Abstract

Objective. This study is aimed to verify whether the decreased VEGF/PEDF ratio can serve as an indicator for the protective effect of angiotensin-converting enzyme inhibitors (ACEI) on diabetic retinopathy (DR), and to investigate the role of mitochondrial reactive oxygen species (ROS) in the down-regulated VEGF/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 UCP-2 in the rat retinas or BRECs 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/PEDF ratio was increased in the retina of diabetic rats; perindopril lowered the increased VEGF/PEDF ratio in diabetic rats and ameliorated the retinal damages. In BRECs, perindopril lowered the hyperglycemia-induced elevation of VEGF/PEDF ratio by reducing mitochondrial ROS. Besides, we found the decreased ROS production was a result of perindopril-induced up-regulation 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/PEDF ratio, which involves the mitochondria-ROS pathway through PPARγ-mediated changes of UCP-2. This study paves a way for future application of ACEI in treatment of DR.