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首页> 外文期刊>American Journal of Physiology >TGF-beta1 mediates sirolimus and cyclosporine A-induced alteration of barrier function in renal epithelial cells via a noncanonical ERK1/2 signaling pathway.
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TGF-beta1 mediates sirolimus and cyclosporine A-induced alteration of barrier function in renal epithelial cells via a noncanonical ERK1/2 signaling pathway.

机译：TGF-β1介导西罗莫司和环孢菌素A引起的肾上皮细胞屏障功能的改变，通过非甘露透的ERK1 / 2信号通路。

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The immunosuppressant drugs cyclosporine A (CsA) and sirolimus (SRL) used in combination demonstrated beneficial effects in organ transplantation, but this combination can also result in increased adverse effects. We previously showed that not only CsA treatment but also its combination with SRL decreased paracellular permeability in renal proximal tubular cells by modification of the tight junction proteins, claudins, through ERK1/2 signaling pathway. In this present study, evidence is presented that not only CsA but also the combination of CsA/SRL may have adverse effects on the barrier function of renal proximal cells, at least in part, through the expression of the cytokine transforming growth factor (TGF)-beta(1). CsA treatment upregulated TGF-beta(1) gene expression and this upregulation was enhanced when CsA and SRL were applied together. Addition of TGF-beta(1) (5 ng/ml) altered the barrier function with increased transepithelial electrical resistance (TER) and claudin-1 expression. Use of a TGF-beta(1)-blocking antibody or blockage of TGF-beta(1) receptor kinase activity with SD208 prevented the CsA- and CsA/SRL-induced increase in TER. No evidence was found in the present studies to indicate that CsA or CsA/SRL treatment activated the TGF-beta(1) Smad canonical signaling pathway, whereas addition of TGF-beta(1) (5 ng/ml) did activate the Smad pathway. Addition of the ERK1/2 signaling inhibitor U0126 was able to prevent the TGF-beta(1)-mediated increase in TER and claudin expression. It is most likely that the CsA- and CsA/SRL-induced increases in TGF-beta(1) expression may not be sufficient to trigger the Smad pathway but however may trigger other TGF-beta(1) receptor-mediated signaling including the ERK1/2 signaling pathway.
机译：用于组合使用的免疫抑制药物环孢菌素A（CSA）和西罗莫司（SRL）在器官移植中表现出有益的效果，但这种组合也可能导致不良反应增加。我们以前表明，不仅是CSA治疗，而且其与SRL的组合通过修饰通过ERK1 / 2信号传导途径来改变紧密结蛋白，CLAUDINS来降低肾近端管状细胞的肾盂渗透性。在本研究中，提出了证据，不仅CSA，而且CSA / SR1的组合至少部分地通过细胞因子转化生长因子（TGF）的表达对肾近代细胞的阻隔功能具有不利影响-beta（1）。 CSA治疗上调的TGF-β（1）基因表达，当CSA和SRL一起施加CSA和SRL时，增强了这种上调。添加TGF-β（1）（5ng / mL）改变了屏障功能，随着促进的肺部型电阻（TER）和CLAUDIN-1表达增加。使用具有SD208的TGF-β（1） - 阻断抗体或TGF-β（1）受体激酶活性的堵塞阻止了CSA和CSA / SRL诱导的TER增加。本研究中没有发现证据表明CSA或CSA / SRL治疗活化了TGF-β（1）次级规范信号传导途径，而加入TGF-β（1）（5ng / ml）使得活性途径活化。添加ERK1 / 2信号抑制剂U0126能够防止TGF-β（1）介导的TER和CLAUDIN表达的增加。最有可能在TGF-β（1）表达中的CSA和CSA / SRL诱导的增加可能不足以触发Smad途径，但然而，可以触发包括ERK1的其他TGF-β（1）受体介导的信号传导/ 2信号通路。

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