Angiotensin II type 1 receptor antagonism mediates uncoupling protein 2-driven oxidative stress and ameliorates pancreatic islet β-cell function in young type 2 diabetic mice
Angiotensin II type 1 receptor antagonism mediates uncoupling protein 2-driven oxidative stress and ameliorates pancreatic islet β-cell function in young type 2 diabetic mice
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DOI：
10.1089/ars.2007.1590
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发表时间：
2007-07-01
影响因子：
6.6
通讯作者：
Leung, Po Sing
中科院分区：
文献类型：
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作者：
Chu, Kwan Yi;Leung, Po Sing
我们最近发现了一个局部胰岛肾素血管紧张素系统（RAS），并证明它在肥胖诱导的2型糖尿病（T2DM）动物模型中上调。此外，血管紧张素II型1受体（AT1R）拮抗剂可改善年轻T2DM小鼠的β细胞功能和葡萄糖耐量，并延缓糖尿病的发病。同时，肥胖诱导的T2DM导致氧化应激介导的解偶联蛋白2 （UCP2）的激活，UCP2是胰岛功能的负调节因子。在本研究中，我们假设AT1R拮抗剂的一些保护作用可能是通过干扰这一途径介导的，并在T2DM动物模型中验证了这一假设。Losartan，一种AT1R拮抗剂，给予4周龄肥胖db/db小鼠8周。然后在离体胰岛中分析ucp2驱动的氧化损伤和凋亡。氯沙坦通过下调NADPH氧化酶选择性抑制氧化应激；这反过来抑制UCP2的表达，从而改善β细胞胰岛素分泌，减少db/db小鼠胰岛细胞凋亡诱导的β细胞质量损失。这些数据表明，年轻糖尿病小鼠的胰岛AT1R激活可以通过ucp驱动的氧化损伤产生进行性胰岛β细胞衰竭。
We recently identified a local pancreatic islet renin-angiotensin system (RAS), and demonstrated that it is upregulated in an animal model of obesity-induced type 2 diabetes mellitus (T2DM). Moreover, angiotensin II type 1 receptor (AT1R) antagonism improves beta-cell function and glucose tolerance in young T2DM mice and delays the onset of diabetes. Meanwhile, obesity-induced T2DM results in oxidative stress-mediated activation of uncoupling protein 2 (UCP2), a negative regulator of islet function. In the present study, we postulated that some of the protective effects of AT1R antagonism might be mediated through interference with this pathway and tested this hypothesis in a T2DM animal model. Losartan, an AT1R antagonist, was given to 4-week-old obese db/db mice for a period of 8 weeks. UCP2-driven oxidative damage and apoptosis were then analyzed in isolated islets. Losartan selectively inhibited oxidative stress via downregulation of NADPH oxidase; this in turn suppressed UCP2 expression, thus improving beta-cell insulin secretion and decreasing apoptosis-induced beta-cell mass loss in db/db mouse islets. These data indicate that islet AT1R activation in young diabetic mice can generate progressive islet beta-cell failure through UCP-driven oxidative damage.