2013-08-012024-05-16https://scholars.lib.ntu.edu.tw/handle/123456789/668689摘要：臨床與基礎的研究都已揭示急性腎損傷會導致後續長期腎臟功能的逐漸惡化。台灣由於慢性腎病與末期腎病的高盛行率，已經帶來巨大的社經負擔，因此，進一步瞭解急性腎損傷導致慢性腎病的機轉，並找出可能治療的方式，便顯得相當重要。第二型血管生成素Angiopoietin (Angpt)-2，能夠激活內皮細胞，促使其接受外在刺激而產生各種發炎或促血管生成因子，也能促進內皮前驅細胞的移動、管狀化與存活，而這些作用都是腎臟在急性傷害後會產生的重要反應。同時，臨床研究發現急性腎損傷或慢性腎病的患者，血中Angpt-2濃度會明顯增加。吾人因而推論Anpgt-2極可能參與了急性腎損傷後重要的病理機轉。本研究設計為三年期計畫。首先，吾人將利用小鼠的缺血-再灌流急性腎損傷模式，研究Angpt-2在腎臟與全身的表現，並利用細胞實驗，探討其表現的訊息傳遞機轉。其次，吾人計畫培育可誘導性腎小管上皮細胞專一性的Angpt-2基因剔除轉殖鼠，利用此轉殖鼠專一性的誘導剔除腎小管上皮細胞Angpt-2 基因，同時也將利用正常鼠給予Angpt-2抑制劑（L1-10）的全身性藥物治療，加以研究Angpt-2在缺血-再灌流急性腎損傷後對於腎小館傷害、發炎、纖維化、與微血管損失等反應的作用。再者，吾人計畫建立小鼠骨髓移植模式，將帶有綠色螢光的骨髓細胞移植到細胞不具綠色螢光的正常鼠或可誘導專一性Angpt-2基因剔除轉殖鼠 ，用以研究Angpt-2對於內皮前驅細胞的影響與腎臟變化。吾人期望藉由此計畫的各項實驗結果，能進一步瞭解Angpt-2在急性腎損傷後扮演的功能，並能據此發展出可能改善急性腎損傷後長期腎臟功能惡化的治療策略。<br> Abstract: Based on both clinical and basic researches, acute kidney injury (AKI) had been provenleading to progressive chronic renal function impairment. The high prevalence rate of chronickidney disease (CKD) and end-stage renal disease produces huge socioeconomic burden inTaiwan. It is very important to understand the mechanisms of AKI-CKD transition andidentifying potential intervention targets. Angiopoietin (Angpt)-2, a Tie2 receptor ligand, hasbeen identified as regulator of angiogenesis and vascular homeostasis. It can destabilize thequiescent endothelium and prime it to respond to exogenous stimuli with facilitating theactivities of inflammatory and angiogenic cytokines. It can also stimulate endothelialprogenitor cells migration, tube formation, and survival. Since the inflammation, endothelialalterations, and angiogenesis had been found to be evident in the kidney after acute injury,Angpt-2 may participate in disease process after AKI. This is supported by the clinicalobservations that circulating Angpt-2 was elevated in patients experience AKI or with CKD.We hypnotize that Angpt-2 upregulated in the injured renal tubules contribute to thepathogenesis and recovery of AKI. Thus we design this project to investigate the role ofAngpt-2 in AKI. In the first years, we will evaluate the expression and distribution of Angpt-2in vivo in experimental ischemia-reperfusion-induced AKI mice. Subsequently, we willexamine the expression and signal transduction pathway of Angpt-2 on renal tubular epithelialcells and endothelial progenitor cells under the stimulation of hypoxia condition. In thesecond year, we plan to generate doxycycline-dependent tubular epithelial cell-specificAngpt-2 gene knock out mice. To study the role of Angpt-2, we will investigate the changes intubular injury, inflammation, fibrosis, and capillary rarefaction by using this geneticallymodified mice or by treating wide-type mice with Angpt-2 antagonist L1-10 systemicallyafter ischemia-reperfusion-induced AKI. In the third year, we plan to set up a bone marrowchimerism model with green fluorescent protein (GFP)-bearing bone marrow cells to traceendothelial progenitor cells. Therefore, we could investigate the effects of Angpt-2 on theendothelial progenitor cells after ischemia-reperfusion-induced AKI in tubular epithelial cellspecificAngpt-2 knock out mice recipient transplanted with GFP-bearing bone marrow cells.We expect that data obtained from this project will further enhance our understandingconcerning the pathogenetic role of Angpt-2 and develop therapeutic strategies against thegradual kidney function decline after AKI.急性腎損傷血管生成第二型血管生成素血管內皮細胞纖維化發炎 反應Acute kidney injuryAngiogenesisAngiopoietin 2Endothelial cellFibrosisInflammation