complications that include retinopathy. Diabetic retinopathy is characterized by vascular abnor- malities, but there is also evidence of neural alterations. Electroretinogram responses and light and color sensi- tivity are reduced in patients at early diabetic retinopathy [1, 2]. Similarly, electrophysiological changes occur in the rat retina at early experimental diabetes induction [3–5]. In spite of these results, pathogenesis of the retinopathy is not clear, but it is known that hyperglycemia is a principal factor [6]. A variety of effects have been associated to diabetes alterations, and there is growing evidence which indicates that oxidative stress participates in the disease [7, 8]. The retina by its high metabolic activity, light exposure and high content of polyunsaturated fatty acids is extre- mely susceptible to oxidative stress [9]. Indeed, increase in reactive oxygen species (ROS) production and mitochon- dria (a major endogenous source of ROS) dysfunction has been demonstrated in the retina of longstanding (2–12 months) diabetic animals [10, 11]. Thus, oxidative stress, which is commonly defined as an excess production of ROS relative to the antioxidant defense [12], could play a pivotal role in diabetic retinopathy and not only bethe result of the disease. Therefore, the aim of the present study was to investi- gate the time course changes of several used biomarkers for & Rocı ´o Salceda rsalceda@ifc.unam.mx 1 Divisio´ n de Neurociencias, Departamento de Neurodesarrollo y Fisiologı ´a, Instituto de Fisiologı ´a Celular, Universidad Nacional Auto´noma de Me´xico, Apdo. Postal 70-253, CP 04510 Mexico, D. F., Mexico 123 Neurochem Res DOI 10.1007/s11064-015-1798-4