Beneficial efects of fenofibrate in retinal pigment epithelium by the modulation of stress and survival signaling under diabetic conditions

Abstract

[Objective]: This study investigated the effect of hyperglycemia and hypoxia (two major components of the diabetic milieu) on apoptosis and survival in retinal pigment epithelium (RPE) and whether fenofibric acid is able to prevent the deleterious effects induced by these conditions. [Research Design and Meethods]: ARPE-19 cells were cultured under hyperglycemia and/or hypoxia in the absence or presence of fenofibric acid. Stressmediated and survival signaling was analyzed by western blot and real-time PCR. Immunofluorescence studies of tight junction proteins were also performed. Key molecules that regulate pro-apoptotic and survival signaling were evaluated in neuroretina and RPE from diabetic patients. [Results]: ARPE-19 cells cultured under hyperglycemia or hypoxia induced phosphorylation of stress-activated kinases JNK, p38 MAPK, PERK and eiF2a, generation of reactive oxygen species (ROS) and disruption of tight junctions. This effect was increased by combination of both conditions. Cells pre-treated with fenofibric acid were protected against these effects. Fenofibric acid increased insulin-like growth factor-I receptor (IGF-IR)-mediated survival signaling in cells cultured under hyperglycemia and hypoxia, thereby suppressing caspase-3 activation and downregulation of Bclx. Moreover, fenofibric acid increased LC3-II, an autophagy marker. Finally, an unbalance between stress-mediated and survival signaling and elevated apoptotic markers were found in RPE and neuroretina from diabetic patients. [Conclussion]: Diabetic milieu triggers activation of stress-inducible kinases in ARPE-19 cells and human RPE. Fenofibric acid elicited a dual protective effect by down-regulation of stress-mediated signaling and induction of survival pathways. This molecular mechanism could be involved in the beneficial effects of fenofibrate reported in clinical trials.