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.
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.
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作者：
Zheng Z;Chen H;Ke G;Fan Y;Zou H;Sun X;Gu Q;Xu X;Ho PC
本研究旨在验证血管内皮生长因子（VEGF）与色素上皮衍生因子（PEDF）比值的降低是否可以作为血管紧张素转换酶抑制剂（ACEIs）对糖尿病视网膜病变（DR）保护作用的指标，并探讨线粒体活性氧（ROS）在VEGF与PEDF比值下调中的作用。将糖尿病大鼠和对照动物随机分配接受培哚普利或溶剂24周，并将牛视网膜毛细血管内皮细胞（BRECs）与正常或高糖（含或不含培哚普利）孵育。Western blotting和real-time RT-PCR检测VEGF、PEDF、PPARγ和解偶联蛋白-2（UCP-2）在大鼠视网膜和BREC中的表达。ELISA法检测细胞培养液中VEGF和PEDF的水平。用JC-1或CM-H2 DCFDA测定线粒体膜电位（Δ Km）和ROS产生。糖尿病大鼠视网膜VEGF/PEDF比值升高，培哚普利可降低糖尿病大鼠视网膜VEGF/PEDF比值，改善视网膜损伤。在BRECs中，培哚普利通过减少线粒体ROS降低高血糖诱导的VEGF与PEDF比值升高。我们发现ROS产生的减少是培哚普利诱导的PPARγ和UCP-2表达上调以及随后Δ Δ μ m降低的结果。结论ACEI对DR的保护作用与VEGF/PEDF比值降低有关，这涉及通过PPARγ介导的UCP-2变化的α-ROS通路。本研究为ACEI在DR治疗中的应用奠定了基础。
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. 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. 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. 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.
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