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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 林水龍(Shuei-Liong Lin) | |
dc.contributor.author | Shun-Yang Cheng | en |
dc.contributor.author | 鄭舜陽 | zh_TW |
dc.date.accessioned | 2021-06-15T13:24:01Z | - |
dc.date.available | 2018-08-26 | |
dc.date.copyright | 2016-08-26 | |
dc.date.issued | 2016 | |
dc.date.submitted | 2016-06-22 | |
dc.identifier.citation | 1. Himmelfarb, J., et al., Acute kidney injury: changing lexicography, definitions, and epidemiology. Kidney Int, 2007. 71(10): p. 971-6.
2. Devarajan, P., Biomarkers for the Early Detection of Acute Kidney Injury. Curr Opin Pediatr, 2011. 23(2): p. 194-200. 3. Xue, J.L., et al., Incidence and mortality of acute renal failure in Medicare beneficiaries, 1992 to 2001. J Am Soc Nephrol, 2006. 17(4): p. 1135-42. 4. Feest, T.G., et al., Incidence of severe acute renal failure in adults: results of a community based study. BMJ, 1993. 306(6876): p. 481-483. 5. Hoste, E.A., et al., RIFLE criteria for acute kidney injury are associated with hospital mortality in critically ill patients: a cohort analysis. Crit Care, 2006. 10(3): p. R73. 6. Goldberg, R., et al., Long-Term Outcomes of Acute Kidney Injury. Adv Chronic Kidney Dis, 2008. 15(3): p. 297-307. 7. Mehta, R.L., et al., Spectrum of acute renal failure in the intensive care unit: The PICARD experience. Kidney Int, 2004. 66(4): p. 1613-1621. 8. Ishani, A., et al., Acute kidney injury increases risk of ESRD among elderly. J Am Soc Nephrol, 2009. 20(1): p. 223-8. 9. Chawla, L.S., Acute Kidney Injury Leading to Chronic Kidney Disease and Long-Term Outcomes of Acute Kidney Injury:The Best Opportunity to Mitigate Acute Kidney Injury? Contrib Nephrol., 2011. 174: p. 182-190. 10. Amdur, R.L., et al., Outcomes following diagnosis of acute renal failure in U.S. veterans: focus on acute tubular necrosis. Kidney Int, 2009. 76(10): p. 1089-97. 11. Lo, L.J., et al., Dialysis-requiring acute renal failure increases the risk of progressive chronic kidney disease. Kidney Int, 2009. 76(8): p. 893-899. 12. Chawla, L.S., et al., The severity of acute kidney injury predicts progression to chronic kidney disease. Kidney Int, 2011. 79(12): p. 1361-9. 13. Lai, C.-F., et al., Kidney function decline after a non-dialysis-requiring acute kidney injury is associated with higher long-term mortality in critically ill survivors. Critical Care, 2012. 16(4): p. R123-R123. 14. Nagel, T., et al., Shear stress selectively upregulates intercellular adhesion molecule-1 expression in cultured human vascular endothelial cells. J Clin Invest., 1994. 94(2): p. 885-891. 15. John, Y.-J., et al., The cis-acting phorbol ester '12-0-tetradecanoylphorbol 13-acetate'-responsive element is involved in shear stress-induced monocyte chemotactic protein 1 gene expression. PNAS, 1995. 92(17): p. 8069-8073,. 16. Ingram, A.J., et al., Activation of mesangial cell signaling cascades in response to mechanical strain. Kidney Int, 1999. 55(2): p. 476-485. 17. Riser, B.L., et al., Intraglomerular pressure and mesangial stretching stimulate extracellular matrix formation in the rat. J Clin Invest., 1992. 90(5): p. 1932-1943. 18. Riser, B.L., et al, Cyclic Stretching Force Selectively Up-Regulates Transforming Growth Factor-f3 Isoforms in Cultured Rat Mesangial Cells. American journal of Pathology, 1996. 148(6):p. 1915-1923. 19. Riser, B.L., et al, TGF-B receptor expression and binding in rat mesangial cells: Modulation by glucose and cyclic mechanical strain. Kidney Int, 1999. 