Izuhara Yuko, Nangaku Masaomi, Inagi Reiko, Tominaga Naoto, Aizawa Toru, Kurokawa Kiyoshi, van Ypersele de Strihou Charles, Miyata Toshio
Institute of Medical Sciences and Department of Internal Medicine, Tokai University School of Medicine, Kanagawa, Japan.
J Am Soc Nephrol. 2005 Dec;16(12):3631-41. doi: 10.1681/ASN.2005050522. Epub 2005 Oct 19.
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.
临床研究表明，一些抗高血压药物可独立于血压降低发挥肾脏保护作用。近期的体外和体内研究评估了这种保护作用的相关机制。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受体阻滞剂（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、羟基自由基诱导的邻酪氨酸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均能抑制戊糖苷形成，而六种CCB和九种BB均无此作用。ARB以及BB能抑制羟基自由基介导的邻酪氨酸形成，但CCB不能。ARB能有效抑制过渡金属催化的抗坏血酸氧化，而BB和CCB则不能。其次，评估了这些体外作用对肾脏的体内影响。给患有肾病的高血压2型糖尿病大鼠（SHR/NDmcr-cp）连续20周给予奥美沙坦（ARB）或硝苯地平（CCB）或阿替洛尔（BB）。尽管血压降低程度相似，但只有ARB能显著降低蛋白尿，并预防肾小球和肾小管间质损伤（系膜活化、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能防止间质中铁异常沉积，纠正慢性缺氧，降低血红素加氧酶和p47phox（NADPH氧化酶的一个亚基）的表达，并抑制戊糖苷形成（这与蛋白尿密切相关）。这些观察结果证实了ARB独特的肾脏保护特性，其独立于血压降低，但与氧化应激降低（羟基自由基清除和芬顿反应抑制）、慢性缺氧纠正以及晚期糖基化终产物形成和铁异常沉积抑制有关。ARB的这些益处可能有助于在血压降低之外观察到的肾脏保护作用。
