title: Beneficial effects of fenofibrate in retinal pigment epithelium by the modulation of stress and survival signaling under diabetic conditions.
abstract: In this study, we found an imbalance between stress-mediated and survival signaling and elevated apoptotic markers in retinal pigment epithelium (RPE) from diabetic patients. Since fenofibric acid (FA) treatment reduces the progression of diabetic retinopathy (DR), we investigated the effect of hyperglycemia and hypoxia, two components of the diabetic milieu, on stress, apoptosis, and survival pathways in ARPE-19 cells (immortalized human RPE cell line) and whether FA is able to prevent the deleterious effects induced by these conditions. ARPE-19 cells cultured in high-glucose (HG) medium or under hypoxia (1% oxygen)-induced phosphorylation of the stress-activated kinases JNK and p38 MAPK. This effect was increased by the combination of both conditions. Likewise, hyperglycemia and hypoxia triggered the phosphorylation of the endoplasmic reticulum (ER) stress markers PERK and eIF2α and the induction of the pro-apoptotic transcription factor CHOP. Under these experimental conditions, reactive oxygen species (ROS) were elevated and the integrity of tight junctions was disrupted. Conversely, ARPE-19 cells treated with FA were protected against these deleterious effects induced by hyperglycemia and hypoxia. FA 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 down-regulation of BclxL. Moreover, FA increased LC3-II, an autophagy marker. In conclusion, our results demonstrated that FA elicits a dual protective effect in RPE by down-regulation of stress-mediated signaling and induction of autophagy and survival pathways. These molecular mechanisms could be involved in the beneficial effects of fenofibrate reported in clinical trials.
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols (CSIC/UAM), Madrid, Spain.
authors.forename: Soledad
authors.initials: S
authors.lastname: Miranda
authors.forename: Águeda
authors.initials: Á
authors.lastname: González-Rodríguez
authors.forename: Marta
authors.initials: M
authors.lastname: García-Ramírez
authors.forename: Jesús
authors.initials: J
authors.lastname: Revuelta-Cervantes
authors.forename: Cristina
authors.initials: C
authors.lastname: Hernández
authors.forename: Rafael
authors.initials: R
authors.lastname: Simó
authors.forename: Ángela M
authors.initials: ÁM
authors.lastname: Valverde
mesh_terms: D000368:Aged; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D001813:Blood-Retinal Barrier / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D053148:Caspase 3 / Q000378:metabolism; D015687:Cell Hypoxia; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003930:Diabetic Retinopathy / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D011345:Fenofibrate / Q000494:pharmacology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008875:Middle Aged; D010539:Permeability; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects*; D013312:Stress, Physiological / Q000187:drug effects*; D013997:Time Factors; D051742:Transcription Factor CHOP / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D053148:Caspase 3; D015852:Eukaryotic Initiation Factor-2; D011345:Fenofibrate; D048031:JNK Mitogen-Activated Protein Kinases; D008869:Microtubule-Associated Proteins; D017382:Reactive Oxygen Species; D017526:Receptor, IGF Type 1; D051742:Transcription Factor CHOP; D051020:bcl-X Protein; D019892:eIF-2 Kinase; D048051:p38 Mitogen-Activated Protein Kinases; C494811:BCL2L1 protein, human; C497249:DDIT3 protein, human; C477012:MAP1LC3A protein, human; C505407:CASP3 protein, human