Department of Internal Medicine, University of Missouri-Columbia School of Medicine, USA.
Am J Nephrol. 2010;31(3):262-72. doi: 10.1159/000278757. Epub 2010 Jan 25.
BACKGROUND/AIMS: The impact of nebivolol therapy on the renal proximal tubular cell (PTC) structure and function was investigated in a transgenic (TG) rodent model of hypertension and the cardiometabolic syndrome. The TG Ren2 rat develops nephropathy with proteinuria, increased renal angiotensin II levels and oxidative stress, and PTC remodeling. Nebivolol, a beta(1)-antagonist, has recently been shown to reduce albuminuria, in part, through reductions in renal oxidative stress. Accordingly, we hypothesized that nebivolol therapy would attenuate PTC damage and tubulointerstitial fibrosis.
Young Ren2 (R2-N) and SD (SD-N) rats were treated with nebivolol (10 mg/kg/day) or vehicle (R2-C; SD-C) for 3 weeks. PTC structure and function were tested using transmission electron microscopy and functional measurements.
Nebivolol treatment decreased urinary N-acetyl-beta-D-glucosaminidase, tubulointerstitial ultrastructural remodeling and fibrosis, NADPH oxidase activity, 3-nitrotyrosine levels, and increased megalin and lysosomal-associated membrane protein-2 immunostaining in PTCs. Ultrastructural abnormalities that were improved with therapy included altered canalicular structure, reduced endosomes/lysosomes and PTC vacuoles, basement membrane thickening, and mitochondrial remodeling/fragmentation.
These observations support the notion that nebivolol may improve PTC reabsorption of albumin and other glomerular filtered small molecular weight proteins in association with the attenuation of oxidative stress, tubulointerstitial injury and fibrosis in this rat model of metabolic kidney disease.
背景/目的：本研究旨在观察比索洛尔对高血压和代谢综合征转基因（TG）啮齿动物模型肾近端管状细胞（PTC）结构和功能的影响。Ren2 转基因大鼠可发生蛋白尿、肾血管紧张素 II 水平和氧化应激升高以及 PTC 重塑的肾病。最近有研究表明，比索洛尔可减少白蛋白尿，部分原因是降低了肾氧化应激。因此，我们假设比索洛尔治疗可减轻 PTC 损伤和小管间质纤维化。
采用 3 周的比索洛尔（10mg/kg/天）或载体（R2-C；SD-C）治疗年轻的 Ren2（R2-N）和 SD（SD-N）大鼠。采用透射电镜和功能测定检测 PTC 结构和功能。
比索洛尔治疗可降低尿 N-乙酰-β-D-氨基葡萄糖苷酶、小管间质超微结构重塑和纤维化、NADPH 氧化酶活性、3-硝基酪氨酸水平，并增加 PTC 中的 megalin 和溶酶体相关膜蛋白-2 免疫染色。经治疗改善的超微结构异常包括管腔结构改变、内体/溶酶体和 PTC 空泡减少、基底膜增厚以及线粒体重塑/片段化。
这些观察结果支持以下观点，即比索洛尔可能通过减轻氧化应激、小管间质损伤和纤维化，改善该代谢性肾病大鼠模型的 PTC 对白蛋白和其他肾小球滤过的小分子蛋白的重吸收。
