PPARα activation directly upregulates thrombomodulin in the diabetic retina

Akira Shiono, Hiroki Sasaki, Reio Sekine, Yohei Abe, Yoshihiro Matsumura, Takeshi Inagaki, Toshiya Tanaka, Tatsuhiko Kodama, Hiroyuki Aburatani, Juro Sakai, Hitoshi Takagi

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)


Two large clinical studies showed that fenofibrate, a commonly used peroxisome proliferator-activated receptor α (PPARα) agonist, has protective effects against diabetic retinopathy. However, the underlying mechanism has not been clarified. We performed genome-wide analyses of gene expression and PPARα binding sites in vascular endothelial cells treated with the selective PPARα modulator pemafibrate and identified 221 target genes of PPARα including THBD, which encodes thrombomodulin (TM). ChIP-qPCR and luciferase reporter analyses showed that PPARα 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 PPARα activation inhibits inflammatory and vasopermeable responses in the diabetic retina through the upregulation of TM.

Original languageEnglish
Article number10837
JournalScientific reports
Issue number1
Publication statusPublished - 2020 Dec 1
Externally publishedYes

ASJC Scopus subject areas

  • General

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