Sirolimus Prevents Short-Term Renal Changes Induced by Ischemia-Reperfusion Injury in Rats
Sirolimus Prevents Short-Term Renal Changes Induced by Ischemia-Reperfusion Injury in Rats
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DOI：
10.1159/000324577
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发表时间：
2011-01-01
影响因子：
4.2
通讯作者：
Dal Canton, A.
中科院分区：
文献类型：
--
作者：
Esposito, C.;Grosjean, F.;Dal Canton, A.
背景：肾移植患者存在不同程度的缺血再灌注损伤。I/R对移植肾的早期功能和长期存活起着重要作用。我们研究的目的是确定免疫抑制剂是否在一种将I/R与所有免疫反应分离的模型中调节I/R。方法：SD大鼠单侧肾I/R模型，每日给予环孢素(A)、他克莫司(B)、西罗莫司(C)或生理盐水(D)。假手术组大鼠给予生理盐水(E)。30d后，用菊粉清除法测定肾小球滤过率。采用实时荧光定量聚合酶链式反应、免疫印迹和酶谱检测肾组织中转化生长因子-β、纤维连接蛋白和金属蛋白酶活性。结果：西罗莫司可阻止I/R肾小球滤过率下降，但环孢素和他克莫司对其无影响(A、B、C三组分别为403+/-303vs 1,006+/-484亩L/分钟，p<；0.05；126+/-170 vs 567+/-374亩L/min，p<；0.05；633+/-293 vs 786+/-255；A、B、C组分别与对侧肾脏比较)。西罗莫司可减少对照组和钙调神经磷酸酶抑制剂组大鼠肾脏ED-1+细胞的渗出、间质纤维化和小血管内膜增厚。他克莫司和环孢素增加纤维连接蛋白和转化生长因子-β的表达和基质沉积。只有西罗莫司提高了金属蛋白酶的活性。结论：西罗莫司而不是钙调神经磷酸酶抑制剂可预防I/R所致的肾损伤。版权所有(C)2011 S.Karger AG，巴塞尔
Background: Ischemia-reperfusion (I/R) is present at various degrees in kidney transplants. I/R plays a major role in early function and long-term survival of renal allograft. The purpose of our study was to determine if immunosuppressants modulate I/R in a model that separates I/R from all immune responses. Methods: Sprague-Dawley rats with monolateral renal I/R received daily cyclosporine (A), tacrolimus (B), sirolimus (C) or saline (D). Sham-operated rats received saline (E). After 30 days, glomerular filtration rate for each kidney was measured by inulin clearance. Kidney injury was examined, and TGF-beta, fibronectin and metalloproteases were evaluated by real-time PCR, Western blot and zymography. Results: Sirolimus, but not cyclosporine and tacrolimus, prevented a glomerular filtration rate decrease in I/R kidneys (403 +/- 303 vs. 1,006 +/- 484 mu l/min, p < 0.05; 126 +/- 170 vs. 567 +/- 374 mu l/min, p < 0.05; 633 +/- 293 vs. 786 +/- 255; A, B and C group, respectively, I/R vs. contralateral kidneys). Sirolimus reduced ED-1+ cell infiltrate, interstitial fibrosis and intimal thickening of small vessels observed in I/R kidneys of controls and calcineurin inhibitor-treated rats. Tacrolimus and cyclosporine in-creased fibronectin and TGF-beta expression and matrix deposition. Only sirolimus increased metalloprotease activity. Conclusions: Sirolimus but not calcineurin inhibitors prevented I/R-induced kidney injury. Copyright (C) 2011 S. Karger AG, Basel