PRMT-1 and DDAHs-induced ADMA upregulation is involved in ROS- and RAS-mediated diabetic retinopathy
PRMT-1 and DDAHs-induced ADMA upregulation is involved in ROS- and RAS-mediated diabetic retinopathy
复制标题
PRMT-1 和 DDAH 诱导的 ADMA 上调参与 ROS 和 RAS 介导的糖尿病视网膜病变
DOI：
10.1016/j.exer.2009.09.004
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发表时间：
2009-12-01
影响因子：
3.4
通讯作者：
Zheng, Zhi
中科院分区：
文献类型：
--
作者：
Chen, Yihui;Xu, Xun;Zheng, Zhi
不对称二甲基精氨酸（ADMA）是一种内源性竞争性一氧化氮合酶抑制剂，在1型蛋白精氨酸N-甲基转移酶（PRMT-1）存在下产生，并由二甲基精氨酸二甲氨基水解酶（DDAH）代谢。据报道，ADMA与内皮功能障碍有关。本研究的目的是研究PRMT-1和DDAH诱导的糖尿病大鼠视网膜和高糖处理的牛视网膜毛细血管内皮细胞（BRCEC）中ADMA增加是否参与活性氧（ROS）和肾素-血管紧张素系统（RAS）介导的糖尿病视网膜病变。将大鼠分为4组：假注射组、链脲佐菌素（SU）糖尿病模型组、STZ糖尿病模型+ACEI苯那普利治疗12周组、STZ糖尿病模型+ARB替米沙坦治疗12周组。将BRCEC暴露于5 mM葡萄糖、30 mM葡萄糖和30 mM葡萄糖加苯那普利、替米沙坦、二苯基碘鎓（NADPH氧化酶抑制剂，DPI）或N-乙酰-L-半胱氨酸（抗氧化剂和自由基清除剂，NAC），直至第4代。我们发现糖尿病模型大鼠血浆中ADMA浓度显著升高，苯那普利或替米沙坦可显著降低ADMA浓度。糖尿病大鼠视网膜DDAH表达降低，PRMT-1表达升高，苯那普利可逆转DDAH表达的改变。替米沙坦降低PRMT-1表达，增加DDAH II表达，但对DDAH I表达无影响。在体外，暴露于高糖的BRCEC具有升高的ROS产生，降低cGMP，增加PRMT-1表达，降低DDAH活性和DDAH II表达。BRCEC与苯那普利、替米沙坦、DPI或NAC共孵育可逆转高糖的作用。可以得出结论，PRMT-I和DDAH诱导的ADMA水平上调可能参与ROS和RAS介导的糖尿病视网膜病变。(C)2009爱思唯尔有限公司保留所有权利。
Asymmetric dimethylarginine (ADMA), an endogenous competitive inhibitor of nitric oxide synthase, is generated in presence of type 1 protein arginine N-methyltransferase (PRMT-1) and is metabolized by dimethylarginine dimethylaminohydrolases (DDAHs). Reportedly ADMA is associated with endothelial dysfunction. The aim of this study is to investigate whether PRMT-1- and DDAHs-induced ADMA increase in diabetic rat retina and high glucose-treated bovine retinal capillary endothelial cells (BRCECs) is involved in reactive oxygen species (ROS)- and renin-angiotensin system (RAS)-mediated diabetic retinopathy. Rats were divided into four groups: sham-injected group, streptozotocin (SU)-induced diabetic model group, STZ-induced diabetic model plus 12-week ACEI benazepril treatment group, and STZ-induced diabetic model plus 12-week ARB telmisartan treatment group. BRCECs were exposed to 5 mM glucose, 30 mM glucose, and 30 mM glucose plus benazepril, telmisartan, diphenyliodonium (NADPH oxidase inhibitor, DPI), or N-Acetyl-L-cysteine (antioxidant and free radical scavenger, NAC) until passage four. We found that the concentrations of ADMA were significantly elevated in the plasma of diabetic rat models, and were significantly reduced by benazepril or telmisartan. DDAHs expression was decreased and PRMT-1 expression was increased in diabetic rat retina, which was reversed by benazepril. Telmisartan decreased PRMT-1 expression and increased DDAH II expression, but had no effect on DDAH I expression. In vitro, BRCECs exposed to high glucose had elevated ROS production, decreased cGMP, increased PRMT-1 expression, and decreased DDAH activity and DDAH II expression. Coincubating BRCECs with benazepril, telmisartan, DPI or NAC reversed the effects of high glucose. It can be concluded that PRMT-I and DDAHs-induced upregulation of ADMA levels might be involved in ROS- and RAS-mediated diabetic retinopathy. (C) 2009 Elsevier Ltd. All rights reserved.