臺灣博碩士論文加值系統

背景：台灣慢性腎臟病患日益增加，發生率及盛行率不斷的上升，盛行率為11.9%，慢性腎臟病惡化後所使用的替代療法佔用醫療資源越來越多。其中高血壓為慢性腎臟病重要因子，血壓升高會導致鈉的濃度降低，活化腎素-血管收縮素系統；而腎素-血管收縮素系統的基因多形性會驅使體內平衡至一個不正常的狀態，增加罹患慢性腎臟病的易感受性。因此本研究想要探討在台灣人群中，腎素-血管收縮素系統中血管收縮素原(AGT- C803T, T602C,A-20C)、血管收縮素轉化酶(ACE-A2350G)和血管收縮素II接受器第一型(AGTR1-A1166C,C573T,C-521T)的基因多形性，還有其他相關危險因子是否與慢性腎臟病具有相關性。
方法：本研究使採用病例對照研究設計，慢性腎臟病病例組來自天主教耕莘醫院，健康對照組則來自三軍總醫院健康檢查之民眾，腎絲球過濾率(GFR)小於60 ml/min/1.73m2為診斷標準，最後收取慢性腎臟病病例組有135名，健康對照組有270名，萃取其血液DNA再進行限制酶片段長度多形性，來確定其基因型。
結果：研究結果顯示，BMI、抽菸狀況、共伴疾病（高血壓、高血脂、糖尿病）及臨床生化值（BUN, creatinine, GFR, glucose, total cholesterol, triglyceride、收縮壓）與慢性腎臟病有顯著關聯。在腎素-血管收縮素系統基因多形性中，經邏輯式回歸分析控制其他變項後，ACE-A2350G中GG基因型與AA基因型進行比較，GG型對於慢性腎臟病為保護因子，統計上達顯著差異(OR=0.34, 95%CI: 0.15-0.78)；再將慢性腎臟病分期，在ACE-A2350G慢性腎臟病第三期病人中，GG基因型是慢性腎臟病的保護因子(OR=0.23, 95%CI: 0.07-0.79)，AGTR1-C573T中CT型對於慢性腎臟病為危險因子(OR=1.82, 95%CI: 1.07-3.09)。
結論：本研究結果顯示，在台灣人口中BMI、抽菸狀況、共伴疾病（高血壓、高血脂、糖尿病）及臨床生化值（BUN, creatinine, GFR, glucose, total cholesterol, triglyceride、收縮壓）為慢性腎臟病的危險因子，而ACE-A2350G與AGTR1-C573T基因多形性與慢性腎臟病有相關，這些因子可做為預測慢性腎臟病發生的危險因子。

Background: Chronic kidney disease (CKD) is highly prevalent in Taiwan and contributes to increased burden of disease in this population. In Taiwan, 11.9% of the general population is estimated to have CKD with the rate projected to increase. The impact of CKD on public health burden is worsening with increasing comorbidities and mortality, and huge medical expenses.Hypertension is the main contributor in the progression of renal failure with the presence or absence of proteinuria and is believed to be the major risk factor for the development of ESRD. It is also predicted that the prevalence of hypertension is increased with decreasing renal function due to a decrease in sodium excretion and activation of the Renin Angiotensin System (RAS). RAS polymorphisms alter the homeostasis to an abnormal state.The aim of the study was to assess the association of the gene polymorphism with CKD in Taiwanese.
Methods: The study group consisted of 135 patients with CKD from Cardinal Tien Hospital. The control group involved 270 healthy individuals from Tri-service General Hospital. All subjects were genotyped for the angiotensinogen (AGT-C803T, T602C, A-20C), angiotensin-1 converting enzyme (ACE-A2350G), and angiotensin II type1 receptor (AGTR1-A1166C, C573T, C-521T) polymorphisms of the RAS genes by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis.
Results: Significant associations were observed in ACE-A2350G and AGTR1-C573T polymorphism between CKD patients and controls. In ACE-A2350G, the GG genotype compared with AA genotype was a protection against CKD (OR=0.34; 95%CI: 0.15-0.78). In AGTR1-C573T, the CT genotype compared with CC genotype was a risk towards CKD (OR=1.82; 95%CI: 1.07-3.09).
Conclusions: We conclude that ACE and AGTR1 polymorphisms were the likely candidate determinants of CKD. However, there was no association of AGT polymorphisms with susceptibility to CKD.

