2014-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/645184急性腎損傷（Acute kidney injury, AKI）是一種嚴重的併發症，導致住院時間延長，加重 病人的死亡率。腎臟遭受急性損傷後，血管內皮受損無法及時復原，導致腎功能無法完 全恢復，腎臟微血管受損和血管內皮損傷的血管重塑功能不足，與日後慢性腎臟病的發 生具有密切相關性。研究發現受損的內皮細胞層可以藉由釋放多種趨化因子，吸引骨髓 釋放至血液中的內皮前驅幹細胞至受損部位進行修復，藉以維持血管內皮細胞層的功能 性與完整性，內皮前驅幹細胞亦被證實在發生缺氧的組織具有促進血管新生的作用 （Postnatal vasculogenesis）。第四型二肽基肽酶（Dipeptidyl peptidase-4, DPP-4）能切解 多種趨化因子和集落刺激因子，其中之ㄧ的基質細胞衍生因子(Stromal cell-derived factor-1, SDF-1)影響幹細胞的遷移能力。體外實驗顯示顆粒單核球群落刺激生長因子 (Granulocyte-macrophage colony- stimulating factor, GM-CSF)處理會促進DDP4表現，影響 SDF-1的半衰期，然而透過DPP4抑制劑的使用，能夠減緩SDF-1的降解，提高帶有趨化 因子受體CXCR4的細胞例如內皮前驅幹細胞歸巢至受損部位的能力。本研究將嘗試探討 急性腎臟損傷模式下：(1)臨床急性腎損傷患者血液中的SDF-1濃度與內皮前驅幹細胞數 量的關連性。(2)體外培養的環境下，分別以GM-CSF與DPP4抑制劑預處理內皮前驅幹細 胞，藉以調節細胞內SDF-1/CXCR4路徑而活化內皮前驅幹細胞的血管新生和移動能力。 (3)GM-CSF與DPP4抑制劑協同投與，提升內皮前驅幹細胞歸巢和分化至受損腎臟部位的 能力，藉由SDF-1/CXCR4路徑改善缺血再灌注後的小鼠腎臟血管修復。我們將使用接受 Tie2-GFP骨髓移植小鼠追蹤內皮前驅幹細胞在腎臟血管受損情況下的移動，佐以SDF-1 腎臟條件式剔除鼠驗證急性腎損傷後SDF-1/CXCR4信號對內皮前驅幹細胞巢歸能力的 影響。Acute kidney injury (AKI) is a serious complication, leading to prolonged hospitalization and patient mortality. When kidney suffer acute injury, vascular endothelial damage can not be recovered fully, result in renal dysfunction, impair renal microvascular endothelial injury, vascular remodeling and has a close correlation with the occurrence of chronic kidney disease. Previous study revealed that the endothelial cell layer could be damaged by the release of a variety of chemokines attract the endothelial progenitor cells released from bone marrow into blood and repair damaged sites of the vascular endothelial cell layer in order to maintain the functional integrity of endothelial progenitor cells was later confirmed in tissue hypoxia has a role in promoting angiogenesis. Dipeptidyl peptidase-4 (DPP-4) could digest lots of chemokines and colony-stimulating factor, such as stromal cell-derived factor (SDF-1) and affect the migration of stem cells. In vitro GM-CSF treatment up-regulates the peptidase DDP4, resulting in down-regulation of the functional ability of functional ability of the CD34+CD38- cells to response to the chemokine SDF-1, which could be overcome through the use of DPP4 inhibitors. However, through the addition of DPP4 inhibitors, it is possible to slow down the degradation of SDF-1, improve the homing ability, such as endothelial progenitor cells which carry the receptor of SDF-1: CXCR4. Our study will attempt to explore under the mode of acute kidney injury: (1) SDF-1 concentrations in the blood of patients with clinical acute kidney injury and endothelial progenitor cell number related. (2) In vitro study, the addition of GM-CSF and DPP4 inhibitors pretreated with endothelial progenitor cells, respectively, in order to regulate intracellular SDF-1/CXCR4 path activated endothelial progenitor cells, angiogenesis and the ability to move. (3) GM-CSF DPP4 inhibitors collaborative administration, to enhance endothelial progenitor cell homing and differentiation to damage the ability of the kidneys parts, mouse kidney after ischemia-reperfusion by SDF-1/CXCR4 path to improve vascular repair . We will use the Tie2-GFP bone marrow transplantation mice to track the homing of endothelial progenitor cells in the case of impaired renal vessels moving SDF-1/CXCR4 signal verification acute kidney injury after endothelial progenitor cells, accompanied by SDF-1 kidney conditional knockout mice ability nest normalized.急性腎損傷DPP4 抑制劑GM-CSF血管內皮前驅幹細胞INDEX WORDS: Acute renal failureDPP-IV InhibitionGM-CSFendothelial progenitor cell