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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
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dc.contributor.advisor | 楊鎧鍵 | zh_TW |
dc.contributor.advisor | Kai-Chien Yang | en |
dc.contributor.author | 趙珮宇 | zh_TW |
dc.contributor.author | Pei-Yu Jhao | en |
dc.date.accessioned | 2021-07-10T22:08:24Z | - |
dc.date.available | 2024-02-28 | - |
dc.date.copyright | 2018-10-09 | - |
dc.date.issued | 2018 | - |
dc.date.submitted | 2002-01-01 | - |
dc.identifier.citation | 1. Biesen WV, Vanholder R and Lameire N. Defining acute renal failure: RIFLE and beyond. Clin J Am Soc Nephrol. 2006 Nov;1:1314-1319.
2. Schiffl H. Renal recovery from acute tubular necrosis requiring renal replacement therapy: a prospective study in critically ill patients. Nephrology Dialysis Transplantation. 2006 May;21:1248-1252. 3. Liaño F, Felipe C, Tenorio MT, Rivera M, Abraira V, Sáez-de-Urturi JM, Ocaña J, Fuentes C and Severiano S. Long-term outcome of acute tubular necrosis: A contribution to its natural history. Kidney International. 2007;71:679-686. 4. Myers BD and Moran SM. Hemodynamically Mediated Acute Renal Failure. New England Journal of Medicine. 1986;314:97-105. 5. Bucaloiu ID, Kirchner HL, Norfolk ER, Hartle JE and Perkins RM. Increased risk of death and de novo chronic kidney disease following reversible acute kidney injury. Kidney International. 2012;81:477-485. 6. Schmitt R, Coca S, Kanbay M, Tinetti ME, Cantley LG and Parikh CR. Recovery of Kidney Function After Acute Kidney Injury in the Elderly: A Systematic Review and Meta-analysis. American Journal of Kidney Diseases. 2008;52:262-271. 7. Waikar SS and Bonventre JV. Chapter 279. Acute Kidney Injury. In: D. L. Longo, A. S. Fauci, D. L. Kasper, S. L. Hauser, J. L. Jameson and J. Loscalzo, eds. Harrison's Principles of Internal Medicine, 18e New York, NY: The McGraw-Hill Companies; 2012. 8. Bock JS and Gottlieb SS. Cardiorenal syndrome: new perspectives. Circulation. 2010;121:2592-2600. 9. Esson ML and Schrier RW. DIagnosis and treatment of acute tubular necrosis. Annals of Internal Medicine. 2002;137:744-752. 10. Ton J. Rabelink, Hetty C. de Boer and Zonneveld AJv. Endothelial activation and circulating markers of endothelial activation in kidney disease. Nature Reviews Nephrology. 2010 Jul;6:404-414. 11. Kelly KJ, Williams WW, Colvin RB, Meehan SM, Springer TA, Gutierrez-Ramos JC and Bonventre JV. Intercellular adhesion molecule-1-deficient mice are protected against ischemic renal injury. Journal of Clinical Investigation. 1996;97:1056-1063. 12. Bonventre JV and Zuk A. Ischemic acute renal failure: An inflammatory disease? Kidney International. 2004;66:480-485. 13. Joseph V. Bonventre and Yang L. Cellular pathophysiology of ischemic acute kidney injury. J Clin Invest. 2011 Nov;121:4210-4221. 14. Gailit J, Colflesh D, Rabiner I, Simone J and Goligorsky MS. Redistribution and dysfunction of integrins in cultured renal epithelial cells exposed to oxidative stress. American Journal of Physiology-Renal Physiology. 1993;264:F149-F157. 15. Zuk A, Bonventre JV and Matlin KS. Expression of fibronectin splice variants in the postischemic rat kidney. American Journal of Physiology-Renal Physiology. 2001;280:F1037-F1053. 16. Coca SG, Yusuf B, Shlipak MG, Garg AX and Parikh CR. Long-term Risk of Mortality and Other Adverse Outcomes After Acute Kidney Injury: A Systematic Review and Meta-analysis. American Journal of Kidney Diseases. 2009;53:961-973. 17. Basile DP. The endothelial cell in ischemic acute kidney injury: implications for acute and chronic function. Kidney International. 