CTLA4Ig通过AKT/FoxO信号通路对他克莫司诱导的肾损伤的保护作用

Patients with end-stage renal disease（ESRD）need lifelong medication of immunosuppressants after kidney transplantation. However，Long-term treatment with immunosuppressants causes irreversible chronic kidney disease and severe complications，which finally impact on the survival of renal allograft patients. Our studies have shown that tacrolimus (TAC) as a common clinical immunosuppressant could lead organic injury via the AKT/FoxO signaling pathway, especially in kidney tissues. Moreover, CTLA4Ig which is a newly discovered immunosuppressant could protect from pancreas injury induced by TAC. However, whether CTLA4Ig could protect from renal injury induced by TAC was still unknown. To elucidate the effect of conversion to CTLA4Ig treatment on the TAC-induced renal injury, we hypothesized that CTLA4Ig could ameliorate renal fibrosis, oxidative stress, and apoptosis induced by TAC via the AKT/FoxO signaling pathway. Through establishing animal and cell model，using immunohistochemistry, western blot, flow cytometry and so on, present study tries to explore the mechanism that CTLA4Ig protect from renal injury induced by TAC. By present study, the interaction and mechanism between immunosuppressants and renal injury will be supplemented, and immunosuppressants could be used more scientifically and rationally in clinical practice.

终末期肾病（ESRD)患者在肾脏移植后需终身服用免疫抑制剂，但长期服用免疫抑制剂可引起慢性肾脏损伤，甚至导致重度感染及恶性肿瘤等并发症，最终影响患者和移植肾的长期存活。项目组前期研究发现：临床上常用的免疫抑制剂他克莫司(TAC)可导致肾脏和胰腺等器官的损伤，CTLA4Ig作为一种新型的免疫抑制剂，对TAC诱导的胰腺损伤具有保护作用。但是，CTLA4Ig对TAC诱导的肾脏损伤是否也有保护作用尚不清楚。基于前期实验同时查阅文献，我们提出假设“CTLA4Ig通过调控AKT/FoxO信号通路，抑制TAC诱导的肾脏纤维化、氧化应激和细胞凋亡，对肾脏损伤起到了保护作用”。本研究拟通过建立动物和细胞模型，研究CTLA4Ig对TAC诱导的肾脏损伤的保护机制。本项目将探讨免疫抑制剂与肾脏损伤之间的相互关系及作用机制，为临床上肾脏移植后免疫抑制剂的使用提供理论基础和应用依据。

终末期肾病（ESRD）需接受肾脏替代治疗，而目前肾脏替代治疗中最理想的治疗方案为肾脏移植,与透析患者相比,肾脏移植虽然能有效提高患者的生活质量, 但现阶段需终身服用免疫抑制剂药物。目前临床常用的免疫抑制剂存在不同程度的副作用, 而且容易导致并发症的发生。CTLA4Ig 是一种新型免疫抑制剂，对急性排斥反应具有较强的治疗效果，且能避免传统免疫抑制剂如钙调磷酸酶抑制剂（CNI）的一些副作用，在器官和组织移植排斥的防治和一些难治性自身免疫性疾病的治疗中有着广阔的应用前景。本研究通过建立慢性 TAC 诱导的肾毒性动物和细胞模型，研究CTLA4Ig对肾脏损伤的保护作用及其相关机制。研究发现CTLA4Ig 通过调控 AKT/FOXO 信号通路，抑制 TAC 诱导的肾脏纤维化、氧化应激和细胞凋 亡，对肾脏损伤起到了保护的作用。