56(2):p. 428-439. 20. Riser, B.L., et al, Regulation of Connective Tissue Growth Factor Activity in Cultured Rat Mesangial Cells and Its Expression in Experimental Diabetic Glomerulosclerosis. J Am Soc Nephrol, 2000. 11(1): p. 25-38. 21. Becker, B.N., et al., Mechanical Stretch/Relaxation Stimulates a Cellular Renin-Angiotensin System in Cultured Rat Mesangial Cells. Exp Nephrol, 1998. 6(1): p. 57-66. 22. Kagami, S., et al., Angiotensin II stimulates extracellular matrix protein synthesis through induction of transforming growth factor-beta expression in rat glomerular mesangial cells. J Clin Invest, 1994. 93(6): p. 2431-7. 23. Durvasula, R.V., et al., Podocyte injury and targeting therapy: an update. Curr Opin Nephrol Hypertens 2006. 15(1): p. 1-7. 24. Yu, D., et al., Urinary podocyte loss is a more specific marker of ongoing glomerular damage than proteinuria. J Am Soc Nephrol, 2005. 16(6): p. 1733-41. 25. Durvasula, R.V., et al., Activation of a local tissue angiotensin system in podocytes by mechanical strain1. Kidney Int., 2004. 65(1): p. 30-39. 26. Border, W.A. and N.A. Noble, Fibrosis linked to TGF-beta in yet another disease. J Clin Invest, 1995. 96(2): p. 655-6. 27. Isaka, Y., et al., Glomerulosclerosis induced by in vivo transfection of transforming growth factor-beta or platelet-derived growth factor gene into the rat kidney. J Clin Invest, 1993. 92(6): p. 2597-601. 28. Leonard L. Wu, et al., Transformin growth factorf31 and renal injury folowing subtotal nephrectomy in the rat Role of the renin-angiotensin system. Kidney Int, 1997. 51(5): p. 1553-1567. 29. Taal, M.W., et al., Proinflammatory gene expression and macrophage recruitment in the rat remnant kidney. Kidney International, 2000. 58(4): p. 1664-1676. 30. Lavoie, P., et al., Neutralization of transforming growth factor-[beta] attenuates hypertension and prevents renal injury in uremic rats. J Hypertens., 2005. 23(10): p. 1895–1903. 31. Ruiz-Ortega M, et al., Angiotensin II Participates in Mononuclear Cell Recruitment in Experimental Immune Complex Nephritis Through Nuclear Factor-κB Activation and Monocyte Chemoattractant Protein-1 Synthesis. J Immunol 1998. 161(1): p. 430-439. 32. Osamu Takase, et al., NF-jB–dependent increase in intrarenal angiotensin II induced by proteinuria. Kidney Int, 2005. 68(2): p. 464–473. 33. Hahn AW, et al., Activation of human peripheral monocytes by angiotensin II. FEBS Lett., 1994. 347(2-3): p. 178-180. 34. Fujimoto, S., et al., Olmesartan Ameliorates Progressive Glomerular Injury in Subtotal Nephrectomized Rats through Suppression of Superoxide Production. Hypertens Res, 2008. 31(2): p. 305-313. 35. Ozawa, Y., et al., Sustained renal interstitial macrophage infiltration following chronic angiotensin II infusions. Am J Physiol Renal Physiol, 2007. 292(1): p. F330-9. 36. Abbate, M., C. Zoja, and G. Remuzzi, How does proteinuria cause progressive renal damage? J Am Soc Nephrol, 2006. 17(11): p. 2974-84. 37. Kobori, H., et al., The intrarenal renin-angiotensin system: from physiology to the pathobiology of hypertension and kidney disease. Pharmacol Rev, 2007. 59(3): p. 251-87. 38. Kimbrough, HM., et al ., Effect of Intrarenal Angiotensin II Blockade on Renal Function in Conscious Dogs. Circ Res., 1977. 40(2): p. 174-8. 39. Kang, J.J., et al., The collecting duct is the major source of prorenin in diabetes. Hypertension, 2008. 51(6): p. 1597-604. 