2007;72:151-156. 18. Yang L, Besschetnova TY, Brooks CR, Shah JV and Bonventre JV. Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury. Nature medicine. 2010;16:535-143. 19. LinChen and Yang T. Central role of dysregulation of TGF-β/Smad in CKD progression and potential targets of its treatment. Biomedicine & Pharmacotherapy. 2018;101:670-681. 20. Webster AC, Nagler EV, Morton RL and Masson P. Chronic Kidney Disease. The Lancet. 2017;389:1238-1252. 21. Meng XM, Nikolic-Paterson DJ and Lan HY. TGF-β : The master regulator of fibrosis. Nature Reviews Nephrology. 2016;12:325-338. 22. Sureshbabu A, Muhsin SA and Choi ME. TGF-β signaling in the kidney: profibrotic and protective effects. American Journal of Physiology - Renal Physiology. 2016;310:F596-F606. 23. Alexander RP, Fang G, Rozowsky J, Snyder M and Gerstein MB. Annotating non-coding regions of the genome. Nature Reviews Genetics. 2010;11:559. 24. Uchida S and Dimmeler S. Long Noncoding RNAs in Cardiovascular Diseases. Circulation Research. 2015;116:737. 25. Wang KC and Chang HY. Molecular mechanisms of long noncoding RNAs. Molecular cell. 2011;43:904-914. 26. Xu S, Sankar S and Neamati N. Protein disulfide isomerase: a promising target for cancer therapy. Drug Discovery Today. 2014;19:222-240. 27. Benham AM. The Protein Disulfide Isomerase Family: Key Players in Health and Disease. Antioxidants & Redox Signaling. 2012;16:781-789. 28. Shih Y-C, Chen C-L, Zhang Y, Mellor RL, Kanter EM, Fang Y, Wang H-C, Hung C-T, Nong J-Y, Chen H-J, Lee T-H, Tseng Y-S, Chen C-N, Wu C-C, Lin S-L, Yamada KA, Nerbonne JM and Yang K-C. Endoplasmic Reticulum Protein TXNDC5 Augments Myocardial Fibrosis by Facilitating Extracellular Matrix Protein Folding and Redox-Sensitive Cardiac Fibroblast Activation. Circulation Research. 2018;122:1052-1068. 29. Horna-Terrón E, Pradilla-Dieste A, Sánchez-de-Diego C and Osada J. TXNDC5, a Newly Discovered Disulfide Isomerase with a Key Role in Cell Physiology and Pathology. International Journal of Molecular Sciences. 2014;15. 30. Montgomery TA, Xu L, Mason S, Chinnadurai A, Lee CG, Elias JA and Cantley LG. Breast Regression Protein–39/Chitinase 3–Like 1 Promotes Renal Fibrosis after Kidney Injury via Activation of Myofibroblasts. Journal of the American Society of Nephrology. 2017;28:3218-3226. 31. Chen X, Nadiarynkh O, Plotnikov S and Campagnola PJ. Second harmonic generation microscopy for quantitative analysis of collagen fibrillar structure. Nature Protocols. 2012;7:654. 32. Richter K and Kietzmann T. Reactive oxygen species and fibrosis: further evidence of a significant liaison. Cell and Tissue Research. 2016;365:591-605. 33. Sedeek M, Nasrallah R, Touyz RM and Hebert RL. NADPH oxidases, reactive oxygen species, and the kidney: friend and foe. J Am Soc Nephrol. 2013;24:1512-8. 34. Buckley CD, Pilling D, Lord JM, Akbar AN, Scheel-Toellner D and Salmon M. Fibroblasts regulate the switch from acute resolving to chronic persistent inflammation. Trends in Immunology. 2001;22:199-204. 35. Bratton DL and Henson PM. Neutrophil Clearance: when the party’s over, cleanup begins. Trends in immunology. 2011;32:350-357. 36. Murray PJ and Wynn TA. Protective and pathogenic functions of macrophage subsets. Nature reviews Immunology. 2011;11:723-737. 37. Verrecchia F and Mauviel A. Transforming growth factor-β and fibrosis. World Journal of Gastroenterology : WJG. 2007;13:3056-3062. 38. Wynn TA. FIBROTIC DISEASE AND THE T(H)1/T(H)2 PARADIGM. Nature reviews Immunology. 2004;4:583-594. | - |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/77553 | - |
