請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/40477
完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 吳寬墩(Kwan-Dun Wu) | |
dc.contributor.author | Feng-Jung Yang | en |
dc.contributor.author | 楊豐榮 | zh_TW |
dc.date.accessioned | 2021-06-14T16:48:46Z | - |
dc.date.available | 2010-09-11 | |
dc.date.copyright | 2008-09-11 | |
dc.date.issued | 2008 | |
dc.date.submitted | 2008-07-31 | |
dc.identifier.citation | (1) Anavekar NS, Pfeffer MA. Cardiovascular risk in chronic kidney disease. Kidney Int Suppl 2004 November;(92):S11-S15.
(2) Teng M, Wolf M, Lowrie E, Ofsthun N, Lazarus JM, Thadhani R. Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy. N Engl J Med 2003 July 31;349(5):446-56. (3) Ebrahimpour P, Fakhrzadeh H, Heshmat R, Bandarian F, Larijani B. Serum uric acid levels and risk of metabolic syndrome in healthy adults. Endocr Pract 2008 April;14(3):298-304. (4) Segura J, Campo C, Ruilope LM. How relevant and frequent is the presence of mild renal insufficiency in essential hypertension? J Clin Hypertens (Greenwich ) 2002 September;4(5):332-6. (5) Leoncini G, Viazzi F, Parodi D, Ratto E, Vettoretti S, Vaccaro V et al. Mild renal dysfunction and cardiovascular risk in hypertensive patients. J Am Soc Nephrol 2004 January;15 Suppl 1:S88-S90. (6) Iseki K, Oshiro S, Tozawa M, Iseki C, Ikemiya Y, Takishita S. Significance of hyperuricemia on the early detection of renal failure in a cohort of screened subjects. Hypertens Res 2001 November;24(6):691-7. (7) Andress DL. Vitamin D in chronic kidney disease: a systemic role for selective vitamin D receptor activation. Kidney Int 2006 January;69(1):33-43. (8) Teng M, Wolf M, Lowrie E, Ofsthun N, Lazarus JM, Thadhani R. Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy. N Engl J Med 2003 July 31;349(5):446-56. (9) Teng M, Wolf M, Ofsthun MN, Lazarus JM, Hernan MA, Camargo CA, Jr. et al. Activated injectable vitamin D and hemodialysis survival: a historical cohort study. J Am Soc Nephrol 2005 April;16(4):1115-25. (10) Naves-Diaz M, varez-Hernandez D, Passlick-Deetjen J, Guinsburg A, Marelli C, Rodriguez-Puyol D et al. Oral active vitamin D is associated with improved survival in hemodialysis patients. Kidney Int 2008 July 16. (11) Ducy P, Zhang R, Geoffroy V, Ridall AL, Karsenty G. Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell 1997 May 30;89(5):747-54. (12) Aihara K, Azuma H, Akaike M, Ikeda Y, Yamashita M, Sudo T et al. Disruption of nuclear vitamin D receptor gene causes enhanced thrombogenicity in mice. J Biol Chem 2004 August 20;279(34):35798-802. (13) Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP. 1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system. J Clin Invest 2002 July;110(2):229-38. (14) Xiang W, Kong J, Chen S, Cao LP, Qiao G, Zheng W et al. Cardiac hypertrophy in vitamin D receptor knockout mice: role of the systemic and cardiac renin-angiotensin systems. Am J Physiol Endocrinol Metab 2005 January;288(1):E125-E132. (15) Klaus G. Renoprotection with vitamin D: specific for diabetic nephropathy? Kidney