Department of Ophthalmology, Shanghai First People's Hospital, Shanghai Jiaotong University, Shanghai 200080, China.
Exp Eye Res. 2009 Dec;89(6):1028-34. doi: 10.1016/j.exer.2009.09.004. Epub 2009 Sep 11.
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 (STZ)-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 5mM glucose, 30mM glucose, and 30mM 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.
不对称二甲基精氨酸（ADMA）是一氧化氮合酶的内源性竞争性抑制剂，在 1 型蛋白精氨酸 N-甲基转移酶（PRMT-1）存在的情况下生成，并被二甲基精氨酸二甲氨基水解酶（DDAHs）代谢。据报道，ADMA 与血管内皮功能障碍有关。本研究旨在探讨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 PRMT-1 和 DDAHs 诱导的 ADMA 增加是否涉及活性氧（ROS）和肾素-血管紧张素系统（RAS）介导的糖尿病视网膜病变。大鼠分为四组：假注射组、链脲佐菌素（STZ）诱导的糖尿病模型组、STZ 诱导的糖尿病模型加 12 周 ACEI 贝那普利治疗组和 STZ 诱导的糖尿病模型加 12 周 ARB 替米沙坦治疗组。BRCEC 暴露于 5mM 葡萄糖、30mM 葡萄糖和 30mM 葡萄糖加贝那普利、替米沙坦、二苯基碘𬭩（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），直到第四代。我们发现，糖尿病大鼠模型血浆中的 ADMA 浓度显著升高，贝那普利或替米沙坦可显著降低其浓度。糖尿病大鼠视网膜中 DDAHs 表达降低，PRMT-1 表达升高，贝那普利可逆转这种情况。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，高糖培养的 BRCEC 产生的 ROS 增加，cGMP 减少，PRMT-1 表达增加，DDAH 活性和 DDAH II 表达减少。同时孵育 BRCEC 与贝那普利、替米沙坦、DPI 或 NAC 可逆转高糖的作用。由此可以得出结论，PRMT-I 和 DDAHs 诱导的 ADMA 水平上调可能参与了 ROS 和 RAS 介导的糖尿病视网膜病变。
