SDF-1/CXCR7在供肾缺血预适应双动员内皮祖细胞/肾祖细胞修复移植肾中的作用及机制

Ischemic Reperfusion Injury(IRI) is one of the most important causes of the renal graft dysfunction, and in the daily clinical practice, there is no effective management in the prevention and treatment of IRI. Our previous studies have confirmed that ischemic preconditioning(IPC) can facilitate the repairment of renal IRI by mobilizing endothelial progenitor cells(EPC) and renal progenitor cells(RPC), as a way to alleviate IRI significantly and protect the graft kidney greatly. According to some other studies, SDF-1/CXCR7 axis can contribute to the survival, proliferation and adhesion of EPC and RPC, while the exact role and underlying mechanism of this axis during the renal allograft repair process of both EPC and RPC induced by IPC still remains unclear. Here comes our speculation, IPC of donor kidney could mobilize RPC and EPC to participate in the repair of renal allograft, and SDF-1/CXCR7 axis may have a central role during this process. After establishing the ischemia preconditioned kidney transplantation animal models, via adopting the technologies like dual-mode mark in vitro, tracking in vivo and gene transfection from both in vitro and in vivo perspectives, this project aims to: study the renoprotective role of EPC and RPC induced by donor IPC on allograft peritubular capillaries(PTC) endothelium and tubular epithelium; explore the exact role and underlying mechanism of SDF-1/CXCR7 axis on the renal allograft repairing process of IPC-induced EPC and RPC. Thus, it will provide a theoretical and practical base for the prevention and treatment of IRI in kidney transplantation.

缺血再灌注损伤（IRI）是影响移植肾功能恢复的重要因素，目前尚缺乏有效的防治手段。我们的前期研究显示：缺血预适应（IPC）可动员内皮祖细胞/肾祖细胞（EPC/RPC）参与肾脏IRI的修复，显著改善移植肾以及肾脏IRI。另有报道：SDF-1/CXCR7可介导EPC/RPC的生存、增殖及粘附效应，但SDF-1/CXCR7在IPC动员EPC/RPC修复移植肾中的作用及机制目前尚不清楚。我们推测：SDF-1/CXCR7可能在调控供肾IPC双动员EPC/RPC修复移植肾中具关键性作用。本项目拟建立供肾IPC肾移植模型，采用双模标记、活体示踪、细胞转染等技术进行体内、外实验，探索供肾IPC双动员EPC/RPC在移植肾管周毛细血管（PTC）、肾小管上皮修复中的作用，阐明SDF-1/CXCR7在供肾IPC动员EPC/RPC修复移植肾中的具体作用机制，可为移植肾IRI的防治提供新的理论依据和治疗靶点。

缺血再灌注损伤（IRI）是导致移植肾功能延迟恢复（DGF）的重要原因，目前尚缺乏有效的防治手段。缺血预适应（IPC）作为一种有效减轻脏器IRI的方法，在脑、心、肝及小肠等器官IRI的保护作用已经得到证实，但对移植肾的保护作用尚未明确。本研究旨在观察IPC动员的内皮组细胞（EPC）/肾组细胞（RPC）对移植肾IRI的保护和修复作用，并探讨其可能的机制。我们发现IPC干预可显著减轻肾小管损伤，改善肾功能；同时IPC可上调SDF-1/CXCR7，动员EPC和RPC归巢至受损肾脏，促进多种血管源性生长因子的释放，并促进肾小管上皮细胞和管周毛细血管（PTC）的修复。通过对供体源性EPC进行标记示踪，证实外源性EPC在肾脏IRI后亦可通过IPC干预归巢至受损肾脏，发挥保护和修复作用。另外，通过CXCR7转染EPC及RPC，我们进一步证实，上调CXCR7可显著增强EPC和RPC的抗凋亡能力和旁分泌功能，并促进其对IRI后肾脏的修复作用；而抑制CXCR7则会使这些效果减弱。结果表明，供肾IPC可双动员EPC/RPC归巢至IRI肾脏，促进肾小管上皮和PTC的修复，同时可通过旁分泌释放多种活性因子，最终减轻移植肾IRI，改善移植后肾功能，而SDF-1/CXCR7可能在这一过程中发挥了重要作用。