Int 2008 January;73(2):141-3. (16) Cozzolino M, Gallieni M, Brancaccio D, Arcidiacono T, Bianchi G, Vezzoli G. Vitamin D retains an important role in the pathogenesis and management of secondary hyperparathyroidism in chronic renal failure. J Nephrol 2006 September;19(5):566-77. (17) Wu-Wong JR, Tian J, Nakane M, Ma J, Fey TA, Kroeger P et al. Cardiovascular disease in chronic kidney failure: the role of VDR activators. Curr Opin Investig Drugs 2006 March;7(3):206-13. (18) Wu-Wong JR. Vitamin D receptor: a highly versatile nuclear receptor. Kidney Int 2007 August;72(3):237-9. (19) Namba M, Kikuchi K, Komura H, Suzuki S, Satoh N, Ohtomo T et al. [Study on uric acid metabolism in patients with primary aldosteronism]. Nippon Naibunpi Gakkai Zasshi 1992 January 20;68(1):51-61. (20) Yokogoshi Y, Saito S. [Abnormal serum uric acid level in endocrine disorders]. Nippon Rinsho 1996 December;54(12):3360-3. (21) Schulz S, Schagdarsurengin U, Suss T, Muller-Werdan U, Werdan K, Glaser C. Relation between the tumor necrosis factor-alpha (TNF-alpha) gene and protein expression, and clinical, biochemical, and genetic markers: age, body mass index and uric acid are independent predictors for an elevated TNF-alpha plasma level in a complex risk model. Eur Cytokine Netw 2004 April;15(2):105-11. (22) Bucher M, Ittner KP, Hobbhahn J, Taeger K, Kurtz A. Downregulation of angiotensin II type 1 receptors during sepsis. Hypertension 2001 August;38(2):177-82. (23) Ouellette DR, Kelly JW, Anders GT. Serum angiotensin-converting enzyme level is elevated in patients with human immunodeficiency virus infection. Arch Intern Med 1992 February;152(2):321-4. (24) Wu VC, Huang JW, Hsueh PR, Yang YF, Tsai HB, Kan WC et al. Renal hypouricemia is an ominous sign in patients with severe acute respiratory syndrome. Am J Kidney Dis 2005 January;45(1):88-95. (25) Khan SR. Crystal-induced inflammation of the kidneys: results from human studies, animal models, and tissue-culture studies. Clin Exp Nephrol 2004 June;8(2):75-88. (26) Ebrahimpour P, Fakhrzadeh H, Heshmat R, Bandarian F, Larijani B. Serum uric acid levels and risk of metabolic syndrome in healthy adults. Endocr Pract 2008 April;14(3):298-304. (27) Vaziri ND, Bai Y, Ni Z, Quiroz Y, Pandian R, Rodriguez-Iturbe B. Intra-renal angiotensin II/AT1 receptor, oxidative stress, inflammation, and progressive injury in renal mass reduction. J Pharmacol Exp Ther 2007 October;323(1):85-93. (28) Zhou X, Matavelli L, Frohlich ED. Uric acid: its relationship to renal hemodynamics and the renal renin-angiotensin system. Curr Hypertens Rep 2006 May;8(2):120-4. (29) Vaziri ND, Bai Y, Ni Z, Quiroz Y, Pandian R, Rodriguez-Iturbe B. Intra-renal angiotensin II/AT1 receptor, oxidative stress, inflammation, and progressive injury in renal mass reduction. J Pharmacol Exp Ther 2007 October;323(1):85-93. (30) Rayner BL, Trinder YA, Baines D, Isaacs S, Opie LH. Effect of losartan versus candesartan on uric acid, renal function, and fibrinogen in patients with hypertension and hyperuricemia