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

Abstract

Aims/hypothesis 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. Methods 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-1β, 10 ng/ml, added at days 16 and 17). Fenofibric acid, 25 μmol/l and 100 μmol/l, was added on the last 3 days of the experiment (one application/day). RPE cell permeability was evaluated by measuring apicalbasolateral 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. Results 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 Dglucose, 25 mmol/l, and IL-1β, 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-1β and the hyperpermeability induced by IL-1β was blocked by silencing AMPK. Conclusions/interpretation Disruption of RPE induced by IL-1β 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.

RPE barrier breakdown in diabetic retinopathy: seeing is believing

“…In ARPE-19 cells grown in high-glucose media, fenofibrate upregulated the expression of fibronectin and collagen IV, basement membrane components known to cause endothelial barrier breakdown [68]. Fenofibrate also reduced the IL-1β-induced RPE barrier permeability in ARPE-19 cultures grown in high-glucose media by suppressing adenosine monophosphate-activated protein kinase [68,69]. Interestingly, fenofibrate may have a general beneficial effect on reducing high glucose-or hypoxiainduced oxidative and ER stresses in the RPE by reducing stress-mediated signaling and by inducing autophagy and survival pathways [70].…”

Systemic medical management of diabetic retinopathy

“…[49] Reduced concentrations of TNF-α, Interleukin-6, and interleukin-1β have been seen with fenofibrates. [405051]Antioxidant property: Fenofibrates were shown to reduce the concentrations of melondialdehyde- a lipidperoxide formed due to reactive oxygen species. [52]…”

Primary prevention of diabetic retinopathy with fibrates: a retrospective, matched cohort study

“…Glucolipotoxicity-induced NF-kB activation can also increase the expression of the proinflammatory cytokine TNF-α, resulting in the upregulation of adhesion molecules, leucocyte and monocyte activation and vessel loss 28 29. Fenofibric acid is also known to prevent the disruption of retinal pigment epithelium (RPE) cells by the stress-induced cytokine IL-1β, achieved through the suppression of AMP-activated protein kinase activation 30. In addition, further protection by fenofibric acid of the RPE may occur through the induction of autophagy and insulin-like growth factor-1 receptor mediated survival (antiapoptotic) pathways 31.…”