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PPAR? activation directly upregulates thrombomodulin in the diabetic retina.

ABSTRACT: Two large clinical studies showed that fenofibrate, a commonly used peroxisome proliferator-activated receptor ? (PPAR?) 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? binding sites in vascular endothelial cells treated with the selective PPAR? modulator pemafibrate and identified 221 target genes of PPAR? including THBD, which encodes thrombomodulin (TM). ChIP-qPCR and luciferase reporter analyses showed that PPAR? 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? activation inhibits inflammatory and vasopermeable responses in the diabetic retina through the upregulation of TM.

SUBMITTER: Shiono A

PROVIDER: S-EPMC7331602 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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PPARα activation directly upregulates thrombomodulin in the diabetic retina.

Shiono Akira A Sasaki Hiroki H Sekine Reio R Abe Yohei Y Matsumura Yoshihiro Y Inagaki Takeshi T Tanaka Toshiya T Kodama Tatsuhiko T Aburatani Hiroyuki H Sakai Juro J Takagi Hitoshi H

Scientific reports 20200702 1

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- ...[more]

PMID: 32616724

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Project description:Diabetic retinopathy, a retinal vascular disease, is inhibited in animals treated with aminoguanidine, an inhibitor of inducible nitric-oxide synthase. This treatment also reduces retinal protein nitration, which is greater in diabetic rat retina than nondiabetic retina. As an approach to understanding the molecular mechanisms of diabetic retinopathy, we sought the identity of nitrotyrosine-containing proteins in retina from streptozotocin-induced diabetic rats and in a rat retinal Müller cell line grown in high glucose (25 mM). Anti-nitrotyrosine immunoprecipitation products from rat retina and Müller cells were analyzed by LC-MS/MS. Ten nitrated proteins in diabetic rat retina and three nitrated proteins in Müller cells grown in high glucose were identified; three additional nitrotyrosine-containing proteins were tentatively identified from diabetic retina. The identified nitrotyrosine-containing proteins participate in a variety of processes including glucose metabolism, signal transduction, and transcription/translation. Among the nitrated proteins were insulin-responsive glucose transporter type 4 (GLUT-4), which has been implicated previously in the pathogenesis of diabetes mellitus; exocyst complex component Exo70, which functions in insulin-stimulated glucose uptake of GLUT-4-containing vesicles; and fibroblast growth factor receptor 2, which influences retinal vascularization via fibroblast growth factor signaling. Nitration of tyrosine phosphorylation sites were identified in five proteins, including GLUT-4, exocyst complex component Exo70, protein-tyrosine phosphatase eta, sensory neuron synuclein, and inositol trisphosphate receptor 3. Quantitation of nitration and phosphorylation at common tyrosine modification sites in GLUT-4 and protein-tyrosine phosphatase eta from diabetic and nondiabetic animals suggests that nitration reduced tyrosine phosphorylation approximately 2X in these proteins from diabetic retina. The present results provide new insights regarding tyrosine nitration and its potential role in the molecular mechanisms of diabetic retinopathy.

Dataset Information

PPAR? activation directly upregulates thrombomodulin in the diabetic retina.

Publications

PPARα activation directly upregulates thrombomodulin in the diabetic retina.

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