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PPARα activation directly upregulates thrombomodulin in the diabetic retina.
Sci Rep. 2020 Jul 02; 10(1):10837.SR

Abstract

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.

Authors+Show Affiliations

Department of Ophthalmology, St. Marianna University of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, Kanagawa, Japan.Department of Ophthalmology, St. Marianna University of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, Kanagawa, Japan.Department of Ophthalmology, St. Marianna University of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, Kanagawa, Japan.Division of Metabolic Medicine, The University of Tokyo, RCAST, 4-6-1 Komaba, Meguro-ku, Tokyo, Japan.Division of Metabolic Medicine, The University of Tokyo, RCAST, 4-6-1 Komaba, Meguro-ku, Tokyo, Japan.Laboratory of Epigenetics and Metabolism, IMCR, Gunma University, 3-39-15 Showa-cho, Maebashi, Gunma, Japan.Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo, Japan.Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo, Japan.Genome Science Division, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo, Japan.Division of Metabolic Medicine, The University of Tokyo, RCAST, 4-6-1 Komaba, Meguro-ku, Tokyo, Japan. Molecular Physiology and Metabolism Division, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba, Sendai, Miyagi, Japan.Department of Ophthalmology, St. Marianna University of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, Kanagawa, Japan. htakagimarianna@gmail.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32616724

Citation

Shiono, Akira, et al. "PPARα Activation Directly Upregulates Thrombomodulin in the Diabetic Retina." Scientific Reports, vol. 10, no. 1, 2020, p. 10837.
Shiono A, Sasaki H, Sekine R, et al. PPARα activation directly upregulates thrombomodulin in the diabetic retina. Sci Rep. 2020;10(1):10837.
Shiono, A., Sasaki, H., Sekine, R., Abe, Y., Matsumura, Y., Inagaki, T., Tanaka, T., Kodama, T., Aburatani, H., Sakai, J., & Takagi, H. (2020). PPARα activation directly upregulates thrombomodulin in the diabetic retina. Scientific Reports, 10(1), 10837. https://doi.org/10.1038/s41598-020-67579-1
Shiono A, et al. PPARα Activation Directly Upregulates Thrombomodulin in the Diabetic Retina. Sci Rep. 2020 Jul 2;10(1):10837. PubMed PMID: 32616724.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - PPARα activation directly upregulates thrombomodulin in the diabetic retina. AU - Shiono,Akira, AU - Sasaki,Hiroki, AU - Sekine,Reio, AU - Abe,Yohei, AU - Matsumura,Yoshihiro, AU - Inagaki,Takeshi, AU - Tanaka,Toshiya, AU - Kodama,Tatsuhiko, AU - Aburatani,Hiroyuki, AU - Sakai,Juro, AU - Takagi,Hitoshi, Y1 - 2020/07/02/ PY - 2019/10/11/received PY - 2020/06/08/accepted PY - 2020/7/4/entrez PY - 2020/7/4/pubmed PY - 2020/7/4/medline SP - 10837 EP - 10837 JF - Scientific reports JO - Sci Rep VL - 10 IS - 1 N2 - 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. SN - 2045-2322 UR - https://www.unboundmedicine.com/medline/citation/32616724/PPARα_activation_directly_upregulates_thrombomodulin_in_the_diabetic_retina L2 - http://dx.doi.org/10.1038/s41598-020-67579-1 DB - PRIME DP - Unbound Medicine ER -
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