目錄 I
表目錄 III
圖目錄 V
中文摘要 VI
第一章 前言 1
第一節 研究背景 1
第二節 研究目的 4
第二章 文獻探討 6
第一節 慢性腎臟病 6
第二節 腎素-血管收縮素系統（RAS） 17
第三節 腎素-血管收縮素系統基因多形性 19
第三章 材料與方法 27
第一節 研究設計 27
第二節 研究資料之收集 29
第四節 研究架構 31
第五節 實驗方法 32
第四章 統計分析 43
第五章 結果 45
第一節 研究對象人口學背景資料 45
第二節 腎素-血管收縮素基因多形性之哈-溫平衡 48
第三節 腎素-血管收縮素系統基因多形性與慢性腎臟病相關性 50
第三節 腎素-血管收縮素系統單套型分析（Haplotype analysis） 82
第四節 RFLP分析結果 86
第六章 討論 93
第一節 與慢性腎臟病相關之危險因子 93
第二節 探討AGT基因多形性 95
第三節 探討ACE基因多形性 101
第四節 探討AGTR1基因多形性 103
第五節 探討RAS單套型 110
第六節 研究限制 112
第七章 結論與未來展望 113
第八章 參考文獻 115


表目錄
表1.美國腎臟基金會之慢性腎臟病分期標準 7
表2.AGT之基因多形性與病理狀態之相關性 21
表3.ACE之基因多形性與病理狀態之相關性 23
表4.AGTR1之基因多形性與病理狀態之相關性 26
表5.腎素-血管收縮素系統基因多形性位點與引子序列 37
表6.PCR試劑配置 38
表7.PCR反應條件 39
表8.RFLP反應試劑與條件 41
表9.慢性腎臟病病例組與對照組人口學變項與臨床生化值分布情形 47
表10.對照組RAS系統基因多形性之哈-溫平衡檢定 49
表11.慢性腎臟病病例組與對照組AGT-C803T基因型、對偶基因頻率與顯隱式模式分布 52
表12.慢性腎臟病病例組與對照組AGT-T602C基因型、對偶基因頻率與顯隱式模式分布 54
表13.慢性腎臟病病例組與對照組AGT-A-20C基因型、對偶基因頻率分布 56
表14.慢性腎臟病病人分期與對照組在AGT基因分布頻率 58
表15.慢性腎臟病病人分期與對照組在AGT基因邏輯式迴歸分析 61
表16.慢性腎臟病病例組與對照組ACE-A2350G基因型、對偶基因頻率與顯隱式模式分布 64
表17.慢性腎臟病病人分期與對照組在ACE基因分布頻率 66
表18.慢性腎臟病病人分期與對照組在ACE基因邏輯式迴歸分析 68
表19.慢性腎臟病病例組與對照組AGTR1-A1166C基因型、對偶基因頻率分布 70
表20.慢性腎臟病病例組與對照組AGTR1-C573T基因型、對偶基因與顯隱式模式頻率分布 73
表21.慢性腎臟病病例組與對照組AGTR1-C-521T基因型、對偶基因頻率與顯隱式模式分布 76
表22.慢性腎臟病病人分期與對照組在AGTR1基因多形性分布頻率 78
表23.慢性腎臟病病人分期與對照組在AGTR1基因邏輯式迴歸分析 81
表24.AGT單套型與慢性腎臟病的相關性分析 83
表25.AGTR1單套型與慢性腎臟病的相關性分析 85
表26.RAS基因多形性在不同種族中對偶基因之分布頻率 109


圖目錄
圖1.慢性腎臟病之末期腎病變發生率和盛行率之國際比較 2
圖2.RAS對於生理功能上的機轉 11
圖 3.慢性腎臟病與基因的關連性 16
圖4.RAS的生理功能機制圖 18
圖5.AGT基因多形性之連鎖不平衡檢定 83
圖6.AGTR1基因多形性之連鎖不平衡檢定 85
圖7.AGT-C803T基因多形性之瓊脂凝膠電泳圖 86
圖 8.AGT-T602CM基因多形性之瓊脂凝膠電泳圖 87
圖9.AGT-A-20C基因多形性之瓊脂凝膠電泳圖 88
圖10. ACE-A2350G基因多形性之瓊脂凝膠電泳圖 89
圖11.AGTR1-A1166C基因多形性之瓊脂凝膠電泳圖 90
圖12. AGTR1-C573T基因多形性之瓊脂凝膠電泳圖 91
圖13. AGTR1-C-521T基因多形性之瓊脂凝膠電泳圖 92

第八章 參考文獻
1. Abdi, R., Tran, T. B., Zee, R., Brenner, B. M., & Milford, E. L. (2001). Angiotensin gene polymorphism as a determinant of posttransplantation renal dysfunction and hypertension. Transplantation, 72(4), 726-729.
