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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, PPAR7, 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 perindoprilinduced 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 paves a way for future application of ACEI in treatment of DR. Diabetes 58:954-964, 2009
Diabetic retinopathy (DR) is a major cause of blindness in the working-age population in developed countries (1), and to search for effective treatment and prevention measures has long been a focus of study. The EUCLID Study Group reported that the antihypertensive drug lisinopril, an angiotensin-converting enzyme inhibitor (ACEI), reduced the risk of retinopathy progression by ~50% in patients with type 1 diabetes, thus greatly reducing the possibility of proliferative diabetic retinopathy (PDR) (2). Recently, another ACEI, Perindopril, has been found capable of improving the visual functions, retinal electrogenesis, and disturbed blood-retinal barrier in patients with preproliferative diabetic retinopathy (DR) (3). Studies also indicated that the protective effect of ACEI on DR-related damage was associated with a decreased expression of vascular endothelial growth factor (VEGF) in...