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研究生:李築宜
研究生(外文):Chu-I Lee
論文名稱:瘦素、第二型血管張力素及結締組織生長因子在高度糖化終產物對NRK-49F細胞所致生物效應的角色
論文名稱(外文):Leptin, angiotensin II and CTGF in advanced glycation end-product-induced effects in NRK-49F cells
指導教授:莊麗月莊麗月引用關係
指導教授(外文):Lea-Yea Chuang
學位類別:博士
校院名稱:高雄醫學大學
系所名稱:醫學研究所博士班
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2005
畢業學年度:93
語文別:中文
論文頁數:136
中文關鍵詞:第二型血管張力素結締組織生長因子高度糖化終產物瘦素
外文關鍵詞:angiotensin IICTGFAGELeptin
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糖尿病腎病變的病理特徵為腎絲球病變和腎小管間質擴張,並且最後惡化成腎臟纖維化,此纖維化並且包括腎小管間質纖維化。例如,我們曾經證明在腎間質纖维母細胞(NRK-49F cells)內,高度糖化終產物(AGE)會經由JAK2訊息傳導路徑誘發細胞增生和膠原蛋白產生。瘦素(leptin)是一個藉著長型瘦素接受器 (Ob-Rb) 而活化 Janus kinas 2 (JAK2) 的細胞激素。近年來許多研究結果顯示瘦素和結締組織生長因子(CTGF)也可能與腎臟纖維化有關係。然而在高度糖化終產物誘發之下的生物效應,其中瘦素和結締組織生長因子之間的關係與所扮演的角色,目前為止並不清楚。第二型血管張力素(Ang II)和結締組織生長因子在糖尿病腎病變的致病因更是非常重要的兩個調節因子。因此,我們探討了在NRK-49F細胞株內關於在高度糖化終產物所誘發的生物效應之下,瘦素、第二型血管張力素、JAK2和結締組織生長因子的角色。
首先我們發現瘦素和高度糖化終產物在第三天和第七天能增加細胞增生和膠原蛋白表現。高度糖化終產物也呈時間性地於第二天至三天後增加瘦素蛋白質的表現。高度糖化終產物在第三天增加結締組織生長因子mRNA表現,在第五天增加結締組織生長因子蛋白質的表現。AG-490(JAK2抑制劑)能逆轉高度糖化終產物所誘發的瘦素mRNA和蛋白質的表現。AG-490和Ob-Rb反義股寡去氧核糖核酸(antisense ODNs)能逆轉高度糖化終產物所誘發的結締組織生長因子mRNA和蛋白質的表現。AG-490和結締組織生長因子反義股寡去氧核糖核酸(CTGF-antisense ODNs)能逆轉高度糖化終產物所誘發的細胞增生和膠原蛋白表現。此外,瘦素呈劑量性地(0.2-1μg/ml)和時間性地(1-2天)增加結締組織生長因子蛋白質的表現,AG-490於第二天刺激細胞後能逆轉瘦素(1μg/ml)所誘發的結締組織生長因子蛋白質的表現。而AG-490和結締組織生長因子反義股寡去氧核糖核酸在與細胞培養三天後能逆轉瘦素所誘發的細胞增生和膠原蛋白表現。
AngII (10-7 M)則在第三天增加細胞增生和第一型膠原蛋白質產生。AGE(150μg/ml)在第二天增加血管張力素原(angiotensinogen)蛋白質的表現;並且這個生物效應能被AG-490 (JAK2蛋白質抑制劑)所逆轉。AngII (10-7 M)在第一天增加結締組織生長因子mRNA的表現,並且在第二天增加結締組織生長因子蛋白質表現;這些生物效應均能被AG-490 (JAK2蛋白質抑制劑)所逆轉。另外,losartan (血管張力素第一型接受器阻斷劑)和captopril (血管張力素轉化酶抑制劑)兩者均能逆轉因高度糖化終產物所誘發的結締組織生長因子mRNA和蛋白質的表現,以及逆轉因高度糖化終產物所誘發的細胞增生和第一型膠原蛋白質產生的效應。AG-490和CTGF antisense(不是sense)ODN也能在第三天逆轉AngII (10-7 M)所誘發的細胞增生和第一型膠原蛋白質產生。
我們得到的結論是,在NRK-49F細胞內AGE (150μg/ml)所誘發的細胞增生和第一型膠原蛋白產生與經由AngII-JAK2-CTGF和leptin-JAK2-CTGF的訊息傳遞路徑調控有關。還有,第二型血管張力素和瘦素所誘發的細胞增生和第一型膠原蛋白產生也和JAK2-CTGF訊息傳導路徑有關。此外,已經有報告證實第二型血管張力素能誘發瘦素產生。因此我們預期在這些細胞內,高度糖化終產物所誘發的細胞增生和第一型膠原蛋白表現依賴AGE-Ang II-leptin-JAK2-CTGF路徑的調控。
Diabetic nephropathy (DN) is characterized by glomerulopathy and tubulointerstitial expansion followed by renal fibrosis, including tubulointerstitial fibrosis. For example, we have shown that advanced glycation end-product (AGE)-induced mitogenesis and collagen production are dependent on the JAK2 pathway in normal rat kidney interstitial fibroblasts (NRK-49F cells). Leptin is a Janus kinase 2 (JAK2)-activating cytokine via the long form leptin receptor (Ob-Rb). Leptin and connective tissue growth factor (CTGF) are involved in renal fibrosis. However, the relationship between leptin and CTGF in terms of AGE-induced effects remains unknown. Moreover, angiotensin II (Ang II) and CTGF are important in the pathogenesis of DN. Thus, we studied the role of leptin, Ang II, JAK2 and CTGF in AGE-induced effects in NRK-49F cells.