2.Abdollahi, M. R., Lewis, R. M., Gaunt, T. R., Cumming, D. V., Rodriguez, S., Rose-Zerilli, M., Collins, A. R., Syddall, H. E., Howell, W. M., Cooper, C., et al. (2007). Quantitated transcript haplotypes (QTH) of AGTR1, reduced abundance of mRNA haplotypes containing 1166C (rs5186:A>C), and relevance to metabolic syndrome traits. Hum Mutat, 28(4), 365-373.
3.Amin, R., Turner, C., van Aken, S., Bahu, T. K., Watts, A., Lindsell, D. R., Dalton, R. N., & Dunger, D. B. (2005). The relationship between microalbuminuria and glomerular filtration rate in young type 1 diabetic subjects: The Oxford Regional Prospective Study. Kidney Int, 68(4), 1740-1749.
4.Anbazhagan, K., Sampathkumar, K., Ramakrishnan, M., Gomathi, P., Gomathi, S., & Selvam, G. S. (2009). Analysis of polymorphism in renin angiotensin system and other related genes in South Indian chronic kidney disease patients. Clin Chim Acta, 406(1-2), 108-112.
5.Appel, G. B., & Appel, A. S. (2004). Angiotensin II receptor antagonists: role in hypertension, cardiovascular disease, and renoprotection. Prog Cardiovasc Dis, 47(2), 105-115.
6.Baggio, B., Budakovic, A., Dalla Vestra, M., Saller, A., Bruseghin, M., & Fioretto, P. (2002). Effects of cigarette smoking on glomerular structure and function in type 2 diabetic patients. J Am Soc Nephrol, 13(11), 2730-2736.
7.Balakrishnan, V. S., Jaber, B. L., Natov, S. N., Cendoroglo, M., King, A. J., Schmid, C. H., & Pereira, B. J. (1998). Interleukin-1 receptor antagonist synthesis by peripheral blood mononuclear cells in hemodialysis patients. Kidney Int, 54(6), 2106-2112.
8.Bonnardeaux, A., Davies, E., Jeunemaitre, X., Fery, I., Charru, A., Clauser, E., Tiret, L., Cambien, F., Corvol, P., & Soubrier, F. (1994). Angiotensin II type 1 receptor gene polymorphisms in human essential hypertension. Hypertension, 24(1), 63-69.
9.Bowden, D. W. (2003). Genetics of kidney disease. Kidney Int Suppl(83), S8-12.
10.Buraczynska, M., Ksiazek, P., Drop, A., Zaluska, W., Spasiewicz, D., & Ksiazek, A. (2006). Genetic polymorphisms of the renin-angiotensin system in end-stage renal disease. Nephrol Dial Transplant, 21(4), 979-983.
11.Burgess, E. (1999). Conservative treatment to slow deterioration of renal function: evidence-based recommendations. Kidney Int Suppl, 70, S17-25.
12.Chan, L. Y., Leung, J. C., Tang, S. C., Choy, C. B., & Lai, K. N. (2005). Tubular expression of angiotensin II receptors and their regulation in IgA nephropathy. J Am Soc Nephrol, 16(8), 2306-2317.
13.Chang, S. N., Lin, J. W., Juang, J. M., Tsai, C. T., Hwang, J. J., & Chiang, F. T. (2010). Association between genetic polymorphisms in the renin-angiotensin system and systolic heart failure revised by a propensity score-based analysis. Cardiology, 116(4), 279-285.
14.Chaves, F. J., Corella, D., Sorli, J. V., Marin-Garcia, P., Guillen, M., & Redon, J. (2004). Polymorphisms of the renin-angiotensin system influence height in normotensive women in a Spanish population. J Clin Endocrinol Metab, 89(5), 2301-2305.
15.Chen, J., Chen, J. K., Neilson, E. G., & Harris, R. C. (2006). Role of EGF receptor activation in angiotensin II-induced renal epithelial cell hypertrophy. J Am Soc Nephrol, 17(6), 1615-1623.
16.Chen, Y., Lasaitiene, D., & Friberg, P. (2004). The renin-angiotensin system in kidney development. Acta Physiol Scand, 181(4), 529-535.
17.Cosentino, F., Savoia, C., De Paolis, P., Francia, P., Russo, A., Maffei, A., Venturelli, V., Schiavoni, M., Lembo, G., & Volpe, M. (2005). Angiotensin II type 2 receptors contribute to vascular responses in spontaneously hypertensive rats treated with angiotensin II type 1 receptor antagonists. Am J Hypertens, 18(4 Pt 1), 493-499.