40. Atlas, S.A., The Renin-Angiotensin Aldosterone System: Pathophysiological Role and Pharmacologic Inhibition. J Manag Care Pharm., 2007. 13(8 Suppl B):p. 9-20 41. Prieto-Carrasquero, M.C., et al., AT1 receptor-mediated enhancement of collecting duct renin in angiotensin II-dependent hypertensive rats. Am J Physiol Renal Physiol, 2005. 289(3): p. F632-7. 42. Kobori, H., et al., Young Scholars Award Lecture: Intratubular angiotensinogen in hypertension and kidney diseases. Am J Hypertens, 2006. 19(5): p. 541-50. 43. Robert, M., et al., Role of the Angiotensin Type 2 Receptor in the Regulation of Blood Pressure and Renal Function. Hypertension, 2000. 35 (1 Pt 2): p. 155-163. 44. Huang, X.R., et al., Chymase Is Upregulated in Diabetic Nephropathy: Implications for an Alternative Pathway of Angiotensin II-Mediated Diabetic Renal and Vascular Disease. J Am Soc Nephrol, 2003. 14(7): p. 1738-1747. 45. Edmund, J., et al., The Effect of Angiotensin-Converting-Enzyme Inhibition on Diabetic Nephropathy. N Engl J Med 1993. 329: p. 1456-1462. 46. The GISEN Group., Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. Lancet, 1997. 349(9069): p. 1857-1863. 47. Lewis, E.J., et al., Renoprotective Effect of the Angiotensin-Receptor Antagonist Irbesartan in Patients with Nephropathy Due to Type 2 Diabetes. N Engl J Med, 2001. 345(12): p. 851-860. 48. Ruster, C. and G. Wolf, Renin-angiotensin-aldosterone system and progression of renal disease. J Am Soc Nephrol, 2006. 17(11): p. 2985-91. 49. Siragy, H.M. and Carey, R.M., Role of the intrarenal renin-angiotensin-aldosterone system in chronic kidney disease. Am J Nephrol, 2010. 31(6): p. 541-50. 50. Perazella, M.A. and Coca, S.G., Three feasible strategies to minimize kidney injury in 'incipient AKI'. Nat Rev Nephrol, 2013. 9(8): p. 484-90. 51. Balasubramanian, G., et al., Early Nephrologist Involvement in Hospital-Acquired Acute Kidney Injury: A Pilot Study. Am J Kidney Dis, 2011. 57(2): p. 228-234. 52. Ronco, C. and M.H. Rosner, Acute kidney injury and residual renal function. Crit Care, 2012. 16(4): p. 144. 53. Yang, L., et al., Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury. Nat Med, 2010. 16(5): p. 535-543. 54. Yang, L., et al., Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury. Nat Med, 2010. 16(5): p. 535-43, 1p following 143. 55. Wang, Q., Blood Pressure, Cardiac, and Renal Responses to Salt and Deoxycorticosterone Acetate in Mice: Role of Renin Genes. J Am Soc Nephrol, 2002. 13(6): p. 1509-1516. 56. Chang, F.C., et al., Angiopoietin-2-induced arterial stiffness in CKD. J Am Soc Nephrol, 2014. 25(6): p. 1198-209. 57. Ma, L.J. and A.B. Fogo, Model of robust induction of glomerulosclerosis in mice: Importance of genetic background. Kidney Int., 2003. 64(1): p. 350-355. 58. Ko, G.J., et al., Transcriptional analysis of kidneys during repair from AKI reveals possible roles for NGAL and KIM-1 as biomarkers of AKI-to-CKD transition. Am J Physiol Renal Physiol, 2010. 298(6): p. F1472-83. 59. Humphreys, B.D., et al., Intrinsic Epithelial Cells Repair the Kidney after Injury. Cell Stem Cell, 2008. 2(3): p. 284-291. 60. Endo, T., et al., Exploring the origin and limitations of kidney regeneration. J Pathol, 2015. 236(2): p. 251-63. 61. Venkatachalam, M.A., et al., Failed Tubule Recovery, AKI-CKD Transition, and Kidney Disease Progression. J Am Soc Nephrol, 2015. 26(8): p. 1765-76. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/51025 | - |
