Fan Yu-Yan, Baba Ryoko, Nagai Yukiko, Miyatake Akira, Hosomi Naohisa, Kimura Shoji, Sun Guang-Ping, Kohno Masakazu, Fujita Mamoru, Abe Youichi, Nishiyama Akira
Department of Pharmacology, Kagawa University Medical School, Kagawa, Japan.
Hypertens Res. 2006 Mar;29(3):169-78. doi: 10.1291/hypres.29.169.
Recent studies have suggested that aldosterone plays a role in the pathogenesis of renal injury. In this study, we investigated whether local angiotensin II (Ang II) activity contributes to the progression of renal injury in aldosterone/salt-induced hypertensive rats. Uninephrectomized rats were treated with 1% NaCl in a drinking solution and one of the following combinations for 6 weeks: vehicle (2% ethanol, s.c.; n=9), aldosterone (0.75 mug/h, s.c.; n=8), aldosterone+Ang II type 1 receptor blocker olmesartan (10 mg/kg/day, p.o.; n=8), or aldosterone+olmesartan (100 mg/kg/day, p.o.; n=9). Aldosterone/salt-treated hypertensive rats exhibited severe proteinuria and renal injury characterized by glomerular sclerosis and tubulointerstitial fibrosis. Aldosterone/salt-induced renal injury was associated with augmented expression of angiotensin converting enzyme and Ang II levels in the renal cortex and medullary tissues. Renal cortical and medullary mRNA expression of transforming growth factor-beta (TGF-beta) and connective tissue growth factor (CTGF) as well as the collagen contents were increased in aldosterone/salt-treated hypertensive rats. Treatment with olmesartan (10 or 100 mg/kg/day) had no effect on blood pressure but attenuated proteinuria in a dose-dependent manner. Olmesartan at 10 mg/kg/day tended to decrease renal cortical and medullary Ang II levels, TGF-beta and CTGF expression, and collagen contents; however, these changes were not significant. On the other hand, an ultrahigh dose of olmesartan (100 mg/kg/day) significantly decreased these values and ameliorated renal injury. These data suggest that augmented local Ang II activity contributes, at least partially, to the progression of aldosterone/salt-dependent renal injury.
近期研究表明，醛固酮在肾损伤的发病机制中起作用。在本研究中，我们调查了局部血管紧张素II（Ang II）活性是否促进醛固酮/盐诱导的高血压大鼠肾损伤的进展。将单侧肾切除的大鼠用含1% NaCl的饮水溶液及以下组合之一处理6周：溶剂（2%乙醇，皮下注射；n = 9）、醛固酮（0.75 μg/h，皮下注射；n = 8）、醛固酮 + 1型Ang II受体阻滞剂奥美沙坦（10 mg/kg/天，口服；n = 8）或醛固酮 + 奥美沙坦（100 mg/kg/天，口服；n = 9）。醛固酮/盐处理的高血压大鼠表现出严重蛋白尿和以肾小球硬化及肾小管间质纤维化为特征的肾损伤。醛固酮/盐诱导的肾损伤与肾皮质和髓质组织中血管紧张素转换酶表达增加及Ang II水平升高有关。醛固酮/盐处理的高血压大鼠肾皮质和髓质中转化生长因子-β（TGF-β）和结缔组织生长因子（CTGF）的mRNA表达以及胶原蛋白含量均增加。用奥美沙坦（10或100 mg/kg/天）治疗对血压无影响，但能以剂量依赖方式减轻蛋白尿。10 mg/kg/天的奥美沙坦倾向于降低肾皮质和髓质的Ang II水平、TGF-β和CTGF表达以及胶原蛋白含量；然而，这些变化并不显著。另一方面，超高剂量的奥美沙坦（100 mg/kg/天）显著降低了这些值并改善了肾损伤。这些数据表明，局部Ang II活性增强至少部分促进了醛固酮/盐依赖性肾损伤的进展。