18.Davis, J. O., Hartroft, P. M., Titus, E. O., Carpenter, C. C., Ayers, C. R., & Spiegel, H. E. (1962). The role of the renin-angiotensin system in the control of aldosterone secretion. J Clin Invest, 41, 378-389.
19.De Paolis, P., Porcellini, A., Savoia, C., Lombardi, A., Gigante, B., Frati, G., Rubattu, S., Musumeci, B., & Volpe, M. (2002). Functional cross-talk between angiotensin II and epidermal growth factor receptors in NIH3T3 fibroblasts. J Hypertens, 20(4), 693-699.
20.Dzau, V. J. (1998). Mechanism of protective effects of ACE inhibition on coronary artery disease. Eur Heart J, 19 Suppl J, J2-6.
21.Erdos, E. G. (1976). Conversion of angiotensin I to angiotensin II. Am J Med, 60(6), 749-759.
22.Eriksen, B. O., & Ingebretsen, O. C. (2006). The progression of chronic kidney disease: a 10-year population-based study of the effects of gender and age. Kidney Int, 69(2), 375-382.
23.Ewert, S., Sjoberg, T., Johansson, B., Duvetorp, A., Holm, M., & Fandriks, L. (2006). Dynamic expression of the angiotensin II type 2 receptor and duodenal mucosal alkaline secretion in the Sprague-Dawley rat. Exp Physiol, 91(1), 191-199.
24.Ewert, S., Spak, E., Olbers, T., Johnsson, E., Edebo, A., & Fandriks, L. (2006). Angiotensin II induced contraction of rat and human small intestinal wall musculature in vitro. Acta Physiol (Oxf), 188(1), 33-40.
25.Fernandez-Llama, P., Poch, E., Oriola, J., Botey, A., Rivera, F., & Revert, L. (1998). Angiotensinogen gene M235T and T174M polymorphisms in essential hypertension: relation with target organ damage. Am J Hypertens, 11(4 Pt 1), 439-444.
26.Fogo, A. B. (2000). Glomerular hypertension, abnormal glomerular growth, and progression of renal diseases. Kidney Int Suppl, 75, S15-21.
27.Fox, C. S., Larson, M. G., Leip, E. P., Culleton, B., Wilson, P. W., & Levy, D. (2004). Predictors of new-onset kidney disease in a community-based population. JAMA, 291(7), 844-850.
28.Frimat, L., Philippe, C., Maghakian, M. N., Jonveaux, P., Hurault de Ligny, B., Guillemin, F., & Kessler, M. (2000). Polymorphism of angiotensin converting enzyme, angiotensinogen, and angiotensin II type 1 receptor genes and end-stage renal failure in IgA nephropathy: IGARAS--a study of 274 Men. J Am Soc Nephrol, 11(11), 2062-2067.
29.Gardemann, A., Stricker, J., Humme, J., Nguyen, Q. D., Katz, N., Philipp, M., Tillmanns, H., Hehrlein, F. W., & Haberbosch, W. (1999). Angiotensinogen T174M and M235T gene polymorphisms are associated with the extent of coronary atherosclerosis. Atherosclerosis, 145(2), 309-314.
30.Gigante, B., Piras, O., Savoia, C., De Paolis, P., Rubattu, S., Panina, G., & Volpe, M. (2000). Role of angiotensin II AT1 and AT2 subtype receptors in the regulation of atrial natriuretic peptide expression in salt-restricted rats. Basic Res Cardiol, 95(1), 64-69.
31.Girndt, M., Ulrich, C., Kaul, H., Sester, U., Sester, M., & Kohler, H. (2003). Uremia-associated immune defect: the IL-10-CRP axis. Kidney Int Suppl(84), S76-79.
32.Goldbergova, M., Spinarova, L., Spinar, J., Toman, J., Vasku, A., & Vacha, J. (2003). Association of two angiotensinogen gene polymorphisms, M235T and G(-6)A, with chronic heart failure. Int J Cardiol, 89(2-3), 267-272.
33.Gonzalez, M., Lobos, L., Castillo, F., Galleguillos, L., Lopez, N. C., & Michea, L. (2005). High-salt diet inhibits expression of angiotensin type 2 receptor in resistance arteries. Hypertension, 45(5), 853-859.
34.Hayashi, K., Miyamoto, A., Berisha, B., Kosmann, M. R., Okuda, K., & Schams, D. (2000). Regulation of angiotensin II production and angiotensin receptors in microvascular endothelial cells from bovine corpus luteum. Biol Reprod, 62(1), 162-167.