associated with diuretics. Am J Hypertens 2006 February;19(2):208-13. (31) Manolis AJ, Grossman E, Jelakovic B, Jacovides A, Bernhardi DC, Cabrera WJ et al. Effects of losartan and candesartan monotherapy and losartan/hydrochlorothiazide combination therapy in patients with mild to moderate hypertension. Losartan Trial Investigators. Clin Ther 2000 October;22(10):1186-203. (32) Rayner BL, Trinder YA, Baines D, Isaacs S, Opie LH. Effect of losartan versus candesartan on uric acid, renal function, and fibrinogen in patients with hypertension and hyperuricemia associated with diuretics. Am J Hypertens 2006 February;19(2):208-13. (33) Iwanaga T, Sato M, Maeda T, Ogihara T, Tamai I. Concentration-dependent mode of interaction of angiotensin II receptor blockers with uric acid transporter. J Pharmacol Exp Ther 2007 January;320(1):211-7. (34) Iwanaga T, Sato M, Maeda T, Ogihara T, Tamai I. Concentration-dependent mode of interaction of angiotensin II receptor blockers with uric acid transporter. J Pharmacol Exp Ther 2007 January;320(1):211-7. (35) Manolis AJ, Grossman E, Jelakovic B, Jacovides A, Bernhardi DC, Cabrera WJ et al. Effects of losartan and candesartan monotherapy and losartan/hydrochlorothiazide combination therapy in patients with mild to moderate hypertension. Losartan Trial Investigators. Clin Ther 2000 October;22(10):1186-203. (36) Enomoto A, Kimura H, Chairoungdua A, Shigeta Y, Jutabha P, Cha SH et al. Molecular identification of a renal urate anion exchanger that regulates blood urate levels. Nature 2002 May 23;417(6887):447-52. (37) Leonard M, Ryan MP, Watson AJ, Schramek H, Healy E. Role of MAP kinase pathways in mediating IL-6 production in human primary mesangial and proximal tubular cells. Kidney Int 1999 October;56(4):1366-77. (38) Navar LG, Nishiyama A. Why are angiotensin concentrations so high in the kidney? Curr Opin Nephrol Hypertens 2004 January;13(1):107-15. (39) Andress DL. Vitamin D in chronic kidney disease: a systemic role for selective vitamin D receptor activation. Kidney Int 2006 January;69(1):33-43. (40) Bellows CG, Reimers SM, Heersche JN. Expression of mRNAs for type-I collagen, bone sialoprotein, osteocalcin, and osteopontin at different stages of osteoblastic differentiation and their regulation by 1,25 dihydroxyvitamin D3. Cell Tissue Res 1999 August;297(2):249-59. (41) Boonstra A, Barrat FJ, Crain C, Heath VL, Savelkoul HF, O'Garra A. 1alpha,25-Dihydroxyvitamin d3 has a direct effect on naive CD4(+) T cells to enhance the development of Th2 cells. J Immunol 2001 November 1;167(9):4974-80. (42) Aihara K, Azuma H, Akaike M, Ikeda Y, Yamashita M, Sudo T et al. Disruption of nuclear vitamin D receptor gene causes enhanced thrombogenicity in mice. J Biol Chem 2004 August 20;279(34):35798-802. (43) Aihara K, Azuma H, Akaike M, Ikeda Y, Yamashita M, Sudo T et al. Disruption of nuclear vitamin D receptor gene causes enhanced thrombogenicity in mice. J Biol Chem 2004 August 20;279(34):35798-802. (44) Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP. 