dc.description.abstract | 許多臨床研究上的證據顯示,急性腎損傷是造成慢性腎臟病的發生,以及造成其惡化的重要風險因子。慢性腎臟病,除了會演變成末期腎臟病外,也會增加心血管疾病跟死亡的風險,從臨床研究上發現,不管急性腎損傷嚴重與否,都會提高未來發展成慢性腎臟病的機率。直到今日,關於急性腎損傷進展成慢性腎臟病的機制,仍然不清楚,也因此,在我們的研究中,我們建立了動物模型,用來研究在急性腎損傷發生,腎功能完全回復後,是透過什麼機制,進一步進展成慢性腎臟病並使其惡化。在我們的實驗中,首要目標,是建立能觀察到,因為急性腎損傷,而發展成慢性腎臟病的動物模型,我們採用CD-1八週大的公鼠,先將其右側的腎臟切除,在切除後兩週,於控制老鼠體溫於攝氏37度的環境下,利用微小的動脈夾,夾住左側腎臟血管28分鐘,使左側腎臟遭受缺血後再灌流的傷害,在傷害後兩天,小鼠血液中的尿素氮和肌酸酐的數值,都會顯著上升,在傷害後14天,約有20%的小鼠會死亡,活下來的小鼠,在傷害後一個月,其血液中尿素氮和肌酸酐濃度,都會回復到與只有單側腎切除以及假手術的組別無異的程度,但在這些受傷害小鼠,於傷害後一個月的腎臟組織切片中,發現到局部性的腎小管萎縮、腎間質有細胞浸潤,以及腎臟纖維化等異常的狀況,另外也觀察到腎臟內有些基因表現量發生改變,如第一、第三型膠原纖維、平滑肌動蛋白、腎損傷分子、嗜中性白血球明膠酶相關運載蛋白、第一型血管張力素受器、血管收縮素原等基因的表現量,都顯著上升,且在術後五個月的小鼠身上發現,其血壓會上升,尿液中微白蛋白/肌酸酐比值(蛋白尿)、血液中的尿素氮和肌酸酐都會惡化,腎臟纖維化的情形也會更嚴重。於是我們進一步研究在我們的動物模式中,高血壓跟腎臟內的腎素-血管張力素系統,是否在急性腎損傷復原後,到發生慢性腎臟病的過程,有其角色存在。我們在缺血後再灌流的術式之後一個月開始在老鼠的飲水中給予血管張力素受體阻斷劑,或者直接使血管舒張的單純降血壓藥物進行治療,以只有切除單側腎臟的老鼠作為控制組,觀察各組血壓、蛋白尿、以及血液中尿素氮和肌酸酐的數值,結果發現,在完全不治療的組別,其死亡率、蛋白尿、血壓、血液中的尿素氮和肌酸酐,以及腎臟纖維化的情況等指標,都較控制組要來得嚴重,但這些指標在給予血管張力素受體阻斷劑的組別,其血液中的尿素氮和肌酸酐都維持在與控制組相同的水準,但這樣的保護效果卻沒有出現在使用單純降血壓藥物將血壓控制良好的組別上。由我們動物實驗的結果,我們猜測在急性腎損傷發生後,儘管生化檢測的數值回復到正常,但腎臟病沒有完全修復,腎臟內的腎素血管收縮素系統會被活化,而這個系統的活化,是造成腎臟緊接著走向慢性腎臟病的一個可能機制。未來,我們希望能進一步在臨床的實驗上,證實給予曾經發生過急性腎損傷的病人血管張力素受體阻斷劑,能預防其進展為慢性腎臟病甚至死亡的風險。 | zh_TW |
dc.description.abstract | Evidence from many clinical studies supports that acute kidney injury (AKI) is an important risk factor for incident chronic kidney disease (CKD) and disease progression. Not only does CKD lead to end-stage renal disease (ESRD), but it also increases the risk of cardiovascular disease or even death. Clinical studies often disclose that the higher the AKI severity of a patient is, the more likely her/his kidneys progress into CKD. To this day, the mechanism underlying the incident CKD and disease progression after AKI remains illusive. We therefore conducted this study to get insight into the mechanism underlying the development and progression of CKD after functional recovery from AKI in a murine model. In our pilot study to set up a murine model of AKI-CKD continuum, we performed right uni-nephrectomy (NX) first in a group of male adult CD-1 mice. We then induced ischemia-reperfusion injury (IRI) to left kidney using non-traumatic micro-aneurysm clip to clamp renal artery with core body temperature maintained at 370C under a homeothermic blanket system 2 weeks later. Severe AKI with significant elevation of plasma levels of blood urea nitrogen (BUN) and creatinine was demonstrated 2 days after 28-minute warm ischemia and then reperfusion. Although 20% of mice died within 2 weeks after NX+IRI, functional recovery shown by the decrease of plasma BUN and creatinine to the levels seen in sham and NX control mice was observed by 4 weeks after injury. However focal tubular atrophy, increased interstitial cell infiltration and fibrosis were seen in the kidneys of mice 4 weeks after NX+IRI. Gene expression, including Col1a1, Acta2, Lcn2, Havcr1, Agtr1a and Agt which encoded collagen I 1 chain, -smooth muscle actin, neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, type 1a angiotensin II receptor and angiotensinogen respectively, was increased in the kidneys of mice 4 weeks after NX+IRI. Moreover, the systolic blood pressure (BP), urinary albumin-creatinine ratio (ACR), plasma levels of BUN and creatinine and kidney fibrosis increased in mice 5 months after NX+IRI. We then investigated the roles of hypertension and intrarenal RAS activation in the development and progression of CKD after functional recovery from AKI using the murine model of AKI-CKD continuum. Drinking water with or without type 1a angiotensin II receptor blocker