Drug Design, Development and Therapy (Nov 2023)
Fenofibrate Ameliorates Retinal Pigment Epithelium Injury Induced by Excessive Fat Through Upregulation of PI3K/AKT Signaling
Abstract
Xue Wang,1– 3 Xiaomei Liu,2 Radouil Tzekov,4 Chaofeng Yu,1 Jiasong Yang,1,5 Yuliang Feng,1 Yajun Wu,1 Yali Xu,1 Shiying Li,6 Wensheng Li1,5,7 1Aier School of Ophthalmology, Central South University, Changsha, People’s Republic of China; 2Suzhou Institute of Biomedical Engineering and Technology, University of Science and Technology of China, Suzhou, People’s Republic of China; 3Department of Ophthalmology, Second Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China; 4Department of Ophthalmology, University of South Florida, Tampa, FL, USA; 5Shanghai Aier Eye Hospital, Shanghai, People’s Republic of China; 6Department of Ophthalmology, Xiang’an Hospital of Xiamen University, Xiamen University, Xiamen, People’s Republic of China; 7Shanghai Aier Eye Insititute, Shanghai, People’s Republic of ChinaCorrespondence: Wensheng Li, Shanghai Aier Eye Hospital, 83 Wuzhong Road, Shanghai, People’s Republic of China, Email [email protected] Shiying Li, Department of Ophthalmology, Xiang’an Hospital of Xiamen University, Xiamen University, Xiamen, People’s Republic of China, Email [email protected]: This study aimed to determine the effect and its mechanism of fenofibrate on retinal pigment epithelium (RPE) injury induced by excessive fat in vitro and in vivo.Methods: ARPE-19 cells were co-incubated with palmitic acid (PA) and fenofibric acid (the active form of fenofibrate after metabolism in vivo) and mice fed with high-fat diet (HFD) were supplemented with fenofibrate. The following methods were used: Western blot and immunofluorescent staining to determine expressions of reactive oxygen species (ROS)–associated factors and proinflammatory cytokines; electroretinogram (ERG) c-wave to evaluate RPE function; TUNEL staining to detect the apoptotic cell in RPE tissue. Additionally, ARPE19 cells were treated with PI3K/AKT inhibitor or agonist to investigate the mechanism of fenofibric acid inhibiting PA-induced RPE damage.Results: We found that the application of PA inhibited RPE cell viability in a dose-dependent manner, and increased the levels of NAPDH oxidase 4 (NOX4), 3-nitrotyrosin (3-NT), intracellular adhesion molecule-1(ICAM1), tumor necrosis factor alpha (TNFα) and vascular endothelial growth factor (VEGF) at 400μM. The application of fenofibric acid resulted in the inhibition of NOX4, 3-NT, TNFα, ICAM1 and VEGF expression in ARPE-19 cells treated with PA. Moreover, wortmannin, as a selective inhibitor of PI3K/AKT pathway, abolished the effects of fenofibrate on the oxidative stress and inflammation in ARPE-19 cells. In addition, 740Y-P, a selective agonist of PI3K/AKT pathway, enhanced the protective action of fenofibrate. Meanwhile, in vivo dosing of fenofibrate ameliorated the downregulated amplitudes of ERG c-wave in HFD-fed mice and suppressed the HFD-induced oxidative injury and inflammatory response in RPE tissues.Conclusion: Our results suggested that fenofibrate ameliorated RPE cell damage induced by excessive fat in vitro and in vivo, in part, through activation of the PI3K/AKT signaling pathway.Keywords: fenofibrate, RPE, palmitic acid, high-fat diet, oxidative stress, inflammation