1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system. J Clin Invest 2002 July;110(2):229-38. (45) Xiang W, Kong J, Chen S, Cao LP, Qiao G, Zheng W et al. Cardiac hypertrophy in vitamin D receptor knockout mice: role of the systemic and cardiac renin-angiotensin systems. Am J Physiol Endocrinol Metab 2005 January;288(1):E125-E132. (46) Xiang W, Kong J, Chen S, Cao LP, Qiao G, Zheng W et al. Cardiac hypertrophy in vitamin D receptor knockout mice: role of the systemic and cardiac renin-angiotensin systems. Am J Physiol Endocrinol Metab 2005 January;288(1):E125-E132. (47) Lemmila S, Saha H, Virtanen V, la-Houhala I, Pasternack A. Effect of intravenous calcitriol on cardiac systolic and diastolic function in patients on hemodialysis. Am J Nephrol 1998;18(5):404-10. (48) Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP. 1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system. J Clin Invest 2002 July;110(2):229-38. (49) Smotkin-Tangorra M, Purushothaman R, Gupta A, Nejati G, Anhalt H, Ten S. Prevalence of vitamin D insufficiency in obese children and adolescents. J Pediatr Endocrinol Metab 2007 July;20(7):817-23. (50) Smotkin-Tangorra M, Purushothaman R, Gupta A, Nejati G, Anhalt H, Ten S. Prevalence of vitamin D insufficiency in obese children and adolescents. J Pediatr Endocrinol Metab 2007 July;20(7):817-23. (51) Botella-Carretero JI, varez-Blasco F, Villafruela JJ, Balsa JA, Vazquez C, Escobar-Morreale HF. Vitamin D deficiency is associated with the metabolic syndrome in morbid obesity. Clin Nutr 2007 October;26(5):573-80. (52) de B, I, Ioannou GN, Kestenbaum B, Brunzell JD, Weiss NS. 25-Hydroxyvitamin D levels and albuminuria in the Third National Health and Nutrition Examination Survey (NHANES III). Am J Kidney Dis 2007 July;50(1):69-77. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/40477 | - |
dc.description.abstract | A. 背景
在臨床上觀察,腎臟對體液的調節可以改變電解質以及代謝物的排泄。譬如,體液減少時,腎臟對於尿酸的排泄減少,導致血中尿酸升高;此外,體液減少時也會發生高血鈣症,其主要原因也是腎臟對鈣離子的排泄減少。相反的,體液擴張的時候,尿酸和鈣離子的排泄都增加。 這些現象的機轉過去研究很多,通常是以生理的技術和觀點解釋,但在分子層次的研究則很少。以尿酸為例,其在腎小管的再吸收(reabsorption),其中牽涉和陰離子的主動交換體(active anion excahnger),而其所需的運轉能量則是靠著鈉離子落差(Na gradient)產生的力量。排尿酸藥物(uricosuric agent)可以阻斷這樣的交換體作用。 體液的變化會影響腎素–血管張力素系統,使全身性和腎臟局部的血管張力素II(angiotensin II, AII)增加。AII增加可以增加近端腎小管的鈉離子再吸收,近年來發現,阻斷第一型血管張力素受體(angiotensin type I receptor, AT1R)的藥物(AT1R blockade, ARB),特別是losartan,可以降低尿酸。這類藥物是如何降低尿酸的再吸收,仍不完全清楚。近年,有關尿酸運轉的分子被發現,稱之為第一型尿酸運轉體(URAT1),這個分子如何被調控仍不很清楚。 體液減少影響的鈣離子的排泄,主要發生在近端和遠端腎小管,但是維生素D(vitamin D)的作用在過去的研究顯示,只有在遠端腎小管。然而,研究顯示vitamin D受體(vitamin D receptor, VDR)除了遠端腎小管外,也分布在近端腎小管;果如此,此分布在近端腎小管的VDR是否參與鈣離子的排泄,其調控是否受到AII的影響,是值得研究的主題。 本研究吾人擬在細胞培養層次上,探討AII是否可能經由 AT1R,調節URAT1和VDR的表現,以此作為探討尿酸和鈣離子在近端腎小管的運送機轉模式。 B. 研究設計與方法 腎臟中VDR和URAT-1大多存在近端小管細胞中。以近端小管細胞為主軸,以Angiotensin II作剌激,測定URAT-1/VDR的mRNA and protein 所可能產生的變化。再以Ang II 的拮抗劑,來看是否可以拮抗Ang II所帶來的效果。 C. 結果 Ang II 會增加VDR/URAT-1的表現, Valsartan可部份壓抑VDR/URAT-1 mRNA 及Protein的量的趨勢,PD123319可部份增加VDR/URAT-1 mRNA 及Protein的量的趨勢。 D. 討論 Ang II 可能經由 AT-1的受器,進而調節VDR/URAT-1的反應,可以部份解釋對AT1受器拮抗劑產生預防心血管的效果及產生降尿酸的效果,提供可能的機轉。 | zh_TW |
