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首页> 外文期刊>American Journal of Physiology >Rosuvastatin is additive to high-dose candesartan in slowing progression of experimental mesangioproliferative glomerulosclerosis
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Rosuvastatin is additive to high-dose candesartan in slowing progression of experimental mesangioproliferative glomerulosclerosis

机译：瑞舒伐他汀是大剂量坎地沙坦的添加剂，可减缓实验性血管增生性肾小球硬化的进展

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Rosuvastatin is additive to high-dose candesartan in slowing progression of experimental mesangioproliferative glomerulosclerosis (GS). Progressive mesangioproliferative glomerulonephritis, mostly IgA nephropathy,is a major cause of end-stage kidney disease worldwide. In a chronic-progressive model of mesangioproliferative GS, we tested the renoprotective efficacy of rosuvastatin alone and in combination with a high-dose of the AT_1 blocker candesartan. Treatment was started 1 wk after disease induction (anti-thyl antibody injection into uninephrectomized rats) and continued until week 20. Tubulointerstitialexpression of the key fibrosis mediator transforming growth factor (TGF)-beta served as the main marker of disease progression. Compared with the untreated GS rats (475 +- 52 pg/ml), tubulointerstitial TGF-beta_1 protein expression was significantly reduced by both single therapies (rosuvastatin -47%, candesartan -51%, P < 0.01). Tubulointerstitial matrix accumulation (matrix score in GS: 64 +- 7%) was relatively reduced by -45 and -52%, respectively (P < 0.01). The combination of rosuvastatin and candesartan had significantly greater effects on tubulointerstitial TGF-beta_1 expression (-82% vs. GS) and matrix accumulation (-83% vs. GS) (P < 0.001 vs. GS, P < 0.05 vs. single therapy) than either drug alone. Similar additive beneficial effects were observed for renal fibronectin and tissue inhibitor of metalloproteinase-1 expression, cell proliferation, macrophage infiltration, proteinuria, and kidney function. In conclusion, rosuvastatin limits the progressive course of anti-thy1-induced GS toward chronic tubulointerstitial fibrosis and renal insufficiency to a degree comparable to the one achieved by a high dose of the AT_1 antagonist candesartan. Combined treatment yields significantly greater actions on renal TGF-beta overexpression and matrix accumulation, cell proliferation, and macrophage infiltration. The results suggest that rosuvastatin and an AT_1 blocker independently interfere with separate key pathways involved in the progression of chronic mesangioproliferative GS.
机译：瑞舒伐他汀是大剂量坎地沙坦的添加剂，可减缓实验性血管增生性肾小球硬化（GS）的进程。进行性中血管增生性肾小球肾炎，主要是IgA肾病，是全世界终末期肾脏疾病的主要原因。在血管增生性GS的慢性进行性模型中，我们测试了单独使用瑞舒伐他汀以及与大剂量AT_1阻断剂坎地沙坦联合使用时瑞舒伐他汀的肾脏保护功效。疾病诱导后第一个星期开始治疗（向未进行全直肠切除的大鼠中注射抗Thyl抗体），一直持续到第20周。关键间质纤维化转化生长因子（TGF）-beta的肾小管间质表达是疾病进展的主要标志。与未治疗的GS大鼠（475±52 pg / ml）相比，两种单一疗法均显着降低了肾小管间质TGF-beta_1蛋白的表达（瑞舒伐他汀为-47％，坎地沙坦为-51％，P <0.01）。肾小管间质基质的积聚（GS中的基质评分：64±7％）分别相对降低了-45％和-52％（P <0.01）。罗苏伐他汀和坎地沙坦的组合对肾小管间质TGF-beta_1表达（-82％vs. GS）和基质蓄积（-83％vs. GS）有明显更大的影响（P <0.001 vs. GS，P <0.05 vs.单一疗法） ），而不是单独使用任何一种药物。对于肾纤连蛋白和金属蛋白酶-1表达，细胞增殖，巨噬细胞浸润，蛋白尿和肾功能的组织抑制剂观察到相似的累加有益效果。总之，罗苏伐他汀将抗thy1诱导的GS向慢性肾小管间质纤维化和肾功能不全的进程进行了限制，其程度可与通过大剂量AT_1拮抗剂坎地沙坦实现的程度相当。联合治疗对肾脏TGF-β的过表达和基质蓄积，细胞增殖和巨噬细胞浸润产生明显更大的作用。结果表明，瑞舒伐他汀和AT_1阻滞剂独立干扰慢性中血管增生性GS进程中涉及的独立关键途径。

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