dc.description.abstract | 患有急性腎損傷的患者,即使功能完全恢復,也會增加未來發展成慢性腎病(CKD)和腎功能衰竭的風險。然而腎臟纖維化是導致發生CKD的主要因素,發生CKD後不論是死亡率或是發生其他疾病的共病率都很高。在腎臟纖維化最常見的腎小管間質纖維化中,主要是因為腎臟纖維母細胞的活化、累積過量的細胞外基質(ECM)所導致的。然而目前在臨床上並沒有有效的方法來治療或逆轉腎纖維化,因此我們想找到新的有效目標來治療腎臟纖維化。
我們實驗室最近發現了一種長鏈非編碼核醣核酸 Lnc-fibrogen及其宿主基因內質網蛋白TXNDC5是參與心臟纖維化過程的重要因子。因此本研究的目的是想探討Lnc-fibrogen和TXNDC5是否也參與腎纖維化和CKD。本篇主要使用小鼠單側缺血再灌流損傷(uIRI)誘導的CKD模型,發現腎臟損傷14天後Lnc-fibrogen和Txndc5的基因表現都顯著增加,除此之外ECM相關基因表現包括Col1a1,Col3a1,Ctgf和Eln也隨之增加。另外我們也利用Lnc-fibrogen以及Txndc5基因剔除小鼠進行實驗,發現手術過後受損腎臟的纖維化有顯著改善,並且也產生較少的ECM蛋白。此外,我們發現uIRI誘導的TXNDC5表現增加會去影響下游活化JNK、P38 signaling,而剔除Txndc5之後JNK、P38的活化也會受到抑制。綜合實驗結果,可以證明Lnc-fibrogen及其宿主基因TXNDC5是促進損傷後腎纖維化的關鍵因素。TXNDC5主要是透過活化JNK以及P38 signaling活化腎臟纖維母細胞並促進ECM產生。因此,Lnc-fibrogen和TXNDC5可作為腎臟纖維化治療或預防的新型標的。 | zh_TW |
dc.description.abstract | Patients who had acute kidney injury, even with complete functional recovery, are at increased risk of chronic kidney disease (CKD) and renal failure. CKD is a major cause of morbidity and mortality, and renal fibrosis is an important and common pathway leading to the progression of CKD. Renal fibroblast activation, accumulation and excessive extracellular matrix (ECM) production are the key events leading to renal tubulointerstitial fibrosis. Currently, there is no effective therapy to treat or reverse renal fibrosis, and it is critical to identify novel mediators of renal fibrosis to develop potential new therapeutics.
Our laboratory has recently identified a long non-coding RNA Lnc-fibrogen and its host gene thioredoxin domain containing 5 (TXNDC5), an ER-resident protein with the enzyme activity of protein disulfide isomerase, as critical mediators of cardiac fibrosis. The goal of this study was to test the hypothesis that Lnc-fibrogen and TXNDC5 could also be involved in the pathogenesis of renal fibrosis and CKD. Using a mouse model of unilateral ischemia reperfusion injury (uIRI)-induced CKD, we have revealed that Lnc-fibrogen and Txndc5 transcripts were both highly upregulated in mouse fibrotic kidney 14 days after uIRI; the expression levels of Txndc5 also showed strong positive correlation with those of fibrogenic protein genes including Col1a1, Col3a1, Ctgf and ELN. Mice with targeted deletion of Lnc-fibrogen or Txndc5 developed less fibrosis, and produced less ECM proteins in the kidneys following uIRI. Furthermore, we found uIRI-induced increased TXNDC5 levels in renal fibroblasts were accompanied with activated JNK and P38 signaling, whereas Txndc5 knockout abrogated uIRI-induced JNK and P38 activation in renal fibroblasts. Taken together, our data suggest that Lnc-fibrogen and its host gene TXNDC5 are both critical mediators for the development of post-injury renal fibrosis. TXNDC5 promotes renal fibroblast activity and ECM production through activating profibrotic JNK and P38 signaling. Targeting Lnc-fibrogen and TXNDC5, therefore, could be a potential novel therapeutic approach to treat or prevent CKD. | en |
dc.description.provenance | Made available in DSpace on 2021-07-10T22:08:24Z (GMT). No. of bitstreams: 1 ntu-107-R05443009-1.pdf: 4669779 bytes, checksum: 9ff7c3cc8367d05e051aeb492057b4ac (MD5) Previous issue date: 2018 | en |
dc.description.tableofcontents | 中文摘要 2
