Fenofibric acid prevents retinal pigment epithelium disruption induced by interleukin-1β by suppressing AMP-activated protein kinase (AMPK) activation

The mechanisms involved in the beneficial effects of fenofibrate on the development and progression of diabetic macular oedema (DMO) remain to be elucidated. To shed light on this issue we have explored the effect of fenofibric acid on the barrier function of human retinal pigment epithelium (RPE) cells. ARPE-19 cells (a human RPE line) were cultured for 18 days under standard conditions and under conditions leading to the disruption of the monolayer (d-glucose, 25 mmol/l, with IL-1 beta, 10 ng/ml, added at days 16 and 17). Fenofibric acid, 25 mu mol/l and 100 mu mol/l, was added on the last 3 days of the experiment (one application/day). RPE cell permeability was evaluated by measuring apical-basolateral movements of FITC-dextran (40 kDa). The production of tight junction proteins and AMP-activated protein kinase (AMPK) phosphorylation was assessed by western blot. Immunohistochemical studies of tight junction proteins and small interfering RNA transfection to AMPK were also performed in ARPE-19 monolayers. Treatment of ARPE-19 cells with fenofibric acid significantly reduced the increment of permeability and the breakdown of the ARPE-19 cell monolayer induced by d-glucose, 25 mmol/l, and IL-1 beta, 10 ng/ml, in a dose-dependent manner. This effect was unrelated to changes in the content of tight junction proteins. Fenofibric acid prevented the activation of AMPK induced by IL-1 beta and the hyperpermeability induced by IL-1 beta was blocked by silencing AMPK. Disruption of RPE induced by IL-1 beta is prevented by fenofibric acid through its ability to suppress AMPK activation. This mechanism could be involved in the beneficial effects of fenofibrate on DMO development.