losartan or direct vasodilator hydralazine was administered to NX+IRI mice from 4 weeks after injury. Mice with NX only were served as the control. Systolic BP, urinary ACR and plasma levels of BUN and creatinine were evaluated. Compared to NX group, NX+IRI mice showed acute rise of plasma BUN and creatinine on day 2 after IRI. Systolic BP, plasma levels of BUN and creatinine were not different between mice before starting different treatments at 4 weeks after IRI. During the 5-month experimental period, increase of mortality, systolic BP, urinary ACR, plasma levels of BUN and creatinine and kidney fibrosis was noted in NX+IRI group. On the contrary, these parameters in mice with losartan treatment were reduced to the levels observed in NX group. However hydralazine treatment did not provide similar protective effect even though systolic BP was controlled to the levels observed in NX group. These data suggest that kidneys do not repair completely and the CKD will progress even though the kidney function recovers initially in our murine AKI model. Intrarenal RAS activation may underlie one of the mechanisms for the subsequent CKD progression. Future studies are needed to explore the preventive effect of RAS blockade on incident CKD and disease progression in patients recovering from AKI. | en |
dc.description.provenance | Made available in DSpace on 2021-06-15T13:24:01Z (GMT). No. of bitstreams: 1 ntu-105-R02441016-1.pdf: 2973491 bytes, checksum: 6e89cc3679be8d8cf52999e04f3c2d16 (MD5) Previous issue date: 2016 | en |
dc.description.tableofcontents | 口試委員會審定書 #
誌謝 i 中文摘要 ii ABSTRACT iv CONTENTS vi LIST OF FIGURES viii LIST OF TABLES ix Chapter 1 Introduction 1 1.1 Acute kidney injury (AKI) 1 1.1.1 Definition of acute kidney injury 1 1.1.2 Epidemiology of AKI 2 1.2 AKI-CKD TRANSITION 2 1.3 Chronic kidney disease, CKD 3 1.3.1 Definition of CKD 3 1.3.2 Factor influencing the progression of CKD 4 1.4 Renin-Angiotensin System 7 1.4.1 Elements of the intrarenal RAS 8 1.4.2 Role of the RAS in CKD 10 1.4.3 Role of the RAS in AKI 10 1.5 Aim 11 Chapter 2 Method and Material 12 2.1 Materials 12 2.1.1 Animals 12 2.1.2 Buffer 12 2.1.3 Chemicals and ELISA Kits 13 2.1.4 Antibodies 15 2.2 Methods 16 2.2.1 AKI Model 16 2.2.2 Experimental Groups 16 2.2.3 Sacrifice of Animals 16 2.2.4 Blood Pressure Analysis in Mice 16 2.2.5 Tissue Preparation and Histology 17 2.2.6 Immunofluorescence 17 2.2.7 Glomerulosclerosis score 18 2.2.8 Interstitial fibrosis area 18 2.2.9 Glomerular volume 19 2.2.10 Reverse Transcription-Polymerase Chain Reactions (RT-PCR) and Real-Time Polymerase Chain Reaction (RT-qPCR / qPCR) 19 2.2.11 Biochemical analyses of mouse plasma and urine 20 2.2.12 Statistic 20 Chapter 3 Results 22 Chapter 4 Discussion 27 Chapter 5 References 47 | |
dc.language.iso | en | |
dc.title | 血管張力素抑制劑-氯沙坦鉀,能減少急性腎損傷後進展成慢性腎臟病甚至死亡的風險 | zh_TW |
dc.title | Losartan reduces ensuing CKD and mortality after AKI | en |
dc.type | Thesis | |
dc.date.schoolyear | 104-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 吳明修(Ming-Shiou Wu),姜文智(Wen-Chih Chiang) | |
dc.subject.keyword | 急性腎損傷,慢性腎臟病,腎素血管收縮素系統, | zh_TW |
dc.subject.keyword | Acute kidney injury,Chronic kidney disease,Renin-Angiotensin system, | en |
dc.relation.page | 50 | |
dc.identifier.doi | 10.6342/NTU201600404 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2016-06-22 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 生理學研究所 | zh_TW |
顯示於系所單位: | 生理學科所 |
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