dc.description.abstract | Background:
Volume status is linked with the function of our kidney. The body volume decreased with increasing serum uric acid level and serum calcium level due to decreasing the clearance of both. Angiotensin II increased proximal tubule sodium reabsorption. Losartan, a kind of angiotensin type I receptor, AT1R blocker has hypouricemia effect. vitamin D receptor has the effect on the renal distal tubule of calcium metabolism. Reports relating hyperuricemia and hypertension have been filed for many decades. Nevertheless, controversy remains concerning serum uric acid concentration as an independent risk factor underlying coronary heart disease (CHD) and essential hypertension or as an indirect marker of renovascular involvement.Recent studies showed VDR and uric acid are prognostic factors in chronic kidney disease. Renal renin-angiotensin system may play a role in hyperuricemia and cardiovascular negative factor. This study is designed to clarify the interaction among Ang II, Vitamin D receptor, uric acid transporter. The immortalized human kidney (HK-2) cell line used during this work is of proximal tubule origin and was originally isolated from a normal human kidney. Methods: Human proximal tubular cells were cultured in hormonally defined medium. Cells at 80% confluency were exposed to Angiotensin II for 1-24 hours. Activity and expression of URAT-1 was examined by PCR and Western blot analysis. Activity and expression of VDR was examined by PCR and Western blot analysis also. Results: Angiotensin II resulted in a dose-dependent increase in the expression of VDR/URAT-1. AT1 antagonist provided the suppression but showed without significant suppression of Ang II effect. AT2 antagonist provided the augmentation but showed without significant ehancement of Ang II effect Conclusion: The effects of rennin-angiotension system on proximal tubular URAT-1/VDR expression are mediated through the pathway of Angiotensin II. Angiotensin II can up-regulate the URAT-1/VDR and be suppressed with Angiotension II receptor type I blocker. To These findings may provide new insights into the role of RAS system in the development and possible therapeutic intervention in hyperuricemia and CKD. | en |
dc.description.provenance | Made available in DSpace on 2021-06-14T16:48:46Z (GMT). No. of bitstreams: 1 ntu-97-P93421009-1.pdf: 1881710 bytes, checksum: 79cf78b6c63091f0239dedad61497700 (MD5) Previous issue date: 2008 | en |
dc.description.tableofcontents | 序言 7
中文摘要 9 A. 背景 9 B. 研究設計與方法 9 C. 結果 10 D. 討論 10 英文摘要 11 II. 縮寫表 13 III. 圖目錄 15 A. 實驗藥物示意圖 15 圖一1 Angiotensin II 15 圖一-2 Valsartan 16 圖一-3 PD123319 17 B. 本實驗所採用的cDNA序列(標底線為primer辨識處) 18 圖二-1 Uric acid transportor transcript variant 1序列 18 圖二-2 Uric acid transportor transcript variant 2序列 21 圖二-3 VDR transcript variant 1序列 23 圖二-4 VDR transcript variant 2序列 27 圖三Concentrations and sources of proximal tubule and interstitial angiotensinogen, angiotensin I and angiotensin II levels 31 圖四 Immunocytochemistry確定URAT-1存在於本細胞中(A/B) 32 圖五Ang II 對URAT-1 Protein的影響 33 圖六AT1/AT2 拮抗劑對URAT-1的影響 34 圖七Ang II 對VDR mRNA的影響 36 圖八Ang II 對VDR protein的影響-劑量與時間的效應 37 圖九AT1/AT2 拮抗劑對VDR的影響 38 IV. 