Activation of c-Jun NH2-terminal kinase (JNK) pathway during islet transplantation and prevention of islet graft loss by intraportal injection of JNK inhibitor
Activation of c-Jun NH2-terminal kinase (JNK) pathway during islet transplantation and prevention of islet graft loss by intraportal injection of JNK inhibitor
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DOI：
10.1007/s00125-006-0563-2
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发表时间：
2007-03-01
期刊：
影响因子：
8.2
通讯作者：
Matsumoto, S.
中科院分区：
文献类型：
--
作者：
Noguchi, H.;Nakai, Y.;Matsumoto, S.
目的/假说虽然Edmonton方案的应用显著改善了胰岛移植的结果，但来自一个供体胰腺的胰岛移植后的胰岛素独立率仍然很低。在分离过程和随后的临床移植过程中，胰岛会受到严重的不利条件，影响生存并最终导致移植物失败。本研究的目的是定位在胰岛移植过程中介导胰岛丢失的c-jun NH2末端激酶(JNK)通路，并阐明胰岛移植过程中门静脉注射JNK抑制剂是否可以预防胰岛移植物的丢失。方法检测糖尿病小鼠肝脏、脂肪、肌肉和胰岛移植后即刻肝脏中JNK活性。检测门静脉注射JNK抑制肽对胰岛移植的影响。结果至少在移植后24 h，JNK活性逐渐升高。JNK抑制剂的细胞通透性多肽不仅在肝脏中被传递，而且在其他胰岛素靶器官中也被传递，至少在移植后24小时内阻止了肝脏中的JNK激活，并降低了这些胰岛素靶器官中的JNK活性。结论在胰岛移植中，对JNK通路的控制是非常重要的，在胰岛移植过程中门静脉注射JNK抑制剂(在移植液中加入JNK抑制剂)可以防止胰岛细胞的损伤，从而改善胰岛移植的预后。
Aims/hypothesis Although application of the Edmonton protocol has markedly improved the outcome for pancreatic islet transplantation, the insulin independence rate after islet transplantation from one donor pancreas has remained low. During the isolation process and subsequent clinical transplantation, islets are subjected to severe adverse conditions that impair survival and ultimately contribute to graft failure. The aim of this study was to map the c-Jun NH2-terminal kinase (JNK) pathway that mediates islet loss during islet transplantation and to clarify whether intraportal injection with JNK inhibitor during islet transplantation can prevent islet graft loss.Methods We measured JNK activity in the liver, fat and muscle of diabetic mice and in the liver immediately after islet transplantation. We examined the effect of intraportal injection of JNK inhibitory peptide at islet transplantation.Results JNK activity became progressively higher at least until 24 h after transplantation. The cell-permeable peptide of JNK inhibitor was delivered not only in the liver but also in other insulin target organs, preventing JNK activation in the liver at least until 24 h after transplantation and reducing JNK activity in these insulin target organs. Moreover, the peptide inhibitor prevented islet graft loss immediately after transplantation and improved islet transplant outcome.Conclusions/interpretation These findings suggest that control of the JNK pathway is extremely important in islet transplantation and that intraportal injection of JNK inhibitor during islet transplantation (addition of JNK inhibitor to transplant media) could prevent the impairment of islet cells, leading to improved outcome for pancreatic islet transplantation.