背景:他克莫司诱导的移植后糖尿病(PTDM)的治疗已成为提高器官移植患者长期生存率的热门话题。然而其发病机制尚未完全阐明。在胰腺中,据报道,NF-κB的上调刺激细胞因子IL-1β/TNF-α分泌,诱导胰腺损伤,同时也报道了雷帕霉素对NF-κB的抑制作用。
目的:本研究旨在阐明他克莫司致胰腺损伤的机制,并探讨小剂量西罗莫司的潜在作用。
方法:Wistar大鼠随机分为正常对照组,PTDM组,西罗莫司干预(SIR)组。转录组分析用于筛选PTDM的潜在机制。采用生化指标检测胰腺损伤指标。病理染色,免疫组织化学染色,免疫荧光染色,使用westernblot验证潜在机制。
结果:与NC组相比,胰岛素水平显著降低(P<0.01),PTDM组胰高血糖素水平明显升高(P<0.01)。转录组分析表明,PTDM组Syk/BLNK/NF-κB信号显著上调。病理染色,免疫组织化学染色,免疫荧光染色,Westernblot证实Syk/BLNK/NF-κB和TNF-α/IL-1β均显著升高(P<0.05或P<0.01),证明他克莫司通过Syk/BLNK/NF-κB信号传导诱导胰腺损伤的机制。此外,与PTDM组相比,体重的水平,FPG,艾米,SIR组GSP改善明显(P<0.05或P<0.01),和p-NF-κB的表达,SIR组TNF-α/IL-1β显著降低(P<0.05或P<0.01),显示Syk/BLNK/NF-κB信号促进他克莫司诱导的胰腺损伤和雷帕霉素降低NF-κB的潜在保护作用。
结论:Syk/BLNK/NF-κB信号促进他克莫司诱导的胰腺损伤,雷帕霉素通过下调NF-κB具有潜在的保护作用。未来需要进一步的验证和临床研究。
BACKGROUND: The treatment of tacrolimus-induced post-transplantation diabetes mellitus (PTDM) has become a hot topic to improve the long-term survival of organ transplant patients, however whose pathogenesis has not been fully elucidated. In pancreas, the up-regulation of NF-κB has been reported to stimulate cytokine IL-1β/TNF-α secretion, inducing pancreatic injury, meanwhile other studies have reported the inhibitory effect of rapamycin on NF-κB.
OBJECTIVE: The aim of this study was to clarify the mechanism of tacrolimus-induced pancreatic injury and to explore the potential effect from small dose of sirolimus.
METHODS: Wistar rats were randomly divided normal control (NC) group, PTDM group, sirolimus intervention (SIR) group. Transcriptomic analysis was used to screen potential mechanism of PTDM. Biochemical index detections were used to test the indicators of pancreatic injury. Pathological staining, immumohistochemical staining, immunofluorescent staining, western blot were used to verify the underlying mechanism.
RESULTS: Compared with NC group, the level of insulin was significant reduction (P < 0.01), inversely the level of glucagon was significantly increase (P < 0.01) in PTDM group. Transcriptomic analysis indicated Syk/BLNK/NF-κB signaling was significantly up-regulated in PTDM group. Pathological staining, immumohistochemical staining, immunofluorescent staining, western blot verified Syk/BLNK/NF-κB and TNF-α/IL-1β were all significantly increased (P < 0.05 or P < 0.01), demonstrating the mechanism of tacrolimus-induced pancreatic injury via Syk/BLNK/NF-κB signaling. In addition, compared with PTDM group, the levels of weight, FPG, AMY, and GSP in SIR group were significant ameliorative (P < 0.05 or P < 0.01), and the expressions of p-NF-κB, TNF-α/IL-1β in SIR group were significantly reduction (P < 0.05 or P < 0.01), showing Syk/BLNK/NF-κB signaling promoted pancreatic injury induced by tacrolimus and potential protective effect from rapamycin reducing NF-κB.
CONCLUSIONS: Syk/BLNK/NF-κB signaling promotes pancreatic injury induced by tacrolimus and rapamycin has a potentially protective effect by down-regulating NF-κB. Further validation and clinical studies are needed in the future.