Caffeine Prevents Blood Retinal Barrier Damage in a Model, In Vitro, of Diabetic Macular Edema

Abstract

Diabetic macular edema (DME) is the major cause of vision loss in patients affected by diabetic retinopathy. Hyperglycemia and hypoxia represent the key elements in the progression of these pathologies, leading to breakdown of the blood-retinal barrier (BRB). Caffeine, a psychoactive substance largely consumed in the world, is a nonselective antagonist of adenosine receptors (AR) and it possesses a protective effect in various diseases, including eye pathologies. Here, we have investigated the effect of this substance on BRB integrity following exposure to hyperglycemic/hypoxic insult. Retinal pigmented epithelial cells, ARPE-19, have been grown on semi-permeable supports mimicking an experimental model, in vitro, of outer BRB. Caffeine treatment has reduced cell monolayer permeability after exposure to high glucose and desferoxamine as shown by TEER and FITC-dextran permeability assays. This effect is also mediated through the restoration of membrane's tight junction expression, ZO-1. Moreover, we have demonstrated that caffeine is able to prevent outer BRB damage by inhibiting apoptotic cell death induced by hyperglycemic/hypoxic insult since it downregulates the proapoptotic Bax and upregulates the anti-apoptotic Bcl-2 genes. Although further studies are needed to better comprise the beneficial effect of caffeine, we can speculate that it might be used as an innovative drug for DME treatment. J. Cell. Biochem. 118: 2371-2379, 2017. © 2017 Wiley Periodicals, Inc.

Compromised Barrier Function in Human Induced Pluripotent Stem-Cell-Derived Retinal Pigment Epithelial Cells from Type 2 Diabetic Patients

“…When RPE specific gene expression or PEDF secretion was assessed, both type 2 diabetic and healthy control hiPSC-RPEs matured well at all glucose concentrations in the presence or absence of added insulin. In previous studies in which human immortalized RPE cells have been cultured in different glucose concentrations, the glucose stimuli extended from three to 18 days [10,28,29,30,31]. Here the hiPSC-RPEs were cultivated in different glucose concentrations for up to five weeks, during which, the cells might have been adapted to different glucose concentrations.…”

Angiopoietin-Like Protein 4 (ANGPTL4) Induces Retinal Pigment Epithelial Barrier Breakdown by Activating Signal Transducer and Activator of Transcription 3 (STAT3): Evidence from ARPE-19 Cells Under Hypoxic Condition and Diabetic Rats

“…Diabetic macular edema is due to damage of the BRB; hypoxia and hyperglycemia make up the major features of BRB pathology [26]. ARPE-19 cells are well established in terms of usage as in vitro outer BRB experimental models [27]. It is known that the pathogenesis of diabetic retinopathy is complicated, involving various mechanisms [28,29].…”

Technical Feasibility and Physiological Relevance of Hypoxic Cell Culture Models

“…Moreover, these studies generally do not include information about the height of the medium overlay above the adherent cell culture, which introduces yet another unknown variable that possibly affects the results and reproducibility (17,18). Furthermore, certain studies employed only chemical insults to mimic hypoxia (134,(140)(141)(142). Logically, some studies then report that cell cultures have no merit in this area of hypoxia research (139), while others state that the results gained from these models are in line with studies in vivo (136,143).…”