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系統識別號 U0026-2708201914185400
論文名稱(中文) 探討MIF在IS誘發的EMT現象所扮演的角色
論文名稱(英文) Role of macrophage migration inhibitory factor in the indoxyl sulfate-induced epithelial–mesenchymal transition
校院名稱 成功大學
系所名稱(中) 醫學檢驗生物技術學系
系所名稱(英) Department of Medical Laboratory Science and Biotechnology
學年度 107
學期 2
出版年 108
研究生(中文) 許詠婷
研究生(英文) Yong-Ting Syu
學號 T36061081
學位類別 碩士
語文別 英文
論文頁數 55頁
口試委員 指導教授-葉才明
口試委員-陳浩仁
口試委員-莊詠鈞
中文關鍵字 慢性腎臟病  上皮間質轉化  硫酸吲哚  巨噬細胞移動抑制因子  活性氧化物質 
英文關鍵字 CKD  EMT  IS  MIF  ROS 
學科別分類
中文摘要 慢性腎臟病 (CKD)是全世界特別是在已開發國家的一種嚴重疾病。腎臟纖維化的過程中,腎臟上皮細胞失去其細胞間的黏附能力,並轉換成間質細胞,而這個過程稱之為上皮間質轉化(EMT)。目前針對於CKD的治療,並沒有一種有效的方法,主要是利用一些輔助性治療或者通過透析移除有害物質。硫酸吲哚 (IS) 是一種難以利用透析方式移除的尿毒素,且IS在血液中含量與CKD的嚴重程度呈現正相關性,先前的研究表明,IS 會誘導細胞產生活性氧化物質 (ROS) 並導致EMT 現象的發生。巨噬細胞移動抑制因子 (MIF) 是一個會參與在各種發炎性疾病的促發炎細胞因子。先前的研究也顯示,CKD的病患血液中的MIF 含量比起一般人要來的高。然而,MIF 在 CKD 扮演的角色作用尚不清楚。在我們的研究中,我們提出 MIF 可能參與在 IS 誘導EMT 現象的假設。我們使用不同劑量的 IS 去刺激近端小管上皮細胞 HK-2 ,並分別加入MIF 抑制劑 (ISO-1, 4-IPP) 或未加入抑制劑的組別。我們也使用西方墨點法檢測EMT 的變化 (E-鈣粘蛋白的減少和α-平滑肌肌動蛋白的增加) 。通過酵素免疫分析法 (ELISA) 測定MIF 分泌的情形。而ROS 的產生則是利用流式細胞儀做檢測。首先,我們發現 IS 可誘導HK-2細胞發生EMT 的現象,也能刺激細胞 MIF 的分泌和產生ROS。此外,我們使用MIF 的抑制劑治療後,發現抑制劑的組別會惡化IS 所誘導的 EMT 現象。另一方面,我們發現MIF重組蛋白(rMIF) 不會誘導細胞發生EMT 的現象。而且ROS 的抑制劑 (NAC)可以減少IS 誘發出的MIF 分泌,且減緩EMT 的變化。進一步,我們發現 MIF也能夠通過減少ROS 的產生來減緩EMT 的現象。通過上面的結果表明,MIF 可能在IS 誘導EMT 現象中扮演保護因子的角色
英文摘要 Chronic kidney disease (CKD) is a serious disease in the whole world especially in developed countries. In the process of renal fibrosis, epithelial cells lose cell-cell adhesion to become mesenchymal cells (epithelial–mesenchymal transition, EMT). Currently, there are no effective treatments, and only supportive treatments or dialysis available for CKD. Indoxyl sulfate (IS) is a kind of uremic toxin which cannot be removed by dialysis, and its level is positively correlated with CKD stage. Previous study has shown that IS could induce EMT through ROS production in epithelial cells. Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine involved in various inflammatory disease. Previous studies have shown that the levels of MIF secretion in CKD patients are higher than normal people. However, the role of MIF in CKD development is unclear. In this study, we propose and test the hypothesis that MIF is involved in IS-induced EMT of kidney epithelial cells. Proximal tubule epithelial cells HK-2 were stimulated with different dose of IS with or without MIF inhibitors (ISO-1 and 4-IPP). Western blot was used to monitor the EMT changes (decrease of E-cadherin and increase of alpha-smooth muscle actin). The MIF secretion was determined by enzyme-linked immunosorbent assay (ELISA).The ROS generation was detected by flow cytometry. First, we found that IS could induce EMT changes, MIF secretion and ROS production in HK-2 cells. Furthermore, treatment of MIF inhibitors could worse of IS-induced EMT. In addition, recombinant MIF (rMIF) could not induce EMT in HK-2. However, the ROS scavenger (NAC) could reduce MIF secretion and EMT change. Moreover, treatment of rMIF could reduce EMT by decreasing ROS production. Taken together, these results suggest that MIF is involved in IS-induced EMT of kidney epithelial cells and MIF probably is a protector in IS-induced EMT
論文目次 中文摘要 I
Abstract II
Acknowledgement III
Table of contents IV
List of figures VII
Abbreviations Index VIII
1. Introduction 1
1.1 Chronic Kidney Disease (CKD) 1
1.1.1 CKD: Prevalence, cause, symptoms, and treatments 1
1.1.2. The inflammation in CKD 2
1.1.3. The difficulty of treatment to CKD 2
1.2. Indoxyl Sulfate (IS) 3
1.2.1. The metabolism of IS 3
1.2.2. The receptors of IS 4
1.2.3. The effects of IS in the body 5
1.3. Epithelial-Mesenchymal transition (EMT) 5
1.3.1. Characteristics of EMT 5
1.3.2. The role of EMT in CKD 7
1.4. Reactive Oxygen Species (ROS) 7
1.5. Macrophage migration inhibitor factor (MIF) 7
1.5.1. The function of MIF 7
1.5.2. The signal and pathway of MIF 8
1.5.3. The involvement of MIF in disease 8
2. Objective and Specific Aims 9
2.1 To observe the effect of indoxyl sulfate treatment in HK-2 cell 9
2.2. To identify the role of MIF in IS-induced EMT in HK-2 cell 9
2.3. To identify the role of MIF in IS-induced ROS in HK-2 cell 9
3.1. Material 10
3.1.1 Cell lines 10
3.1.2. Recombinant Protein 10
3.1.3. Reagents 10
3.1.4Antibodies 11
3.1.5. ELISA kits 12
3.1.5. Consumables 12
3.1.6. Instruments 13
3.2. Methods 14
3.2.1. Cell culture 14
3.2.2. MTT assay 14
3.2.3. LDH assay 14
3.2.4. Cytokine measurement 14
3.2.5. Protein prepare and SDS-PAGE 15
3.2.6. Western Blot 15
3.2.7. Flow cytometry 16
3.2.8. Statistical analysis 16
4. Result 17
4.1 Indoxyl sulfate induces cytotoxicity in proximal tubule epithelial cell (HK-2) 17
4.2 Indoxyl sulfate induces EMT which is blocked by IS receptor inhibitors. 17
4.3. Indoxyl sulfate induces MIF secretion which is blocked by IS receptor inhibitors 18
4.4. MIF is a protector in IS-induced EMT 18
4.5. Indoxyl sulfate induces ROS production which is blocked by IS receptor and ROS scavenger 19
4.6. ROS scavenger reduced IS-induced MIF secretion and EMT 19
4.7. MIF regulated IS-induced ROS production 20
5. Discussion 21
6. Conclusion 24
7. References 25
8. Figures 38
9. Appendix 55

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