Addition of the antioxidant probucol to angiotensin II type I receptor antagonist arrests progressive mesangioproliferative glomerulonephritis in the rat
Addition of the antioxidant probucol to angiotensin II type I receptor antagonist arrests progressive mesangioproliferative glomerulonephritis in the rat
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DOI：
10.1681/asn.2005050519
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发表时间：
2006-03-01
影响因子：
13.6
通讯作者：
Kagami, Shoji
中科院分区：
文献类型：
--
作者：
Kondo, Shuji;Shimizu, Maki;Kagami, Shoji
血管紧张素II（Ang II）以及由NADPH氧化酶产生的活性氧物质（ROS）与肾小球肾炎（GN）的进展有关。本研究在通过给单侧肾切除大鼠注射抗Thy - 1抗体诱导的进行性系膜增生性肾小球肾炎模型中，检验了用血管紧张素II受体阻滞剂（ARB）坎地沙坦和自由基清除剂普罗布考同时阻断Ang II和ROS的效果。将肾炎大鼠分为四组，每天给予以下口服剂量：赋形剂、含1%普罗布考的饲料、饮用水中含70mg/L坎地沙坦以及普罗布考加坎地沙坦。这些治疗持续到第56天。赋形剂治疗的肾炎大鼠出现蛋白尿逐渐升高和肾小球硬化。坎地沙坦使蛋白尿显著低于赋形剂组或普罗布考组。在坎地沙坦中加入普罗布考使尿蛋白排泄恢复正常。除普罗布考外，这些治疗降低了肾炎大鼠的血压升高。有趣的是，坎地沙坦显著减少了肾小球细胞数量和肾小球硬化，加入普罗布考后恢复正常。对转化生长因子 - β1、I型胶原和纤连蛋白的免疫组化研究显示，与坎地沙坦相比，联合治疗消除了肾小球纤维化表现。此外，NADPH氧化酶成分的肾小球表达和超氧化物产生表明，联合治疗完全消除了与NADPH氧化酶相关的ROS产生。总之，我们的研究首次提供证据表明，抗氧化剂普罗布考加入血管紧张素II受体阻滞剂中，可完全阻止肾小球肾炎的蛋白尿和疾病进展。此外，数据表明与NADPH氧化酶相关的ROS产生可能在肾小球肾炎的进展中起关键作用。普罗布考和坎地沙坦的联合可能为进行性肾小球肾炎患者提供一种新的治疗途径。
Angiotensin II (Ang II) and reactive oxidative species (ROS) that are produced by NADPH oxidase have been implicated in the progression of glomerulonephritis (GN). This study examined the effect of simultaneously interrupting Ang 11 and ROS with an Ang II receptor blocker (ARB), candesartan, and a free radical scavenger, probucol, in a model of progressive mesangioproliferative GN induced by the injection of anti-Thy-1 antibody into uninephrectomized rats. Nephritic rats were divided into four groups and given daily oral doses of the following: Vehicle, 1% probucol diet, 70 mg/L candesartan in drinking water, and probucol plus candesartan. These treatments lasted until day 56. Vehicle-treated nephritic rats developed progressively elevated proteinuria and glomerulosclerosis. Candesartan kept proteinuria significantly lower than vehicle or probucol. The addition of probucol to candesartan normalized urinary protein excretion. Increases in BP in nephritic rats were lowered by these treatments, except with probucol. It is interesting that both glomerular cell number and glomerulosclerosis were significantly decreased by candesartan and normalized by the addition of probucol. Immunohistochemical studies for TGF-beta 1, collagen type I, and fibronectin revealed that the combined treatment abolished glomerular fibrotic findings compared with candesartan. In addition, glomerular expression of NADPH oxidase components and superoxide production suggested that the combined treatment completely eliminated NADPH oxidase-associated ROS production. In conclusion, our study provides the first evidence that the antioxidant probucol, when added to an Ang II receptor blockade, fully arrests proteinuria and disease progression in GN. Furthermore, the data suggest that NADPH oxidase-associated ROS production may play a pivotal role in the progression of GN. The combination of probucol and candesartan may represent a novel route of therapy for patients with progressive GN.