Whaley-Connell Adam, Habibi Javad, Johnson Megan, Tilmon Roger, Rehmer Nathan, Rehmer Jenna, Wiedmeyer Charles, Ferrario Carlos M, Sowers James R
The University of Missouri School of Medicine, Department of Internal Medicine, Division of Nephrology and Hypertension CE417, DC043.0, Five, Hospital Dr., Columbia, MO 65212, USA.
Am J Nephrol. 2009;30(4):354-60. doi: 10.1159/000229305. Epub 2009 Jul 17.
BACKGROUND/AIMS: Renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system activation are crucial in the pathogenesis of hypertension, cardiovascular and renal disease. NADPH oxidase-mediated increases in reactive oxygen species (ROS) are an important mediator for RAAS-induced cardiovascular and renal injury. Increased levels of ROS can diminish the bioactivity of nitric oxide (NO), a critical modulator of RAAS effects on the kidney. Thereby, we hypothesized that in vivo nebivolol therapy in a rodent model of activated RAAS would attenuate glomerular damage and proteinuria through its actions to reduce NADPH oxidase activity/ROS and increase bioavailable NO.
We utilized the transgenic Ren2 rat which displays heightened tissue RAAS, hypertension, and proteinuria. Ren2 rats (6-9 weeks of age) and age-matched Sprague-Dawley littermates were treated with nebivolol 10 mg/kg/day (osmotic mini-pump) for 21 days.
Ren2 rats exhibited increases in systolic blood pressure, proteinuria, kidney cortical tissue total NADPH oxidase activity and subunits (Rac1, p67(phox), and p47(phox)), ROS and 3-nitrotyrosine, as well as reductions in podocyte protein markers; each of these parameters improved with nebivolol treatment along with increases in renal endothelial NO synthase expression.
Our data suggest that nebivolol improves proteinuria through reductions in renal RAAS-mediated increases in NADPH oxidase/ROS and increases in bioavailable NO.
背景/目的：肾素-血管紧张素-醛固酮系统（RAAS）和交感神经系统激活在高血压、心血管疾病和肾脏疾病的发病机制中起关键作用。NADPH氧化酶介导的活性氧（ROS）增加是RAAS诱导的心血管和肾脏损伤的重要介质。ROS水平升高会降低一氧化氮（NO）的生物活性，而NO是RAAS对肾脏作用的关键调节因子。因此，我们假设在RAAS激活的啮齿动物模型中，奈必洛尔的体内治疗可通过降低NADPH氧化酶活性/ROS和增加生物可利用的NO来减轻肾小球损伤和蛋白尿。
我们使用了表现出组织RAAS增强、高血压和蛋白尿的转基因Ren2大鼠。将Ren2大鼠（6 - 9周龄）和年龄匹配的Sprague-Dawley同窝幼鼠用奈必洛尔10 mg/kg/天（渗透微型泵）治疗21天。
Ren2大鼠表现出收缩压升高、蛋白尿、肾皮质组织总NADPH氧化酶活性及其亚基（Rac1、p67(phox)和p47(phox)）、ROS和3-硝基酪氨酸增加，以及足细胞蛋白标志物减少；奈必洛尔治疗后这些参数均得到改善，同时肾内皮型NO合酶表达增加。
我们的数据表明，奈必洛尔通过减少肾脏RAAS介导的NADPH氧化酶/ROS增加和生物可利用NO增加来改善蛋白尿。
