THE PATHOGENIC ROLE OF DOWN-REGULATION OF PPAR-ΑLPHA EXPRESSION IN DIABETIC RETINOPATHY

Abstract

Purpose: Diabetic retinopathy is a common cause of vision loss which results from progressive pathological changes including retinal inflammation, vascular leakage, neovascularization (NV) and fibrosis. Recent clinical studies have shown that PPAR-α agonist has therapeutic effect on diabetic retinopathy. The purpose of this study is to investigate the role of PPAR-α in diabetic retinopathy.

Methods: Adult Brown Norway rats, PPAR-α knock-out (KO) mice and C57/BL6 mice were injected with Streptozotocin (STZ) to induce diabetes. PPAR-α, PPAR-β and PPAR-γ expression levels in the retina were compared between STZ-induced diabetic rats, Akita mice and db/db mice and their respective non-diabetic controls using Western blot analyses and real-time RT-PCR. PPARs protein and mRNA levels were measured in hTERT RPE cells and rat Müller cells treated with high glucose medium. Vascular permeability, leukostasis and trypsin digestion were performed in PPAR-α KO mice and C57/BL6 mice 3 months after the STZ injection. Adenovirus expressing PPAR-α was injected intravitreally into diabetic rats, with adenovirus expressing GFP as control.

Results: Both of mRNA and protein levels of PPAR-α were significantly decreased in the retinas of STZ-induced diabetic rats, Akita mice and db/db mice compared with non-diabetic controls, and in the hTERT RPE cells and rat Müller cells treated with high glucose. Retinal vascular permeability, adherent leukocytes, endothelial cell/pericyte ratio were significantly higher in STZ-induced PPAR-α KO mice compared with diabetic C57/BL6 mice. Over-expression of PPAR-α significantly reduced vascular permeability and attenuated over-expression of pro-inflammatory factors in the retinas of STZ-induced diabetic rats.

Conclusions: PPAR-α defect plays an important role in diabetic retinopathy. PPAR-α is a novel therapeutic target for diabetic retinopathy.

Keywords: 499 diabetic retinopathy • 688 retina • 557 inflammation