| First Author | Hu Y | Year | 2013 |
| Journal | Proc Natl Acad Sci U S A | Volume | 110 |
| Issue | 38 | Pages | 15401-6 |
| PubMed ID | 24003152 | Mgi Jnum | J:201158 |
| Mgi Id | MGI:5511096 | Doi | 10.1073/pnas.1307211110 |
| Citation | Hu Y, et al. (2013) Pathogenic role of diabetes-induced PPAR-alpha down-regulation in microvascular dysfunction. Proc Natl Acad Sci U S A 110(38):15401-6 |
| abstractText | Two independent clinical studies have reported that fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARalpha) agonist, has robust therapeutic effects on microvascular complications of diabetes, including diabetic retinopathy (DR) in type 2 diabetic patients. However, the expression and function of PPARalpha in the retina are unclear. Here, we demonstrated that PPARalpha is expressed in multiple cell types in the retina. In both type 1 and type 2 diabetes models, expression of PPARalpha, but not PPARbeta/delta or PPARgamma, was significantly down-regulated in the retina. Furthermore, high-glucose medium was sufficient to down-regulate PPARalpha expression in cultured retinal cells. To further investigate the role of PPARalpha in DR, diabetes was induced in PPARalpha knockout (KO) mice and wild-type (WT) mice. Diabetic PPARalpha KO mice developed more severe DR, as shown by retinal vascular leakage, leukostasis, pericyte loss, capillary degeneration, and over-expression of inflammatory factors, compared with diabetic WT mice. In addition, overexpression of PPARalpha in the retina of diabetic rats significantly alleviated diabetes-induced retinal vascular leakage and retinal inflammation. Furthermore, PPARalpha overexpression inhibited endothelial cell migration and proliferation. These findings revealed that diabetes-induced down-regulation of PPARalpha plays an important role in DR. Up-regulation or activation of PPARalpha may represent a novel therapeutic strategy for DR. |
