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.
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.


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, PPARgamma, 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 (Deltapsim) 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 PPARgamma and UCP-2 expression and the subsequent decrease of Deltapsim.


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 PPARgamma-mediated changes of UCP-2. This study paves a way for future application of ACEI in treatment of DR.
Zheng
Zhi
Z
Department of Ophthalmology, First People's Hospital of Shanghai, Shanghai Jiaotong University, Shanghai, China.
Chen
Haibing
H
Ke
Genjie
G
Fan
Ying
Y
Zou
Haidong
H
Sun
Xiaodong
X
Gu
Qing
Q
Xu
Xun
X
Ho
Patrick C P
PC
D000818:Animals; D002417:Cattle; D008297:Male; D051381:Rats; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology; D003930:Diabetic Retinopathy / Q000517:prevention & control; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D005136:Eye Proteins / Q000235:genetics / Q000502:physiology; D005947:Glucose / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000502:physiology; D051336:Mitochondrial Membranes / Q000502:physiology; D009414:Nerve Growth Factors / Q000235:genetics / Q000502:physiology; D020913:Perindopril / Q000494:pharmacology / Q000627:therapeutic use; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D012171:Retinal Vessels / Q000166:cytology / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015843:Serpins / Q000235:genetics / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000502:physiology
D000806:Angiotensin-Converting Enzyme Inhibitors; D005136:Eye Proteins; D005947:Glucose; D009414:Nerve Growth Factors; D020913:Perindopril; D017382:Reactive Oxygen Species; D015843:Serpins; D042461:Vascular Endothelial Growth Factor A