GLP-1受体激动剂在移植肾慢性排斥反应中的作用及机制研究

Donor vascular endothelial cells play an important role in chronic allograft rejection. Researches have shown that GLP-1 receptor agonist, used to be treated type 2 diabetes, exert a unique beneficial effect on endothelial cells. It was reported that GLP-1 receptor was predominantly localized on the vascular endothelial cells in kidney. Our previous work shown that liraglutide treatment can significantly reduce acute rejection in mouse heart transplantation and inhibit the activation of effector T cells. In the present study, we will investigate whether GLP-1 receptor agonists could improve chronic rejection by regulating endothelial cells in a renal transplantation model. Concrete research contents include: 1) To investigate whether GLP-1 receptor agonists could improve donor quality through protection of endothelial cells during renal cold ischemia; 2) To investigate the effect and underlying mechanism of GLP-1 receptor agonist on the expression of co-stimulatory molecules and adhesion molecules on endothelial cells, and further to explore its effect on the proliferation, activation and differentiation of T cells; 3) To study the role and mechanism of GLP-1 receptor agonist on renal transplantation-associated endothelial-to-mesenchymal transition (EndMT). Our findings in this project will clarify the effect and mechanism of GLP-1 receptor on allograft endothelial cells in renal chronic rejection and provide experimental basis for developing new applications of GLP-1 receptor agonist in transplantation.

供体血管内皮细胞在慢性移植排斥反应中发挥重要作用。研究表明，临床上一种用于治疗二型糖尿病药物GLP-1受体激动剂对内皮细胞具有独特的保护作用，而GLP-1受体在肾脏中主要分布于血管内皮细胞上。我们前期工作发现，利拉鲁肽能明显减轻小鼠心脏的急性排斥反应，抑制效应性T细胞的激活。在本研究中，我们将在大鼠移植肾慢性排斥模型上，研究GLP-1受体激动剂是否能通过调节内皮细胞改善慢性排斥反应。内容包括：1）研究在供肾冷缺血阶段GLP-1受体激动剂能否通过保护内皮细胞改善供体质量；2）研究GLP-1受体激动剂对内皮细胞上共刺激分子及粘附分子表达的调节及其机制，同时探讨其对T细胞增殖、激活、分化的影响；3）研究GLP-1受体激动剂对移植肾内皮向间质转化的作用及机制。本研究将阐明移植肾内皮细胞上GLP-1受体在慢性排斥反应中的作用和机制，为开发GLP-1受体激动剂在移植领域的新用途提供理论依据。

供体血管内皮细胞在慢性移植排斥反应中发挥重要作用。既往文献表明，临床上一种用于治疗二型糖尿病药物GLP-1受体激动剂对内皮细胞具有保护作用，并且GLP-1受体在肾脏中主要分布于血管内皮细胞上。我们已经证明利拉鲁肽能明显减轻小鼠心脏的急性排斥反应，抑制效应性T细胞的激活。在本研究中，我们将在大鼠移植肾慢性排斥模型上，研究GLP-1受体激动剂是否能通过调节内皮细胞改善慢性排斥反应。我们目前已经证明GLP-1受体激动剂对移植肾冷缺血有保护作用，但由于大鼠肾移植慢排模型建立困难，再加上以F344为背景的GLP-1R-/-敲基因大鼠繁育困难，我们对课题进行了调整，具体调整如下：.1..GLP-1受体激动剂利拉鲁肽在移植肾冷缺血中的运用.2..GLP-1受体激动剂利拉鲁肽及其代谢物在急性肾损伤中的运用及其机制研究.我们目前已经证明，.1. 利拉鲁肽对移植肾冷缺血有保护作用，并能减少移植肾冷缺血过程中血管内皮细胞的凋亡。.2. 利拉鲁肽及其代谢物可通过抑制HMGB1的核浆转位和释放减轻急性肾损伤。