Nephroprotection by antifibrotic and anti-inflammatory effects of the vasopeptidase inhibitor AVE7688
Nephroprotection by antifibrotic and anti-inflammatory effects of the vasopeptidase inhibitor AVE7688
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DOI：
10.1111/j.1523-1755.2005.00423.x
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发表时间：
2005-08-01
影响因子：
19.6
通讯作者：
Weber, M
中科院分区：
文献类型：
--
作者：
Gross, O;Koepke, ML;Weber, M
背景慢性肾脏疾病大大增加了心血管事件和死亡的风险。已知血管肽酶抑制剂显示出强的抗高血压作用。在本研究中，我们研究了血管肽酶抑制剂AVE 7688在进行性肾纤维化小鼠模型中的肾保护潜力，而不仅仅是其抗高血压作用。COL 4A 3-/-小鼠接受25 mg AVE 7688/kg体重。在第4周（早期）和第7周（晚期）开始治疗。在7.5或9.5周后每组处死8只小鼠，并测量尿素、全身血压和蛋白尿的血清水平。通过常规组织学、电镜、免疫组织化学和Western印迹法研究肾组织。监测肾纤维化死亡的生存期。与未治疗的动物相比，治疗的小鼠的寿命增加了143%（早期治疗）和53%（晚期治疗）（172 +/-19 vs. 109 +/-15 vs. 71 +/-6天，P < 0.01）。未治疗的COL 4A 3-/-小鼠未发生严重的高血压（平均收缩压116 +/-14mmHg vs.野生型小鼠111 +/-9mmHg），两种治疗均轻度降低全身血压（107 +/-13和105 +/-14mmHg，数据不显著）。AVE 7688使蛋白尿从未治疗小鼠的12 +/- 3 g/L降至2 +/- 1 g/L（早期）和4 +/-1 g/ L（晚期治疗，P < 0.05），血清尿素从247 +/- 27降至57 +/- 10和105 +/- 20 mmol/ L（P < 0.05）。AVE 7688治疗可降低纤维化、炎症和促纤维化细胞因子的程度。结果表明血管肽酶抑制剂在该进行性肾纤维化动物模型中具有强的肾保护作用。除了AVE 7688的抗高血压作用外，本研究中证实的其抗纤维化、抗炎和抗蛋白尿作用可作为人类慢性炎症和纤维化疾病的重要治疗选择。
Background. Chronic renal disease substantially increases the risk of cardiovascular events and death. Vasopeptidase inhibitors are known to show a strong antihypertensive effect. In the present study, we investigated the nephroprotective potential of the vasopeptidase inhibitor AVE7688 beyond its antihypertensive effects in a mouse model of progressive renal fibrosis.Methods. COL4A3 -/- mice received 25 mg AVE7688 per kg body weight. Treatment was initiated in week 4 ( early) and week 7 ( late). Eight mice per group were sacrificed after 7.5 or 9.5 weeks, and serum levels of urea, systemic blood pressure, and proteinuria were measured. Renal tissue was investigated by routine histology, electron microscopy, immunohistochemistry, and Western blotting. Lifespan until death from renal fibrosis was monitored.Results. Lifespan of treated mice increased by 143% ( early therapy) and by 53% ( late therapy) compared to untreated animals (172 +/- 19 vs. 109 +/- 15 vs. 71 +/- 6 days, P < 0.01). Untreated COL4A3-/- mice did not develop severe hypertension ( mean systolic blood pressure 116 +/- 14 vs. 111 +/- 9 mm Hg in wildtype mice), and both therapies mildly reduced systemic blood pressure ( 107 +/- 13 and 105 +/- 14 mm Hg, data not significant). AVE7688 decreased proteinuria from 12 +/- 3 g/L in untreated mice to 2 +/- 1 g/L (early) and to 4 +/- 1g/ L ( late therapy, P < 0.05), as well as serum-urea from 247 +/- 27 to 57 +/- 10 and to 105 +/- 20 mmol/ L (P < 0.05). Extent of fibrosis, inflammation, and profibrotic cytokines was reduced by AVE7688 therapy.Conclusion. The results indicate a strong nephroprotective effect of the vasopeptidase inhibitor in this animal model of progressive renal fibrosis. Besides the antihypertensive action of AVE7688, its antifibrotic, anti-inflammatory, and antiproteinuric effects demonstrated in the present study may serve as an important therapeutic option for chronic inflammatory and fibrotic diseases in man.