Comparison of acute and chronic antioxidant interventions in experimental renovascular disease
Comparison of acute and chronic antioxidant interventions in experimental renovascular disease
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DOI：
10.1152/ajprenal.00385.2003
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发表时间：
2004-06-01
影响因子：
4.2
通讯作者：
Lerman, LO
中科院分区：
文献类型：
--
作者：
Chade, AR;Krier, JD;Lerman, LO
活性氧（ROS）可以直接通过导致血管收缩和间接通过诱导肾脏炎症和组织生长来调节肾脏血流动力学和功能。氧化应激参与肾血管疾病（RVD）的发病机制越来越被认可，但长期组织损伤对肾功能不全的相对贡献仍不清楚。我们推测，在RVD氧化应激引起的功能和结构的改变将更有效地调制慢性比急性抗氧化剂干预。在基线和血管活性激发后，使用电子束计算机断层扫描对猪的肾血流动力学和功能进行体内定量（ACh和硝普钠）; RVD 12周后（通过并发高胆固醇血症和肾动脉狭窄模拟，n = 7）; RVD急性输注SOD模拟tempol（RVD + tempol，n = 7）;长期补充抗氧化剂维生素C（1 g）和E（100 IU/kg; RVD +维生素，n = 7）的RVD;或对照（正常，n = 7）。使用免疫印迹和免疫组织化学离体研究肾组织。所有RVD组的基础肾血流量（RBF）和肾小球滤过率均相似地降低。ACh刺激的RBF在RVD中保持不变，在RVD + tempol中增加，但在RVD +维生素中进一步增加（与正常相似）（P < 0.05 vs. RVD）。此外，RVD +维生素还显示超氧阴离子的存在减少，NAD（P）H-氧化酶和硝基酪氨酸表达减少，内皮一氧化氮合酶表达增加，肾纤维化减轻。早期RVD的慢性抗氧化剂干预比急性干预更有效地改善了肾血流动力学反应，这可能是由于一氧化氮生物利用度增加和结构损伤减少。这些表明，慢性组织变化在RVD中氧化应激介导的肾损害中起重要作用。
Reactive oxygen species (ROS) can modulate renal hemodynamics and function both directly, by leading to vasoconstriction, and indirectly, by inducing renal inflammation and tissue growth. The involvement of oxidative stress in the pathogenesis of renovascular disease (RVD) is increasingly recognized, but the relative contribution of long-term tissue injury to renal dysfunction remains unclear. We hypothesized that functional and structural alterations elicited by oxidative stress in RVD would be more effectively modulated by chronic than by acute antioxidant intervention. Renal hemodynamics and function were quantified in vivo in pigs using electron-beam computed tomography at baseline and after vasoactive challenge (ACh and sodium nitroprusside); after 12 wk of RVD ( simulated by concurrent hypercholesterolemia and renal artery stenosis, n = 7); RVD acutely infused with the SOD-mimetic tempol (RVD + tempol, n = 7); RVD chronically supplemented with antioxidant vitamins C (1 g) and E (100 IU/kg; RVD + vitamins, n = 7); or control (normal, n = 7). Renal tissue was studied ex vivo using immunoblotting and immunohistochemistry. Basal renal blood flow (RBF) and glomerular filtration rate were similarly decreased in all RVD groups. ACh-stimulated RBF remained unchanged in RVD, increased in RVD + tempol, but further increased (similarly to normal) in RVD + vitamins (P < 0.05 vs. RVD). Furthermore, RVD + vitamins also showed a decreased presence of superoxide anion, decreased NAD(P)H-oxidase and nitrotyrosine expression, increased endothelial nitric oxide synthase expression, and attenuated renal fibrosis. Chronic antioxidant intervention in early RVD improved renal hemodynamic responses more effectively than acute intervention, likely due to increased nitric oxide bioavailability and decreased structural injury. These suggest that chronic tissue changes play an important role in renal compromise mediated by oxidative stress in RVD.