Fenofibrate Exerts Protective Effects in Diabetic Retinopathy via Inhibition of the ANGPTL3 Pathway

PURPOSE. Fenofibrate has been demonstrated to exert a promising therapeutic effect against diabetic retinopathy. Angiopoietin-like 3 (ANGPTL3) has been shown to exert significant pathogenic effects on vascular endothelial cells, which are critically involved in the pathogenesis of diabetic retinopathy. The present study aimed to investigate the link between the therapeutic effects of fenofibrate and the pathogenic effects of ANGPTL3 in diabetic retinopathy. METHODS. Diabetic and control rats were randomly assigned to the following treatments: intravitreal injection with ANGPTL3 small interfering RNA (siRNA), recombinant human (rh) ANGPTL3, fed with normal feeds, or fenofibrate-containing feeds for 8 weeks. Human retinal microvascular endothelial cells (HRMECs) were exposed to normal glucose or high glucose levels with ANGPTL3 siRNA, ANGPTL3 RNA overexpression, blank vector, cilengitide, or fenofibrate treatment. Expression levels of ANGPTL3, IL-1, IL-6, Bax, P53, VEGF, and integrin alpha V beta 3 in the retinas of rats and HRMECs were examined by Western blotting and real-time PCR. The apoptosis rates of HRMECs were examined using a TUNEL apoptosis assay kit. RESULTS. Expression levels of ANGPTL3, IL-1 beta, IL-6, Bax, P53, VEGF, and integrin alpha V beta 3 were found to be upregulated after high-glucose stimulation or ANGPTL3 overexpression in HRMECs or diabetic retinal tissue. However, expression levels of the above markers were downregulated following fenofibrate intervention, blockage of integrin alpha V beta 3 receptor, or ANGPTL3 siRNA interference. CONCLUSIONS. We identified fenofibrate exerts its protective effects by inhibiting ANGPTL3-induced apoptosis and inflammation in diabetic retinopathy, which is a novel mechanism.