Krämer Stephanie, Kron Susanne, Wang-Rosenke Yingrui, Loof Tanja, Khadzhynov Dmytro, Morgera Stanislao, Kawachi Hiroshi, Shimizu Fujio, Martini Sebastian, Neumayer Hans-H, Peters Harm
Dept. of Nephrology, Charité Universitätsmedizin Berlin, Campus Mitte, Humboldt Univ., Charitéplatz 1, D-10098 Berlin, Germany.
Am J Physiol Renal Physiol. 2008 Apr;294(4):F801-11. doi: 10.1152/ajprenal.00148.2007. Epub 2008 Jan 23.
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-thy1 antibody injection into uninephrectomized rats) and continued until week 20. Tubulointerstitial expression 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.
在减缓实验性系膜增生性肾小球硬化（GS）进展方面，瑞舒伐他汀与大剂量坎地沙坦具有相加作用。进行性系膜增生性肾小球肾炎，主要是IgA肾病，是全球终末期肾病的主要病因。在系膜增生性GS的慢性进展模型中，我们测试了瑞舒伐他汀单独使用以及与大剂量AT(1)受体阻滞剂坎地沙坦联合使用时的肾脏保护功效。在疾病诱导（向单侧肾切除大鼠注射抗thy1抗体）1周后开始治疗，并持续至第20周。关键纤维化介质转化生长因子（TGF）-β在肾小管间质的表达作为疾病进展的主要标志物。与未治疗的GS大鼠（475±52 pg/ml）相比，两种单一疗法（瑞舒伐他汀降低47%，坎地沙坦降低51%，P<0.01）均使肾小管间质TGF-β(1)蛋白表达显著降低。肾小管间质基质积聚（GS中的基质评分：64±7%）分别相对降低了45%和52%（P<0.01）。瑞舒伐他汀与坎地沙坦联合使用对肾小管间质TGF-β(1)表达（与GS相比降低82%）和基质积聚（与GS相比降低83%）的影响（与GS相比P<0.001，与单一疗法相比P<0.05）显著大于单独使用任何一种药物。在肾纤连蛋白和金属蛋白酶组织抑制剂-1表达、细胞增殖、巨噬细胞浸润、蛋白尿和肾功能方面也观察到了类似的相加有益作用。总之，瑞舒伐他汀将抗thy1诱导的GS向慢性肾小管间质纤维化和肾功能不全的进展过程限制在与大剂量AT(1)拮抗剂坎地沙坦相当的程度。联合治疗对肾脏TGF-β过表达和基质积聚、细胞增殖以及巨噬细胞浸润产生显著更大的作用。结果表明，瑞舒伐他汀和AT(1)受体阻滞剂独立干扰慢性系膜增生性GS进展过程中涉及的不同关键途径。