35.Henkin, L., Bergman, R. N., Bowden, D. W., Ellsworth, D. L., Haffner, S. M., Langefeld, C. D., Mitchell, B. D., Norris, J. M., Rewers, M., Saad, M. F., et al. (2003). Genetic epidemiology of insulin resistance and visceral adiposity. The IRAS Family Study design and methods. Ann Epidemiol, 13(4), 211-217.
36.Heron, M., Hoyert, D. L., Murphy, S. L., Xu, J., Kochanek, K. D., & Tejada-Vera, B. (2009). Deaths: final data for 2006. Natl Vital Stat Rep, 57(14), 1-134.
37.Himmelfarb, J. (2007). Chronic kidney disease and the public health: gaps in evidence from interventional trials. JAMA, 297(23), 2630-2633.
38.Hunley, T. E., Julian, B. A., Phillips, J. A., 3rd, Summar, M. L., Yoshida, H., Horn, R. G., Brown, N. J., Fogo, A., Ichikawa, I., & Kon, V. (1996). Angiotensin converting enzyme gene polymorphism: potential silencer motif and impact on progression in IgA nephropathy. Kidney Int, 49(2), 571-577.
39.Hwang, S. J., Tsai, J. C., & Chen, H. C. (2010). Epidemiology, impact and preventive care of chronic kidney disease in Taiwan. Nephrology (Carlton), 15 Suppl 2, 3-9.
40.Ise, K., Sato, Y., Matsuyama, S., Gunji, T., Ishii, S., Yamashita, M., Kanazawa, Y., & Gotoh, M. (2004). Transforming growth factor-beta signaling is enhanced following mitomycin-C treatment of islet xenograft. Transplant Proc, 36(4), 1183-1185.
41.Iseki, K. (2003). The okinawa screening program. J Am Soc Nephrol, 14(7 Suppl 2), S127-130.
42.Israni, A. K., Li, N., Sidhwani, S., Rosas, S., Kong, X., Joffe, M., Rebbeck, T., & Feldman, H. I. (2007). Association of hypertension genotypes and decline in renal function after kidney transplantation. Transplantation, 84(10), 1240-1247.
43.Ito, M., Oliverio, M. I., Mannon, P. J., Best, C. F., Maeda, N., Smithies, O., & Coffman, T. M. (1995). Regulation of blood pressure by the type 1A angiotensin II receptor gene. Proc Natl Acad Sci U S A, 92(8), 3521-3525.
44.Jugdutt, B. I., Xu, Y., Balghith, M., Moudgil, R., & Menon, V. (2000). Cardioprotection induced by AT1R blockade after reperfused myocardial infarction: association with regional increase in AT2R, IP3R and PKCepsilon proteins and cGMP. J Cardiovasc Pharmacol Ther, 5(4), 301-311.
45.Lai, K. N., Chan, L. Y., Tang, S. C., Tsang, A. W., Li, F. F., Lam, M. F., Lui, S. L., & Leung, J. C. (2004). Mesangial expression of angiotensin II receptor in IgA nephropathy and its regulation by polymeric IgA1. Kidney Int, 66(4), 1403-1416.
46.Liu, K. P., Lin, C. Y., Chen, H. J., Wei, C. F., & Lee-Chen, G. J. (2004). Renin-angiotensin system polymorphisms in Taiwanese primary vesicoureteral reflux. Pediatr Nephrol, 19(6), 594-601.
47.Locatelli, F., Marcelli, D., Comelli, M., Alberti, D., Graziani, G., Buccianti, G., Redaelli, B., & Giangrande, A. (1996). Proteinuria and blood pressure as causal components of progression to end-stage renal failure. Northern Italian Cooperative Study Group. Nephrol Dial Transplant, 11(3), 461-467.
48.Losito, A., Kalidas, K., Santoni, S., & Jeffery, S. (2003). Association of interleukin-6 -174G/C promoter polymorphism with hypertension and left ventricular hypertrophy in dialysis patients. Kidney Int, 64(2), 616-622.
49.Lovati, E., Richard, A., Frey, B. M., Frey, F. J., & Ferrari, P. (2001). Genetic polymorphisms of the renin-angiotensin-aldosterone system in end-stage renal disease. Kidney Int, 60(1), 46-54.
50.Lysaght, M. J. (2002). Maintenance dialysis population dynamics: current trends and long-term implications. J Am Soc Nephrol, 13 Suppl 1, S37-40.
