新型抗糖尿病药物对移植术后免疫抑制剂诱导的肾及胰腺损伤的保护作用及其机制的研究

他克莫司(TAC)作为免疫抑制剂中首选药物被广泛应用于移植术后免疫抑制的治疗，而TAC的肾毒性以及其诱导的移植后新发糖尿病（NODAT）却是制约移植器官长期存活的重要因素。钠-葡萄糖协同转运蛋白2（SGLT-2）是肾小管内参与葡萄糖重吸收的关键蛋白分子，是近年来治疗糖尿病的新靶点。先前研究中发现SGLT-2抑制剂除了能够降低血糖之外还能够减轻TAC对肾小管及胰腺细胞的损伤，具有减少尿蛋白及肾小管纤维化的作用。而这种直接保护作用我们考虑与阻断TAC激活的PI3K/AKT/FoxO信号通路有关。本项目通过体内及体外实验观察SGLT-2抑制剂对TAC诱导的肾及胰腺毒性的保护作用，研究SGLT-2抑制剂对肾小管及胰腺细胞保护作用是否与调节PI3K/AKT/FoxO信号通路相关，为长期服用TAC而引起肾及胰腺损伤患者的治疗提供可靠的理论依据。

Tacrolimus (TAC) is a preferred immunosuppressant drug which widely used in post-transplant immunosuppressive therapy. However, renal toxicity of TAC and TAC induced new-onset diabetes mellitus (NODAT) are still important factors in the long-term survival of the transplanted organs. Sodium-glucose co-transporter 2(SGLT-2) is a key molecule involved in glucose reuptake in renal tubules, which is a new target for diabetes treatment in recent years. Our previous studies have shown that SGLT-2 inhibitor not only lower blood glucose but also reduce the damage of the renal tubules and pancreatic cells by TAC, which has the effect of reduce urinary protein and renal tubular fibrosis. This direct protective effect was considered to be related to block the PI3K/AKT/FoxO signaling pathway activated by TAC. In this project, we will investigate protective effect of SGLT-2 inhibitor on the TAC induced renal and pancreatic injury in vivo and in vitro. In addition, we will further investigate the protective effect of SGLT-2 inhibitor on renal tubules and pancreatic cells is related to the regulation of PI3K/AKT/FoxO signaling pathway. This study will provide the theoretical basis for long-term treatment of patients with renal and pancreatic toxicity of TAC.