Protective Effect of Perindopril on Diabetic Retinopathy Is Associated With Decreased Vascular Endothelial Growth Factor–to–Pigment Epithelium–Derived Factor Ratio

Protective Effect of Perindopril on Diabetic Retinopathy Is Associated With Decreased Vascular Endothelial Growth Factor–to–Pigment Epithelium–Derived Factor Ratio Involvement of a Mitochondria–Reactive Oxygen Species Pathway Zhi Zheng 1 , Haibing Chen 2 , Genjie Ke 3 , Ying Fan 1 , Haidong Zou 1 , Xiaodong Sun 1 , Qing Gu 1 , Xun Xu 1 and Patrick C.P. Ho 4 1 Department of Ophthalmology, First People's Hospital of Shanghai, Shanghai Jiaotong University, Shanghai, China; 2 Department of Endocrinology and Metabolism, the Sixth People's Hospital of Shanghai Affiliated to Shanghai Jiaotong University, Shanghai, China; 3 Department of Ophthalmology, Anhui Provincial Hospital, Hefei, China; 4 Hong Kong Eye Associates, Hong Kong, China. Corresponding author: Xun Xu, xuxun60{at}yahoo.com.cn . Z.Z. and H.C. contributed equally to this work. Abstract OBJECTIVE This study aimed to verify whether the decreased vascular endothelial growth factor (VEGF)–to–pigment epithelium–derived factor (PEDF) ratio can serve as an indicator for the protective effect of angiotensin-converting enzyme inhibitors (ACEIs) on diabetic retinopathy (DR) and to investigate the role of mitochondrial reactive oxygen species (ROS) in the downregulated VEGF-to-PEDF ratio. RESEARCH DESIGN AND METHODS Diabetic rats and control animals were randomly assigned to receive perindopril or vehicle for 24 weeks, and bovine retinal capillary endothelial cells (BRECs) were incubated with normal or high glucose with or without perindopril. VEGF, PEDF, PPARγ, and uncoupling protein-2 (UCP-2) in the rat retinas or BREC extracts were examined by Western blotting and real-time RT-PCR. The levels of VEGF and PEDF in cell culture media were examined by ELISA. Mitochondrial membrane potential (Δψm) and ROS production were assayed using JC-1 or CM-H2DCFDA. RESULTS The VEGF-to-PEDF ratio was increased in the retina of diabetic rats; perindopril lowered the increased VEGF-to-PEDF ratio in diabetic rats and ameliorated the retinal damage. In BRECs, perindopril lowered the hyperglycemia-induced elevation of VEGF-to-PEDF ratio by reducing mitochondrial ROS. We found the decreased ROS production was a result of perindopril-induced upregulation of PPARγ and UCP-2 expression and the subsequent decrease of Δψm. CONCLUSIONS It is concluded that the protective effect of ACEI on DR is associated with a decreased VEGF-to-PEDF ratio, which involves the mitochondria-ROS pathway through PPARγ-mediated changes of UCP-2. This study p