TGF-beta1 release by volatile anesthetics mediates protection against renal proximal tubule cell necrosis
TGF-beta1 release by volatile anesthetics mediates protection against renal proximal tubule cell necrosis
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DOI：
10.1159/000105124
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发表时间：
2007-01-01
影响因子：
4.2
通讯作者：
Emala, Charles W.
中科院分区：
文献类型：
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作者：
Lee, H. Thomas;Kim, Mihwa;Emala, Charles W.
背景/目标：我们以前已经证明，临床上使用的挥发性麻醉剂在体内保护大鼠肾缺血再灌注损伤，并通过激活ERK和Akt以及上调HSP 70来减少体外坏死。在本研究中，我们进一步阐明了挥发性麻醉药介导的体外抗坏死作用的上游细胞信号转导机制。我们假设挥发性麻醉剂扰乱质膜脂质双层的结构，导致磷脂酰丝氨酸（PS）外化到肾小管细胞的外表面，导致转化生长因子-β 1（TGF-β 1），一种具有抗坏死特性的细胞因子的产生增加。方法和结果：在人近端小管（HK-2）细胞培养物中，暴露于挥发性麻醉剂（异氟烷，氟烷，七氟烷）16小时导致膜外化的PS检测阳性膜联蛋白-V染色，并增加TGF-β 1释放到细胞培养基中。外源性TGF-β 1诱导的保护作用和中和性TGF-β 1抗体阻止了挥发性麻醉药对过氧化氢诱导的HK-2细胞坏死的细胞保护作用。结论：挥发性麻醉剂通过PS的膜外化诱导近端小管细胞的细胞保护信号级联，启动TGF-β 1介导的细胞保护。版权所有（c）2007 S. Karger AG，巴塞尔。
Background/Aims: We have previously demonstrated that clinically utilized volatile anesthetics protect against renal ischemia reperfusion injury in rats in vivo and reduce necrosis in vitro via activation of ERK and Akt and by upregulating HSP70. In this study, we further deciphered the upstream cellular signaling mechanism(s) of volatile anesthetic-mediated antinecrotic effects in vitro. We hypothesized that volatile anesthetics perturb the structure of the plasma membrane lipid bilayer, causing externalization of phosphatidylserine ( PS) to the outer surface on renal tubule cells leading to the increased generation of transforming growth factor-beta 1 (TGF-beta 1), a cytokine with antinecrotic properties. Methods and Results: In human proximal tubule (HK-2) cell culture, 16-hour exposure to volatile anesthetics (isoflurane, halothane, sevoflurane) caused membrane externalization of PS detected by positive annexin-V staining and increased the release of TGF-beta 1 into the cell culture media. Exogenous TGF-beta 1 induced protection and neutralizing TGF-beta 1 antibody prevented the cytoprotection by volatile anesthetics against hydrogen peroxide-induced HK-2 cell necrosis. Conclusions: Volatile anesthetics induce a cytoprotective signaling cascade in proximal tubule cells via membrane externalization of PS initiating TGF-beta 1-mediated cytoprotection. Copyright (c) 2007 S. Karger AG, Basel.