Large-scale clinical studies have shown that fenofibrate, a peroxisome proliferator-activated receptor (PPAR) α agonist, inhibits the progression of diabetic retinopathy. We investigated the therapeutic effects of pemafibrate, a selective PPARα modulator (SPPARMα) that is a more specific PPARα agonist than fenofibrate, on retinal diseases. First, we administered pemafibrate in murine models of oxygen-induced retinopathy (OIR) and found that pemafibrate significantly inhibited pathological angiogenesis in the retina compared to the controls. Further, pemafibrate administration increased expression of fibroblast growth factor (FGF) 21 in the liver and increased blood FGF21 levels. It also suppressed the expression of hypoxia-inducible factor (HIF) -1α in the retina and inhibited the expression of vascular endothelial growth factor (VEGF) A. The inhibitory action of long-acting FGF21 was confirmed against HIF activity in cultured retinal cells. Therefore, it was thought that pemafibrate inhibits angiogenesis in the retina via the HIF/VEGF pathway by increasing systemic concentrations of FGF21. Subsequently, we investigated the protective effects of pemafibrate on retinal nerve function in streptozotocin (STZ) -induced diabetic mice. Upon pemafibrate administration in the STZ-induced diabetic mice, the reduced oscillatory potentials (OPs) of the electroretinogram were restored compared to the control group, while an increase in blood FGF21 levels and a decrease in blood triglyceride levels were observed. Furthermore, in the retina of STZ-induced diabetic mice, pemafibrate administration resulted in increased synaptophysin expression compared to control mice, indicating the involvement of retinal nerve function; similarly, long-acting FGF21 administration in cultured nerve cells increased synaptophysin. On the basis of these results, it can be deduced that pemafibrate increases systemic FGF21 levels, thereby increasing synaptophysin expression in the retina and protecting retinal nerve function. Furthermore, studies from our institution have reported that long-acting FGF21 preparations have neuroprotective effects and exhibit inhibitory actions against pathological retinal angiogenesis and increased permeability. Long-acting FGF21 preparations also reportedly improve obesity and lipid profiles, and clinical trials of FGF21 for non-alcoholic steatohepatitis (NASH) are currently underway. These results provide data to support that pemafibrate could be a therapeutic agent for retinopathy. In this report, we showed that pemafibrate inhibits pathological angiogenesis in the OIR murine model and protects neurological function of the retina in a diabetic mouse model via FGF21. We also demonstrated the efficacy of long-acting FGF21 in the retinal disease model. To date, pemafibrate has also been found to be effective in the retina of other animal models, as well as in different cell types, and it is expected to be applied as a novel therapeutic agent for retinal diseases in the future.
Nippon Ganka Gakkai Zasshi (J Jpn Ophthalmol Soc) 125: 1023-1034,2021.