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Open AccessArticle

Pemafibrate Prevents Retinal Pathological Neovascularization by Increasing FGF21 Level in a Murine Oxygen-Induced Retinopathy Model

1
Department of Ophthalmology, School of Medicine, Keio University, Shinjuku-ku, Tokyo 160-8582, Japan
2
Laboratory of Photobiology, School of Medicine, Keio University, Shinjuku-ku, Tokyo 160-8582, Japan
3
Kowa Company, Ltd., Tokyo 160-8582, Japan
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2019, 20(23), 5878; https://doi.org/10.3390/ijms20235878
Received: 28 September 2019 / Revised: 17 November 2019 / Accepted: 21 November 2019 / Published: 23 November 2019
Large-scale clinical trials, such as the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) studies, have shown that the administration of fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARα) agonist, suppresses the progression of diabetic retinopathy. In this paper, we reveal a therapeutic effect of a selective PPARα modulator (SPPARMα), pemafibrate, against pathological angiogenesis in murine models of retinopathy. Oxygen-induced retinopathy (OIR) was induced in C57BL/6J mice by exposure to 85% oxygen from postnatal day eight (P8) for 72 h. Vehicle, pemafibrate or fenofibrate was administrated by oral gavage from P12 to P16 daily. Administration of pemafibrate, but not fenofibrate, significantly reduced pathological angiogenesis in OIR. After oral pemafibrate administration, expression levels of downstream PPARα targets such as acyl-CoA oxidase 1 (Acox1), fatty acid binding protein 4 (Fabp4), and fibroblast growth factor 21 (Fgf21) were significantly increased in the liver but not in the retina. A significant increase in plasma FGF21 and reduced retinal hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor A (Vegfa) were also observed after this treatment. In an in vitro HIF-luciferase assay, a long-acting FGF21 analogue, but not pemafibrate, suppressed HIF activity. These data indicate that SPPARMα pemafibrate administration may prevent retinal pathological neovascularization by upregulating FGF21 in the liver. View Full-Text
Keywords: diabetes retinopathy; selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα); fibroblast growth factor 21 (FGF21); hypoxia-inducible factor (HIF); vascular endothelial growth factor (VEGF) diabetes retinopathy; selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα); fibroblast growth factor 21 (FGF21); hypoxia-inducible factor (HIF); vascular endothelial growth factor (VEGF)
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MDPI and ACS Style

Tomita, Y.; Ozawa, N.; Miwa, Y.; Ishida, A.; Ohta, M.; Tsubota, K.; Kurihara, T. Pemafibrate Prevents Retinal Pathological Neovascularization by Increasing FGF21 Level in a Murine Oxygen-Induced Retinopathy Model. Int. J. Mol. Sci. 2019, 20, 5878.

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