Oxidant stress in kidneys of spontaneously hypertensive rats involves both oxidase overexpression and loss of extracellular superoxide dismutase
Oxidant stress in kidneys of spontaneously hypertensive rats involves both oxidase overexpression and loss of extracellular superoxide dismutase
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DOI：
10.1152/ajprenal.00060.2004
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发表时间：
2004-11-01
影响因子：
4.2
通讯作者：
Huang, H
中科院分区：
文献类型：
--
作者：
Adler, S;Huang, H
氧化应激是导致肾功能障碍和高血压的重要因素。我们先前已经证明，在自发性高血压大鼠(SHR)的肾脏中，由于超氧化物生成增加，一氧化氮(NO)对肾脏耗氧量的调节受到损害。进一步探讨了自发性高血压大鼠肾脏氧化应激增强的机制。缓激肽(BK)或依那普利拉(ENAL)通过刺激内源性NO而抑制皮质耗氧量，在SHR(BK：-14.1+/-1.2%；ENAL：-15.5+/-1.2%)中受到损害，并可通过添加NAD(P)H氧化酶复合体组装抑制剂载脂蛋白(Apoynin)恢复(BK：-21.0+/-0.6%；ENAL：-25.3+/-1.4%)，这表明这是超氧化物生成增强的来源。血管紧张素1型受体阻滞剂氯沙坦的加入也恢复了对对照水平的反应性(BK：-22.0+/-1.1%；ENAL：-23.6+/-1.3%)，这表明Ang II与增强的氧化酶活性有关。血管紧张素转换酶II可在Wistar-京都肾脏中诱导类似的对BK和Enal的反应性缺陷，并可被超氧化物清除剂(Temol)、载脂蛋白或氯沙坦逆转。免疫印迹显示内皮细胞一氧化氮合酶(eNOS 1.9x)和NAD(P)H氧化酶组分(gp91(Phox)1.6x和Rac-1 4.5x)表达增强。自发性高血压大鼠(0.5x)心肌组织中SOD-1和-2的表达无明显变化，而SOD-3的表达显著降低。因此，SHR的生物利用度没有受到损害，这是由于Ang II介导的超氧化物歧化产物的增加与NAD(P)H氧化酶成分的增强有关，尽管eNOS的表达增加了。一种重要的超氧化物清除剂--超氧化物歧化酶-3的缺失也可能导致氧化应激增强。
Oxidant stress is an important contributor to renal dysfunction and hypertension. We have previously demonstrated that regulation of renal oxygen consumption by nitric oxide (NO) is impaired in the kidney of spontaneously hypertensive rats (SHR) due to increased superoxide production. We further explored the mechanisms of enhanced oxidant stress in the kidney of SHR. Suppression of cortical oxygen consumption by bradykinin (BK) or enalaprilat (Enal), which act through stimulation of endogenous NO, was impaired in SHR (BK: -14.1 +/- 1.2%; Enal: -15.5 +/- 1.2%) and was restored by addition of apocynin, an inhibitor of assembly of the NAD(P)H oxidase complex (BK: -21.0 +/- 0.6%; Enal: -25.3 +/- 1.4%), suggesting this as the source of enhanced superoxide production. Addition of an angiotensin type 1 receptor blocker, losartan, also restored responsiveness to control levels (BK: -22.0 +/- 1.1%; Enal: -23.6 +/- 1.3%), suggesting that ANG II is responsible for enhanced oxidase activity. A similar defect in responsiveness to BK and Enal could be induced in Wistar-Kyoto kidneys by ANG II and was reversed by a superoxide scavenger (tempol), apocynin or losartan. Immunoblotting of cortical samples demonstrated enhanced expression of endothelial NO synthase (eNOS 1.9x) and NAD(P)H oxidase components (gp91(phox) 1.6x and Rac-1 4.5x). Expression of SOD-1 and -2 were unchanged, but SOD-3 was significantly decreased in SHR (0.5x). Thus NO bioavailability is impaired in SHR owing to an ANG II-mediated increase in superoxide production in association with enhanced expression of NAD(P)H oxidase components, despite increased expression of eNOS. Loss of SOD-3, an important superoxide scavenger, may also contribute to enhanced oxidant stress.