51.Ma, Y. C., Zuo, L., Chen, J. H., Luo, Q., Yu, X. Q., Li, Y., Xu, J. S., Huang, S. M., Wang, L. N., Huang, W., et al. (2007). Improved GFR estimation by combined creatinine and cystatin C measurements. Kidney Int, 72(12), 1535-1542.
52.Mazzocchi, G., Malendowicz, L. K., Markowska, A., Albertin, G., & Nussdorfer, G. G. (2000). Role of adrenal renin-angiotensin system in the control of aldosterone secretion in sodium-restricted rats. Am J Physiol Endocrinol Metab, 278(6), E1027-1030.
53.Meguid El Nahas, A., & Bello, A. K. (2005). Chronic kidney disease: the global challenge. Lancet, 365(9456), 331-340.
54.Miners, S., Ashby, E., Baig, S., Harrison, R., Tayler, H., Speedy, E., Prince, J. A., Love, S., & Kehoe, P. G. (2009). Angiotensin-converting enzyme levels and activity in Alzheimer's disease: differences in brain and CSF ACE and association with ACE1 genotypes. Am J Transl Res, 1(2), 163-177.
55.Nishikino, M., Matsunaga, T., Yasuda, K., Adachi, T., Moritani, T., Tsujimoto, G., Tsuda, K., & Aoki, N. (2006). Genetic variation in the renin-angiotensin system and autonomic nervous system function in young healthy Japanese subjects. J Clin Endocrinol Metab, 91(11), 4676-4681.
56.Niu, T., Yang, J., Wang, B., Chen, W., Wang, Z., Laird, N., Wei, E., Fang, Z., Lindpaintner, K., Rogus, J. J., et al. (1999). Angiotensinogen gene polymorphisms M235T/T174M: no excess transmission to hypertensive Chinese. Hypertension, 33(2), 698-702.
57.Niu, W., Qi, Y., Gao, P., & Zhu, D. (2010). Association between angiotensin converting enzyme G2350A polymorphism and hypertension risk: a meta-analysis. J Renin Angiotensin Aldosterone Syst.
58.Niu, W., Qi, Y., Hou, S., Zhai, X., Zhou, W., & Qiu, C. (2009). Haplotype-based association of the renin-angiotensin-aldosterone system genes polymorphisms with essential hypertension among Han Chinese: the Fangshan study. J Hypertens, 27(7), 1384-1391.
59.NKF. eGFR. National Kidney Foundation.
60.Nomura, I., Kato, J., & Kitamura, K. (2009). Association between body mass index and chronic kidney disease: a population-based, cross-sectional study of a Japanese community. Vasc Health Risk Manag, 5(1), 315-320.
61.Note on the 2007-2008 Data Documentation. (2011). CDC,NHANES 2007-2008.
62.Oda, N., Minoguchi, K., Yokoe, T., Hashimoto, T., Wada, K., Miyamoto, M., Tanaka, A., Kohno, Y., & Adachi, M. (1999). Effect of suplatast tosilate (IPD-1151T) on cytokine production by allergen-specific human Th1 and Th2 cell lines. Life Sci, 65(8), 763-770.
63.Oda, N., Takeda, Y., Zhu, A., Usukura, M., Yoneda, T., Takata, H., & Mabuchi, H. (2006). Pathophysiological roles of the adrenal renin-angiotensin system in patients with primary aldosteronism. Hypertens Res, 29(1), 9-14.
64.Oishi, Y., Ozono, R., Yoshizumi, M., Akishita, M., Horiuchi, M., & Oshima, T. (2006). AT2 receptor mediates the cardioprotective effects of AT1 receptor antagonist in post-myocardial infarction remodeling. Life Sci, 80(1), 82-88.
65.Okada, H., Inoue, T., Kikuta, T., Watanabe, Y., Kanno, Y., Ban, S., Sugaya, T., Horiuchi, M., & Suzuki, H. (2006). A possible anti-inflammatory role of angiotensin II type 2 receptor in immune-mediated glomerulonephritis during type 1 receptor blockade. Am J Pathol, 169(5), 1577-1589.
66.Okada, H., Watanabe, Y., Inoue, T., Kobayashi, T., Kikuta, T., Kanno, Y., Ban, S., & Suzuki, H. (2004). Angiotensin II type 1 receptor blockade attenuates renal fibrogenesis in an immune-mediated nephritic kidney through counter-activation of angiotensin II type 2 receptor. Biochem Biophys Res Commun, 314(2), 403-408.
67.Orth, S. R. (2002). Smoking and the kidney. J Am Soc Nephrol, 13(6), 1663-1672.
