Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
Hypertension. 2010 Nov;56(5):907-13. doi: 10.1161/HYPERTENSIONAHA.110.159301. Epub 2010 Sep 27.
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 NO. 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:lumen ratios were reduced in SOD1-tg and increased in SOD1-ko mice. Afferent arterioles from nontreated wild types had graded contraction to angiotensin II (sensitivity: 10(-9) mol/L; responsiveness: 40%). Angiotensin II contractions 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. N(G)-nitro-l-arginine methyl ester reduced arteriole diameter of SOD1-tg and enhanced angiotensin II sensitivity and responsiveness of wild-type and SOD1-tg mice to the level of SOD1-ko mice. SOD mimetic treatment with Tempol increased arteriole diameter and normalized the enhanced sensitivity and responsiveness to angiotensin II of SOD1-ko mice 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 NO synthase, NADPH oxidase, or 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 NO bioavailability. This may prevent an early and exaggerated blood pressure response to angiotensin II.
氧化应激与血管重塑和肾小球前阻力增加有关，这两者都与肾脏和心血管疾病的发病机制有关。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 NO 清除。我们通过 SOD1 转基因 (SOD1-tg) 和 SOD1 敲除 (SOD1-ko) 小鼠来研究 SOD1 调节肾脏微血管重塑、血压和小动脉对血管紧张素 II 的反应性和敏感性的假说。通过遥测测量血压，在 SOD1-ko 小鼠中，长时间输注血管紧张素 II 时血压升高更为突然。SOD1-tg 和 SOD1-ko 小鼠的入球小动脉中膜:腔比降低。未经处理的野生型的入球小动脉对血管紧张素 II 呈分级收缩（敏感性：10(-9)mol/L；反应性：40%）。SOD1-tg 中的血管紧张素 II 收缩的敏感性（10(-8)mol/L）和反应性（14%）降低，但 SOD1-ko 中的敏感性（10(-13)mol/L）和反应性（89%）增加。在 10(-9)mol/L 时，SOD1-ko 的血管对血管紧张素 II 的超氧化物形成增加了 4 倍。N(G)-硝基-l-精氨酸甲酯降低 SOD1-tg 中小动脉的直径，并增强了野生型和 SOD1-tg 小鼠对血管紧张素 II 的敏感性和反应性，使其达到 SOD1-ko 小鼠的水平。使用 Tempol 进行 SOD 模拟治疗可增加小动脉的直径，并使 SOD1-ko 小鼠对血管紧张素 II 的敏感性和反应性增强恢复正常，但对野生型或 SOD1-tg 小鼠没有影响。SOD1 缺乏或过表达均不会引起硝酸盐/亚硝酸盐排泄或肾脏中 NO 合酶、NADPH 氧化酶或 SOD2/SOD3 同工型和血管紧张素 II 受体的 mRNA 表达发生变化。总之，SOD1 通过减少超氧化物并维持 NO 的生物利用度来限制入球小动脉的重塑，并降低对血管紧张素 II 的敏感性和反应性。这可能防止对血管紧张素 II 的早期和过度的血压反应。
