Isoflurane mediates protection from renal ischemia-reperfusion injury via sphingosine kinase and sphingosine-1-phosphate-dependent pathways
Isoflurane mediates protection from renal ischemia-reperfusion injury via sphingosine kinase and sphingosine-1-phosphate-dependent pathways
复制标题
DOI：
10.1152/ajprenal.00290.2007
复制
发表时间：
2007-12-01
影响因子：
4.2
通讯作者：
Lee, H. Thomas
中科院分区：
文献类型：
--
作者：
Kim, Minjae;Kim, Mihwa;Lee, H. Thomas
吸入麻醉剂异氟醚已被证明对肾脏缺血再灌注(IR)损伤有保护作用。以往的研究表明，异氟醚可调节肾近端小管上皮细胞的鞘磷脂代谢。我们试图确定异氟醚是否刺激肾近端小管细胞鞘氨醇-1-磷酸(S1P)的合成和鞘氨醇激酶(SK)的活性，从而通过S1P信号通路介导肾脏保护。异氟醚麻醉可减轻肾IR损伤小鼠的肾功能衰竭和坏死程度。异氟醚的这种保护作用可被SK抑制剂(DMS和SKI-II)以及S1P(1)受体拮抗剂(VPC23019)逆转。此外，异氟烷对SK1酶缺陷小鼠的IR损伤没有保护作用。体外培养的人肾近端小管细胞(HK-2)和小鼠肾脏经异氟醚处理后，SK活性和SK1基因表达均增加。异氟醚可增加HK-2细胞中S1P的生成。综上所述，我们的研究结果表明，异氟醚激活肾小管细胞中的SK，并启动S1P->；S1P(1)受体信号通路，从而介导肾脏保护作用。我们的发现可能有助于解开挥发性麻醉剂介导的肾脏保护的细胞信号通路，并导致吸入麻醉剂在围手术期的新的治疗应用。
The inhalational anesthetic isoflurane has been shown to protect against renal ischemia-reperfusion (IR) injury. Previous studies demonstrated that isoflurane modulates sphingolipid metabolism in renal proximal tubule cells. We sought to determine whether isoflurane stimulates sphingosine kinase (SK) activity and synthesis of sphingosine-1-phosphate (S1P) in renal proximal tubule cells to mediate renal protection via the S1P signaling pathway. Isoflurane anesthesia reduced the degree of renal failure and necrosis in a murine model of renal IR injury. This protection with isoflurane was reversed by SK inhibitors (DMS and SKI-II) as well as an S1P(1) receptor antagonist (VPC23019). In addition, mice deficient in SK1 enzyme were not protected from IR injury with isoflurane. SK activity as well as SK1 mRNA expression increased in both cultured human proximal tubule cells (HK-2) and mouse kidneys after exposure to isoflurane. Finally, isoflurane increased the generation of S1P in HK-2 cells. Taken together, our findings indicate that isoflurane activates SK in renal tubule cells and initiates S1P -> S1P(1) receptor signaling to mediate the renal protective effects. Our findings may help to unravel the cellular signaling pathways of volatile anesthetic-mediated renal protection and lead to new therapeutic applications of inhalational anesthetics during the perioperative period.