Pathogenic role of diabetes-induced PPAR-α down-regulation in microvascular dysfunction

Two independent clinical studies have reported that fenofibrate, a peroxisome proliferator-activated receptor alpha(PPAR alpha) 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 PPAR alpha in the retina are unclear. Here, we demonstrated that PPAR alpha is expressed in multiple cell types in the retina. In both type 1 and type 2 diabetes models, expression of PPAR alpha, but not PPAR beta/delta or PPAR gamma, was significantly down-regulated in the retina. Furthermore, high-glucose medium was sufficient to down-regulate PPAR alpha expression in cultured retinal cells. To further investigate the role of PPAR alpha in DR, diabetes was induced in PPAR alpha knockout (KO) mice and wild-type (WT) mice. Diabetic PPAR alpha 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 PPAR alpha in the retina of diabetic rats significantly alleviated diabetes-induced retinal vascular leakage and retinal inflammation. Furthermore, PPAR alpha overexpression inhibited endothelial cell migration and proliferation. These findings revealed that diabetes-induced down-regulation of PPAR alpha plays an important role in DR. Up-regulation or activation of PPAR alpha may represent a novel therapeutic strategy for DR.