PPARα activation directly upregulates thrombomodulin in the diabetic retina

Two large clinical studies showed that fenofibrate, a commonly used peroxisome proliferator-activated receptor alpha (PPAR alpha) agonist, has protective effects against diabetic retinopathy. However, the underlying mechanism has not been clarified. We performed genome-wide analyses of gene expression and PPAR alpha binding sites in vascular endothelial cells treated with the selective PPAR alpha modulator pemafibrate and identified 221 target genes of PPAR alpha including THBD, which encodes thrombomodulin (TM). ChIP-qPCR and luciferase reporter analyses showed that PPAR alpha directly regulated THBD expression via binding to the promoter. In the rat diabetic retina, treatment with pemafibrate inhibited the expression of inflammatory molecules such as VCAM-1 and MCP1, and these effects were attenuated by intravitreal injection of small interfering RNA targeted to THBD. Furthermore, pemafibrate treatment inhibited diabetes-induced vascular leukostasis and leakage through the upregulation of THBD. Our results indicate that PPAR alpha activation inhibits inflammatory and vasopermeable responses in the diabetic retina through the upregulation of TM.