68.Orth, S. R., Schroeder, T., Ritz, E., & Ferrari, P. (2005). Effects of smoking on renal function in patients with type 1 and type 2 diabetes mellitus. Nephrol Dial Transplant, 20(11), 2414-2419.
69.Park, S. K., & Kang, S. K. (1995). Renal function and hemodynamic study in obese Zucker rats. Korean J Intern Med, 10(1), 48-53.
70.Pei, Y., Scholey, J., Thai, K., Suzuki, M., & Cattran, D. (1997). Association of angiotensinogen gene T235 variant with progression of immunoglobin A nephropathy in Caucasian patients. J Clin Invest, 100(4), 814-820.
71.Prasad, P., Tiwari, A. K., Kumar, K. M., Ammini, A. C., Gupta, A., Gupta, R., Sharma, A. K., Rao, A. R., Nagendra, R., Chandra, T. S., et al. (2006). Chronic renal insufficiency among Asian Indians with type 2 diabetes: I. Role of RAAS gene polymorphisms. BMC Med Genet, 7, 42.
72.Ran, J., Hirano, T., & Adachi, M. (2005). Angiotensin II infusion increases hepatic triglyceride production via its type 2 receptor in rats. J Hypertens, 23(8), 1525-1530.
73.Regitz-Zagrosek, V., Neuss, M., Holzmeister, J., Warnecke, C., & Fleck, E. (1996). Molecular biology of angiotensin receptors and their role in human cardiovascular disease. J Mol Med, 74(5), 233-251.
74.Reis, K., Arinsoy, T., Derici, U., Gonen, S., Bicik, Z., Soylemezoglu, O., Yasavul, U., Hasanoglu, E., & Sindel, S. (2005). Angiotensinogen and plasminogen activator inhibitor-1 gene polymorphism in relation to chronic allograft dysfunction. Clin Transplant, 19(1), 10-14.
75.Ruiz-Ortega, M., Ruperez, M., Lorenzo, O., Esteban, V., Blanco, J., Mezzano, S., & Egido, J. (2002). Angiotensin II regulates the synthesis of proinflammatory cytokines and chemokines in the kidney. Kidney Int Suppl(82), S12-22.
76.Saidi, S., Mallat, S. G., Almawi, W. Y., & Mahjoub, T. (2009). Association between renin-angiotensin-aldosterone system genotypes and haplotypes and risk of ischemic stroke of atherosclerotic etiology. Acta Neurol Scand, 119(6), 356-363.
77.Sakharova, O. V., Taal, M. W., & Brenner, B. M. (2001). Pathogenesis of diabetic nephropathy: focus on transforming growth factor-beta and connective tissue growth factor. Curr Opin Nephrol Hypertens, 10(6), 727-738.
78.Sato, N., Katsuya, T., Rakugi, H., Takami, S., Nakata, Y., Miki, T., Higaki, J., & Ogihara, T. (1997). Association of variants in critical core promoter element of angiotensinogen gene with increased risk of essential hypertension in Japanese. Hypertension, 30(3 Pt 1), 321-325.
79.Saucier, N. A., Sinha, M. K., Liang, K. V., Krambeck, A. E., Weaver, A. L., Bergstralh, E. J., Li, X., Rule, A. D., & Lieske, J. C. (2010). Risk factors for CKD in persons with kidney stones: a case-control study in Olmsted County, Minnesota. Am J Kidney Dis, 55(1), 61-68.
80.Schmidt, S., Giessel, R., Bergis, K. H., Strojek, K., Grzeszczak, W., Ganten, D., & Ritz, E. (1996). Angiotensinogen gene M235T polymorphism is not associated with diabetic nephropathy. The Diabetic Nephropathy Study Group. Nephrol Dial Transplant, 11(9), 1755-1761.
81.Seaquist, E. R., Goetz, F. C., Rich, S., & Barbosa, J. (1989). Familial clustering of diabetic kidney disease. Evidence for genetic susceptibility to diabetic nephropathy. N Engl J Med, 320(18), 1161-1165.
82.System., U. S. R. D. (2009). United States Renal Data System.
83.Taal, M. W., & Brenner, B. M. (2006). Predicting initiation and progression of chronic kidney disease: Developing renal risk scores. Kidney Int, 70(10), 1694-1705.
84.van Ittersum, F. J., de Man, A. M., Thijssen, S., de Knijff, P., Slagboom, E., Smulders, Y., Tarnow, L., Donker, A. J., Bilo, H. J., & Stehouwer, C. D. (2000). Genetic polymorphisms of the renin-angiotensin system and complications of insulin-dependent diabetes mellitus. Nephrol Dial Transplant, 15(7), 1000-1007.
