Effect And Mechanism Of Fenofibrate On Subretinal Fibrosis In Advanced Age Related Macular Degeneration

Purpose:Subretinal fibrosis is a common pathological change that leads to vision loss in neovascular age-related macular degeneration(nAMD).Treatment modalities for subretinal fibrosis are limited.The purpose of the present study was to test the effects of fenofibrate,a specific peroxisome proliferator-activated receptor alpha(PPARa)agonist,on subretinal fibrosis of nAMD,and to delineate its molecular mechanism of action.Methods:The very-low density lipoprotein receptor(VLDLR)knockout mouse model,a nAMD model and a rat Muller cell line rMC-1 were used in this study,Vldlr-/-mice were fed with control or fenofibrate-containing chow.rMC-1 cells insulted with TGFβ2 were treated with vehicle or fenofibric acid(Feno-FA).Subretinal fibrosis was evaluated by Western blot analysis and immunohistochemistry of fibrotic markers,vimentin,collagen I,α-SMA and fibronectin.Collagen deposition was detected by Masson staining.TGF-β/Smad2/3 signaling and Wnt signaling were evaluated by Western blot analysis.Glial fibrillary acidic protein(GFAP)and connective tissue growth factor(CTGF)were measured by RT-PCR,Western blot analysis and immunohistochemistry.Results:Increased collagen deposition and protein expression of fibrotic markers indicated the presence of subretinal fibrosis in the retina of Vldlr-/-mice.Fenofibrate suppressed subretinal fibrosis of Vldlr-/-mice by reducing collagen deposition and protein expression of fibrotic markers.The fibrotic pathways TGF-β/Smad2/3 signaling and Wnt signaling were significantly upregulated,while inhibited by fenofibrate in Vldlr-/-retinas.Meanwhile,fenofibrate significantly reduced the downstream CTGF expression of these two pathways.Müller cells were found to be a major source of CTGF and fenofibrate was capable of suppressing Müller cell activation and thus reducing the release of CTGF in Vldlr-/-retinas.In rMC-1 cells treated with TGF-β2,feno-FA reversed TGF-β2 induced-upregulation of Wnt signaling and CTGF expression.Conclusions:Fenofibrate inhibited retinal fibrosis by suppressing TGF-β/Smad signaling and Wnt signaling and reducing the release of CTGF in neovascular AMD.Fenofibrate may be a potential treatment for AMD with fibrosis.