Pemafibrate prevents retinal pathological neovascularization via systemic metabolic cascades in mice

Abstract

Purpose : Large-scale clinical trials such as FIELD and ACCORD have shown that administration of fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARα) agonist, suppresses the progression of diabetic retinopathy. We reported that a therapeutic effect of a selective PPARα modulator (SPPARMα)pemafibrate against pathological angiogenesis and neurodegeneration of murine models of retinopathy (Tomita Y. et al, 2017 ARVO). In the current study, we examine the suppressive mechanism of pemafibrate in retinal pathological angiogenesis.

Methods : Oxygen-induced retinopathy (OIR) was induced in C57BL/6J mice by exposure to 85% oxygen from postnatal day 8 (P8) for 72 hours. Pemafibrate (P group), fenofibrate (F group) and vehicle (V group) were fed by oral gavage from P12 to P16 daily. Mice in normoxia with vehicle were also prepared (NOX group). The expression level of various genes and β-hydroxybutyric acid (β-HB) concentration was measured in the retina, liver, and blood obtained from the sacrificed animals at P17.

Results : In the liver, the expression levels of downstream PPARα targets such as Acox 1, Fabp 4, and Hmgcs2 were significantly increased (P <0.05) in P group and F group compared with V group. In contrast, there were no significant differences in Acox1, Fabp4 and Hmgcs2 in the retina between OIR groups. Plasma concentration of β-HB was significantly increased in P group compared with F group (P <0.05). Ikkα and Hif-1α were significantly decreased in P group compared with V group (P <0.05) in the retina.

Conclusions : Systemic SPPARMα administration upregulated PPARα target genes in the liver, but not in the retina. Maintenance of plasma ketone body concentration and the decrease of the angiogenic transcriptional factors may be a possible mechanism for prevention of pathological neovascularization.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.