85.Vasku, A., Soucek, M., Tschoplova, S., & Stejskalova, A. (2002). An association of BMI with A (-6) G, M235T and T174M polymorphisms in angiotensinogen gene in essential hypertension. J Hum Hypertens, 16(6), 427-430.
86.Wen, C. P., Cheng, T. Y., Tsai, M. K., Chang, Y. C., Chan, H. T., Tsai, S. P., Chiang, P. H., Hsu, C. C., Sung, P. K., Hsu, Y. H., et al. (2008). All-cause mortality attributable to chronic kidney disease: a prospective cohort study based on 462 293 adults in Taiwan. Lancet, 371(9631), 2173-2182.
87.Wong, C., Kanetsky, P., & Raj, D. (2008). Genetic polymorphisms of the RAS-cytokine pathway and chronic kidney disease. Pediatr Nephrol, 23(7), 1037-1051.
88.Woo, K. T., Lau, Y. K., Choong, L. H., Zhao, Y., Tan, H. B., Fook-Chong, S., Tan, E. K., Yap, H. K., & Wong, K. S. (2004). Polymorphism of renin-angiotensin system genes in IgA nephropathy. Nephrology (Carlton), 9(5), 304-309.
89.Wu, C. K., Tsai, C. T., Hwang, J. J., Luo, J. L., Juang, J. J., Hsu, K. L., Lai, L. P., Lin, J. L., Tseng, C. D., & Chiang, F. T. (2008). Renin-angiotensin system gene polymorphisms and diastolic heart failure. Eur J Clin Invest, 38(11), 789-797.
90.Yuan, J., Tang, W., Chun, Y., Ying, H., Yang, Y., & Xiao, C. (2009). Angiotensinogen T174M and M235T variants and hypertension in the Hani and Yi minority groups of China. Biochem Genet, 47(5-6), 344-350.
91.Zhang, X., Erdmann, J., Regitz-Zagrosek, V., Kurzinger, S., Hense, H. W., & Schunkert, H. (2000). Evaluation of three polymorphisms in the promoter region of the angiotensin II type I receptor gene. J Hypertens, 18(3), 267-272.
92.Zhao, Y. Y., Zhou, J., Narayanan, C. S., Cui, Y., & Kumar, A. (1999). Role of C/A polymorphism at -20 on the expression of human angiotensinogen gene. Hypertension, 33(1), 108-115.
93.Zhu, X., Bouzekri, N., Southam, L., Cooper, R. S., Adeyemo, A., McKenzie, C. A., Luke, A., Chen, G., Elston, R. C., & Ward, R. (2001). Linkage and association analysis of angiotensin I-converting enzyme (ACE)-gene polymorphisms with ACE concentration and blood pressure. Am J Hum Genet, 68(5), 1139-1148.
94.王舒民, 楊., 黃秋錦. (2008). 慢性腎臟病與高血壓. 腎臟與透析, 19(2).
95.江守山. (2008). 台灣洗腎有保障 日本、歐美追不上. from http://blog.sina.com.tw/little/article.php?pbgid=41946&entryid=580701
96.行政院衛生署國民健康局. (2010). 2007年台灣地區高血壓高血糖高血脂之追蹤調查研究. 行政院衛生署國民健康局.
97.行政院衛生署國民健康局. (2010). 死因統計表.
98.周先樂. (2000.). 人體生理學. 藝軒圖書出版社.
99.周先樂. ( 2000). 人體生理學, 藝軒圖書出版社.
100.秦亞惠. (2005). Angiotensin-Converting Enzyme Inhibitor(ACEI)與 Angiotensin Receptor Blocker(ARB)臨床應用之差異. 三總藥訊.
101.張文華. (2006). HbA1c-糖化血色素( glycated hemoglobin). from http://health.wedar.com/show.asp?id=824
102.陳瑞祈, 陳., 陳秋月,周明謹,麥秀琴,黃麗利,李素珠,張哲銘. (2010). 慢性腎臟並完整照護計畫介入可延緩腎功能惡化. 台灣腎臟戶喜學會雜誌, 9(2), 34-39.
103.曾慶孝. 老化與糖尿病. from http://www.alum.ntu.edu.tw/print.php?num=43&sn=915&check=
104.腎臟指標. 台灣腎臟醫學會.
105.黃尚志. (2007). 慢性腎臟病防治手冊: 行政院衛生署國民健康局.
106.黃尚志. (2009). 台灣慢性腎臟病流行病學與防治醫療網. 高雄醫學大學.
107.衛生署98年死因統計. (2009). 衛生署.