Renoprotective properties of angiotensin receptor blockers beyond blood pressure lowering
Renoprotective properties of angiotensin receptor blockers beyond blood pressure lowering
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DOI：
10.1681/asn.2005050522
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发表时间：
2005-12-01
影响因子：
13.6
通讯作者：
Miyata, T
中科院分区：
文献类型：
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作者：
Izuhara, Y;Nangaku, M;Miyata, T
临床研究表明，一些抗高血压药物可提供独立于血压降低的肾脏保护作用。最近的体外和体内研究评估了这种保护所涉及的机制。首先，比较了几种血管紧张素 II 1 型受体阻滞剂 (ARB)、钙通道阻滞剂 (CCB) 和 β 阻滞剂 (BB) 对各种介质的体外作用：戊糖苷（一种晚期糖基化终产物）的形成、羟自由基诱导的邻酪氨酸的形成以及过渡金属诱导的抗坏血酸氧化（芬顿反应）。所有六种测试的 ARB 均不抑制戊糖素的形成，但六种 CCB 和九种 BB 均不抑制。 ARB 以及 BB（但不是 CCB）抑制羟自由基介导的邻酪氨酸形成。 ARB 但 BB 和 CCB 均不能有效抑制过渡金属催化的抗坏血酸氧化。其次，评估了这些不同的体外效应对肾脏的体内影响。患有肾病的高血压、2 型糖尿病大鼠 SHR/NDmcr-cp 给予奥美沙坦 (ARB) 或硝苯地平 (CCB) 或阿替洛尔 (BB) 20 周。尽管血压降低程度相似，但只有 ARB 显着降低蛋白尿并预防肾小球和肾小管间质损伤（系膜激活、足细胞损伤、肾小管间质损伤和炎症细胞浸润）。有趣的是，只有 ARB 可以预防间质中的异常铁沉积，纠正慢性缺氧，减少血红素加氧酶和 p47phox（NADPH 氧化酶的一个亚基）的表达，并抑制戊糖苷的形成（与蛋白尿密切相关）。这些观察结果证实了 ARB 独特的肾脏保护特性，与血压降低无关，但与减少氧化应激（羟自由基清除和抑制芬顿反应）、纠正慢性缺氧、抑制晚期糖基化终产物形成和异常铁沉积有关。 ARB 的这些益处可能有助于观察到除降低血压之外的肾脏保护作用。
Clinical studies have demonstrated that some antihypertensive agents provide renoprotection independent of BP lowering. Recent in vitro and in vivo studies evaluated the mechanisms involved in this protection. First, the in vitro effects of several angiotensin II type 1 receptor blockers (ARB), calcium channel blockers (CCB), and beta blockers (BB) on various mediators were compared: Formation of pentosidine (an advanced glycation end product), hydroxyl radical-induced formation of o-tyrosine, and transition metals-induced oxidation of ascorbic acid (the Fenton reaction). All of the six tested ARB but neither the six CCB nor the nine BB inhibited pentosidine formation. ARB, as well as BB but not CCB, inhibited hydroxyl radicals-mediated o-tyrosine formation. ARB but neither BB nor CCB inhibited efficiently transition metals-catalyzed oxidation of ascorbic acid. Second, the in vivo consequences for the kidney of these various in vitro effects were evaluated. Hypertensive, type 2 diabetic rats with nephropathy, SHR/NDmcr-cp, were given for 20 wk either olmesartan (ARB) or nifedipine (CCB), or atenolol (BB). Despite similar BP reduction, only ARB significantly reduced proteinuria and prevented glomerular and tubulointerstitial damage (mesangial activation, podocyte injury, tubulointerstitial injury, and inflammatory cell infiltration). It is interesting that only ARB prevented abnormal iron deposition in the interstitium, corrected chronic hypoxia, reduced expressions of heme oxygenase and p47phox (a subunit of NADPHoxidase), and inhibited pentosidine formation (which correlates well with proteinuria). These observations confirm unique renoprotective properties of ARB, independent of BP lowering but related to decreased oxidative stress (hydroxyl radicals scavenging and inhibition of the Fenton reaction), correction of chronic hypoxia, and inhibition of advanced glycation end product formation and of abnormal iron deposition. These benefits of ARB may contribute to the renoprotection observed beyond BP lowering.