Abstract 3 Table of Contents 5 List of Figures 7 List of Tables 8 Abbreviation Table 9 CHAPTER 1 INTRODUCTION 11 1.1 Acute kidney injury(AKI) and Chronic kidney disease(CKD) 11 1.1.1 Etiology of acute kidney injury 11 1.1.2 The mechanisms of acute kidney injury 13 1.1.3 The progression of AKI to CKD transition 14 1.1.4 Chronic kidney disease and kidney fibrosis 15 1.1.5 The role of transforming growth factor-β1 (TGF-β1) in CKD 15 1.2 Long non-coding RNA (LncRNA) 16 1.2.1 Functions of Long non-coding RNAs 16 1.2.2 Identification of long non-coding RNA Lnc-Fibrogen as a critical mediator of cardiac fibrosis 17 1.3 Protein disulfide isomerase(PDI) 18 1.3.1 Thioredoxin domain containing 5 (TXNDC5) 18 1.4 Aims of the study 19 CHAPTER 2 Materials and Methods 20 2.1 Generation of Lnc-fibrogen and Txndc5 knockout (KO) mice using CRISPR/Cas9 genome-editing technology 20 2.2 Unilateral ischemia reperfusion injury-induced kidney fibrosis 21 2.3 Ngal Elisa assay 21 2.4 Histology 22 2.4.1 immunohistochemistry staining 22 2.4.2 Masson’s Trichrome 23 2.4.3 Picrosirius Red staining 23 2.5 Second Harmonic Generation(SHG) 24 2.6 RNA extraction and qRT-PCR 25 2.7 Western blot analysis 25 2.8 Immunofluorescent staining for tissue sections 26 2.9 Statistical analyses 27 CHAPTER 3 Results-The role of TXNDC5 in AKI to CKD transition 28 3.1 TXNDC5 was increased in the kidney tissues from CKD, but not AKI, patients 28 3.2 TXNDC5 is highly upregulated in mouse kidney tissue with unilateral IRI and strongly enriched in fibrotic areas 28 3.3 TXNDC5 was highly co-localized with collagen-secreting pericytes in the kidneys 29 3.4 Deletion of Txndc5 didn’t impact the severity of kidney injury 30 3.5 Targeted deletion of Txndc5 attenuated renal fibrosis, ECM production and renal inflammation in response to uIRI 31 3.6 Txndc5 deletion attenuates uIRI-induced fibrogenic protein upregulation 32 3.7 JNK and P38, two non-canonical TGF-β signaling molecules, are involved in the fibrogenic effects mediated by TXNDC5 33 3.8 Txndc5 deletion attenuated JNK and P38 activation/phosphorylation in renal pericytes following uIRI 34 CHAPTER 4 Results- The role of Lnc-fibrogen in AKI to CKD transition 36 4.1 Lnc-fibrogen is highly expressed in mice unilateral IRI Injured-kidney 36 4.2 Deletion of Lnc-fibrogen did not impact the severity of acute kidney injury but alleviated the persistent kidney injury following uIRI 36 4.3 Lnc-fibrogen is sufficient to kidney fibrosis by inhibiting the expression of ECM-related and inflammatory-related genes 37 CHAPTER 5 Discussion 39 5.1 Conditional knockout of Txndc5 and Lnc-fibrogen to determine the contribution to specific cell type 39 5.2 Investigate the downstream mechanisms of TGF-β and ROS-mediated kidney fibrosis in kidney fibroblast. 39 5.3 The interaction between fibroblasts and inflammatory cells 41 Reference 43 Figures 46 Appendix 72 | - |
dc.language.iso | zh_TW | - |
dc.title | 長鏈非編碼核醣核酸Lnc-fibrogen及內質網蛋白TXNDC5在急性腎損傷到慢性腎病變的角色 | zh_TW |
dc.title | The role of Lnc-fibrogen and ER protein TXNDC5 in acute kidney injury to chronic kidney disease | en |
dc.type | Thesis | - |
dc.date.schoolyear | 106-2 | - |
dc.description.degree | 碩士 | - |
dc.contributor.oralexamcommittee | 林水龍;姜文智 | zh_TW |
dc.contributor.oralexamcommittee | Shuei-Liong Lin;Wen-Chih Chiang | en |
dc.subject.keyword | 急性腎損傷,慢性腎病變,腎臟纖維化,內質網蛋白TXNDC5,長鏈非編碼核醣核酸Lnc-fibrogen,TGF-β signaling,小鼠單側缺血再灌流損傷, | zh_TW |
dc.subject.keyword | Acute kidney injury,Chronic kidney disease,Kidney fibrosis,Thioredoxin domain containing 5 (TXNDC5),Long noncoding RNA Lnc-fibrogen,TGF-β signaling,unilateral ischemia injury, | en |
dc.relation.page | 74 | - |
dc.identifier.doi | 10.6342/NTU201802663 | - |
dc.rights.note | 未授權 | - |
dc.date.accepted | 2018-08-09 | - |
dc.contributor.author-college | 醫學院 | - |
dc.contributor.author-dept | 藥理學研究所 | - |
顯示於系所單位: | 藥理學科所 |
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