表目錄 39 表一人體尿酸的衡定 39 表二Four compartment theory 40 表三Proposed membrane topology model of the urate/anion exchanger URAT1 (SLC22A12) 41 表四Urate transport in the human renal proximal tubule 42 表五AT1拮抗劑的比較 43 表六維生素D的身體中的代謝路徑及維生素D在腎臟中的角色 44 表七維生素D受器(VDR)存在的組織 45 表八VDR活化產生調控的蛋白質 46 V. 論文正文 47 A. 研究背景 47 1. 維生素D和renin-angiotensin system的關係 48 2. 尿酸的角色和renin-angiotensin system的關係 48 B. 實驗假說 50 C. 實驗目的 51 D. 研究方法與材料 51 1. 實驗材料 51 2. 細胞培養 54 3. Immunocytochemistry確定URAT-1的存在 55 4. Angiotensin II對HK2 細胞的URAT-1和VDR影響-劑量與時間的效應 55 5. AT1與AT2拮抗劑對URAT-1和VDR調控的影響 56 6. 以反轉錄聚合酵素連鎖反應(RT-PCR)測定URAT-1 mRNA的表現 56 7. 以西方墨點法(Western blot)測定URAT-1蛋白質表現 57 8. 統計方法 58 E. 結果 59 1. 細胞培養和基本的技術的培養: 59 2. Immunocytochemistry確定URAT-1存在於本細胞中。 59 3. Ang II 對URAT-1 mRNA/Protein的影響-劑量與時間的效應 59 4. Ang II 對 VDR mRNA/Protein的影響-劑量與時間的效應 60 5. AT1拮抗劑(Valsartan)對URAT-1 mRNA/Protein的影響 60 6. AT2拮抗劑(PD123319)對URAT-1 mRNA/Protein的影響 60 7. AT1拮抗劑(Valsartan)和AT2拮抗劑(PD123319)對URAT-1 mRNA/Protein的影響 60 8. AT1拮抗劑(Valsartan)對VDR mRNA/Protein的影響 61 9. AT2拮抗劑(PD123319)對VDR mRNA/Protein的影響 61 10. AT1拮抗劑(Valsartan)和AT2拮抗劑(PD123319)對VDR Mrna/ Protein的影響--------------------------------------------------------------------61 F. 討論及展望 62 VI. 參考文獻 66 圖目錄 A. 實驗藥物示意圖 15 圖一1 Angiotensin II 15 圖一-2 Valsartan 16 圖一-3 PD123319 17 B. 本實驗所採用的cDNA序列(標底線為primer辨識處) 18 圖二-1 Uric acid transportor transcript variant 1序列 18 圖二-2 Uric acid transportor transcript variant 2序列 21 圖二-3 VDR transcript variant 1序列 23 圖二-4 VDR transcript variant 2序列 27 圖三Concentrations and sources of proximal tubule and interstitial angiotensinogen, angiotensin I and angiotensin II levels 31 圖四 Immunocytochemistry確定URAT-1存在於本細胞中(A/B) 32 圖五Ang II 對URAT-1 Protein的影響 33 圖六AT1/AT2 拮抗劑對URAT-1的影響 34 圖七Ang II 對VDR mRNA的影響 36 圖八Ang II 對VDR protein的影響-劑量與時間的效應 37 圖九AT1/AT2 拮抗劑對VDR的影響 38 表目錄 表一人體尿酸的衡定 39 表二:Four compartment theory 40 表三Proposed membrane topology model of the urate/anion exchanger URAT1 (SLC22A12) 41 表四Urate transport in the human renal proximal tubule 42 表五AT1拮抗劑的比較 43 表六維生素D的身體中的代謝路徑及維生素D在腎臟中的角色 44 表七維生素D受器(VDR)存在的組織 45 表八VDR活化產生調控的蛋白質 46 | |
dc.language.iso | zh-TW | |
dc.title | 腎臟近端腎小管中維生素D、尿酸代謝與第二型血管加壓素之關係探討 | zh_TW |
dc.title | The relationship between Vitamin D, Urate metabolism and Angiotensin II in renal proximal tubule | en |
dc.type | Thesis | |
dc.date.schoolyear | 96-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 何奕倫,蔡墩仁 | |
dc.subject.keyword | 維生素 D受器,尿酸,第二型血管加壓素,近端小管細胞, | zh_TW |
dc.subject.keyword | URAT-1,uric acid,Vit D,Vit D receptor,CKD,Angiotensin II,renal proximal tubule cel, | en |
dc.relation.page | 73 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2008-07-31 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 臨床醫學研究所 | zh_TW |
顯示於系所單位: | 臨床醫學研究所 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-97-1.pdf 目前未授權公開取用 | 1.84 MB | Adobe PDF |
系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。