Superoxide dismutase 1 limits renal microvascular remodeling and attenuates arteriole and blood pressure responses to angiotensin II via modulation of nitric oxide bioavailability.
Superoxide dismutase 1 limits renal microvascular remodeling and attenuates arteriole and blood pressure responses to angiotensin II via modulation of nitric oxide bioavailability.
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DOI：
10.1161/hypertensionaha.110.159301
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发表时间：
2010-11
期刊：
影响因子：
--
通讯作者：
Persson AE
中科院分区：
文献类型：
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作者：
Carlström M;Lai EY;Ma Z;Steege A;Patzak A;Eriksson UJ;Lundberg JO;Wilcox CS;Persson AE
氧化应激与血管重塑和肾小球前阻力增加有关，这两者都涉及肾脏和心血管疾病的发病机制。血管紧张素II诱导超氧化物的产生，超氧化物被超氧化物歧化酶（SOD）代谢或被一氧化氮清除。我们使用SOD 1转基因（SOD 1-tg）和SOD 1敲除（SOD 1-ko）小鼠研究了SOD 1调节肾微血管重塑、血压和小动脉反应性以及对血管紧张素II的敏感性的假设。血压，遥测，上升更突然在长期血管紧张素II输注SOD 1-ko小鼠。SOD 1-tg小鼠的传入小动脉中膜-管腔比降低，SOD 1-ko小鼠的传入小动脉中膜-管腔比升高。来自未处理野生型的传入小动脉对血管紧张素II有分级收缩（敏感性：10-9 mol/l，反应性：40%）。血管紧张素II收缩在SOD 1-tg中较不敏感（10-8 mol/l）和反应性（14%），但在SOD 1-ko小鼠中更敏感（10-13 mol/l）和反应性（89%）。在10-9 mol/l的血管紧张素II下，来自SOD 1-ko的小动脉的超氧化物形成增加了4倍。L-NAME可降低SOD 1-tg的小动脉直径，增强野生型和SOD 1-tg对血管紧张素II的敏感性和反应性。Tempol增加了小动脉直径，使SOD 1-ko对血管紧张素II的敏感性和反应性增强正常化，但对野生型或SOD 1-tg小鼠没有影响。无论是SOD 1-缺陷，也没有过度表达与硝酸盐/亚硝酸盐排泄的变化，或肾NOS-，NADPH氧化酶-，SOD 2/SOD 3-亚型和血管紧张素II受体的mRNA表达。总之，SOD 1通过减少超氧化物和维持一氧化氮的生物利用度来限制传入小动脉重塑并降低对血管紧张素II的敏感性和反应性。这可能会防止对血管紧张素II的早期和过度血压反应。
Oxidative stress is associated with vascular remodeling and increased preglomerular resistance that are both implicated in the pathogenesis of renal and cardiovascular disease. Angiotensin II induces superoxide production which is metabolized by superoxide dismutase (SOD) or scavenged by nitric oxide. We investigated the hypothesis that SOD1 regulates renal microvascular remodeling, blood pressure and arteriolar responsiveness and sensitivity to angiotensin II, using SOD1-transgenic (SOD1-tg) and SOD1-knockout (SOD1-ko) mice. Blood pressure, measured telemetrically, rose more abruptly during prolonged angiotensin II infusion in SOD1-ko mice. The afferent arteriole media-to-lumen ratios were reduced in SOD1-tg and increased in SOD1-ko mice. Afferent arterioles from non-treated wild-types had graded contraction to angiotensin II (sensitivity: 10-9 mol/l, responsiveness: 40%). Angiotensin II contraction were less sensitive (10-8 mol/l) and responsive (14%) in SOD1-tg, but more sensitive (10-13 mol/l) and responsive (89%) in SOD1-ko mice. Arterioles from SOD1-ko had 4-fold increased superoxide formation with angiotensin II at 10-9 mol/l. L-NAME reduced arteriole diameter of SOD1-tg, and enhanced angiotensin II sensitivity and responsiveness of wild-type and SOD1-tg to the level of SOD1-ko mice. Tempol increased arteriole diameter and normalized the enhanced sensitivity and responsiveness to angiotensin II of SOD1-ko, but did not affect wild-type or SOD1-tg mice. Neither SOD1-deficiency nor overexpression was associated with changes in nitrate/nitrite excretion, or renal mRNA expression of NOS-, NADPH oxidase-, SOD2/SOD3-isoforms, and angiotensin II receptors. In conclusion, SOD1 limits afferent arteriole remodeling and reduces sensitivity and responsiveness to angiotensin II by reducing superoxide and maintaining nitric oxide bioavailability. This may prevent an early and exaggerated blood pressure response to angiotensin II.