Kidney Int:他克莫司可致肾小动脉玻璃样变

2012-12-10 Kidney Int Kidney Int

  他克莫司致肾小动脉玻璃样变的病理机制         Valorie L Chiasson等人发表在《国际肾脏杂志》(Kidney Int)上的一项研究表明:他克莫司是一种移植领域常用的免疫抑制剂,主要通过抑制白介素-2(L-2)的释放作用,其免疫抑制效果较环孢素(CsA)强100倍。   小动脉玻璃样变是肾移植患者长期服用他克莫司治疗常见的组织学病理表现,但是相关病理生理机

  他克莫司致肾小动脉玻璃样变的病理机制

  

  

  Valorie L Chiasson等人发表在《国际肾脏杂志》(Kidney Int)上的一项研究表明:他克莫司是一种移植领域常用的免疫抑制剂,主要通过抑制白介素-2(L-2)的释放作用,其免疫抑制效果较环孢素(CsA)强100倍。

  小动脉玻璃样变是肾移植患者长期服用他克莫司治疗常见的组织学病理表现,但是相关病理生理机制目前并不明确。

  已有研究发现,除了能够提高TGF-b的水平,他克莫司还可通过结合FKBP12—FK506结合蛋白12,抑制钙调神经磷酸酶的活性。

  而FKBP12本身即可抑制TGF-b受体的活化。因此,当他克莫司与FKBP12结合后,可能会“去除”FKBP12对TGF-b受体的抑制,而TGF-b受体的激活可能与长期服用他克莫司致小动脉玻璃样变有关。

  小鼠模型研究证实,内皮细胞特异性敲除FKBP12,足以激活内皮TGF-b受体,肾小动脉玻璃样变,这一病理改变与服用他克莫司类似。分离小鼠主动脉至于含他克莫司的,TGF-b受体激活增加,胶原和纤维连接蛋白表达增加。上述效应并不依赖钙调神经磷酸酶,小分子TGF-b受体抑制剂SB-505124则具有保护。

  基于上述研究发现,研究者认为,内皮细胞TGF-b受体激活是导致血管重构和肾小动脉玻璃样变的关键。



ABSTRACT
Arteriolar hyalinosis is a common histological finding in renal transplant recipients treated with the calcineurin inhibitor tacrolimus; however, the pathophysiologic mechanisms remain unknown. In addition to increasing transforming growth factor (TGF)-β levels, tacrolimus inhibits calcineurin by binding to FK506-binding protein 12 (FKBP12). FKBP12 alone also inhibits TGF-β receptor activation. Here we tested whether tacrolimus binding to FKBP12 removes an inhibition of the TGF-β receptor, allowing ligand binding, ultimately leading to receptor activation and arteriolar hyalinosis. We found that specific deletion of FKBP12 from endothelial cells was sufficient to activate endothelial TGF-β receptors and induce renal arteriolar hyalinosis in these knockout mice, similar to that induced by tacrolimus. Tacrolimus-treated and knockout mice exhibited significantly increased levels of aortic TGF-β receptor activation as evidenced by SMAD2/3 phosphorylation, along with increased collagen and fibronectin expression compared to controls. Treatment of isolated mouse aortas with tacrolimus increased TGF-β receptor activation and collagen and fibronectin expression. These effects were independent of calcineurin, absent in endothelial denuded aortic rings, and could be prevented by the small molecule TGF-β receptor inhibitor SB-505124. Thus, endothelial cell TGF-β receptor activation is sufficient to cause vascular remodeling and renal arteriolar hyalinosis.

    

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    2012-12-12 gwc389

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