We found that leptin and AGE increased mitogenesis and type I collagen protein expression at 3 d and 7 d, respectively. AGE also increased leptin mRNA and protein expression at 2 d and 3 d. AGE increased CTGF mRNA and protein expression at 3 d and 5 d. AG-490 (JAK2 inhibitor) abrogated AGE-induced leptin mRNA and protein expression. AG-490 and Ob-Rb antisense oligodeoxynucleotides (ODN) abrogated AGE-induced CTGF mRNA and protein expression. AG-490 and CTGF antisense ODN abrogated AGE-induced mitogenesis and collagen protein expression. Additionally, leptin dose (0.2-1 �慊/ml) and time (1-2 d)-dependently increased CTGF protein expression. AG-490 abrogated leptin (1 �慊/ml)-induced CTGF protein expression at 2 d. AG-490 and CTGF antisense ODN abrogated leptin-induced mitogenesis and collagen protein expression at 3 d.
Additionally, we found that Ang II (10-7 M) increased mitogenesis and type I collagen production at 3 d. We also found that AGE increased angiotensinogen protein at 2 d, which was attenuated by AG-490 (a JAK2 inhibitor). Ang II (10-7 M) increased CTGF mRNA and protein expression at 1 d and 2 d, which were attenuated by AG-490. Moreover, losartan (a type I angiotensin receptor blocker) and captopril (an angiotensin converting enzyme inhibitor) attenuated AGE-induced CTGF mRNA/protein expression while attenuating AGE-induced mitogenesis and type I collagen production. Moreover, AG-490 and CTGF antisense (but not sense) oligodeoxynucleotide attenuated Ang II (10-7 M)-induced mitogenesis and type I collagen production at 3 d.
We conclude that AGE-induced mitogenesis and type I collagen production are dependent on the Ang II-JAK2-CTGF and leptin-JAK2-CTGF pathways while Ang II and leptin-induced mitogenesis and type I collagen production are dependent on the JAK2-CTGF pathway. Moreover, because previous studies by others showed that Ang II can induce leptin, we speculate that AGE-induced mitogenesis and type I collagen production may be dependent on the AGE-Ang II-leptin-JAK2-CTGF pathway in these cells.
目 次

中文總摘要 ---------------------------------------1
英文總摘要 ---------------------------------------4
縮寫表 --------------------------------------------7
化學藥品與試劑組 ----------------------------------9
總緒論 --------------------------------------------11
第一節 高度糖化終產物與糖尿病腎病變---------------------11
第二節 生長因子與糖尿病腎病變---------------------------18
第三節 瘦素與糖尿病腎病變-------------------------------21
第四節 第二型血管張力素與糖尿病腎病變-------------------25
第五節 結締組織生長因子與糖尿病腎病變-------------------31
第六節 JAK2訊息傳遞路徑之探討--------------------------38
第七節 研究方向與目的-----------------------------------42
第一章 瘦素和結締組織生長因子在高度糖化終產物對
NRK-49細胞所致生物效應的角色--------------45
英文摘要-------------------------------------------46
中文摘要-------------------------------------------48
緒論-----------------------------------------------50
材料與方法---------------------------------------- 53
高度糖化終產物之製備------------------------------------53
細胞培養------------------------------------------------53
胸腺嘧啶標誌法------------------------------------------54
碳酸十二酯鈉-聚丙烯胺凝膠電泳---------------------------55
西方墨點法----------------------------------------------55
合成反向寡去氧核糖核酸與細胞轉殖------------------------56
反轉錄酶聚合鏈反應--------------------------------------57
RNA萃取與北方墨點法-------------------------------------57
膠原蛋白電泳分析----------------------------------------58
實驗統計------------------------------------------------59
結果----------------------------------------------60
討論----------------------------------------------66
圖表----------------------------------------------70
圖一----------------------------------------------------71
圖二----------------------------------------------------72
圖三----------------------------------------------------73
圖四----------------------------------------------------74
圖五----------------------------------------------------75
圖六---------------------------------------------------76
圖七---------------------------------------------------77
圖八---------------------------------------------------78
圖九---------------------------------------------------79
圖十---------------------------------------------------80
圖十一-------------------------------------------------81
第二章 高度糖化終產物於NRK-49F細胞內所誘發的細
胞增生和膠原蛋白產生依賴第二型血管張力素
和結締組織生長因子的調控-----------------82
英文摘要-----------------------------------------83
中文摘要-----------------------------------------85
緒論---------------------------------------------87
材料與方法---------------------------------------89
高度糖化終產物之製備----------------------------------89
細胞培養----------------------------------------------89
胸腺嘧啶標誌法----------------------------------------90
碳酸十二酯鈉-聚丙烯胺凝膠電泳-------------------------91
西方墨點法--------------------------------------------91
合成反向寡去氧核糖核酸與細胞轉殖----------------------92
膠原蛋白電泳分析---------------------------------------92
RNA萃取與北方墨點法-----------------------------------94
實驗統計----------------------------------------94
結果 -------------------------------------------95
討論 -------------------------------------------100
圖表 -------------------------------------------104
圖一--------------------------------------------------105
圖二--------------------------------------------------106
圖三--------------------------------------------------107
圖四--------------------------------------------------108
圖五--------------------------------------------------109
圖六--------------------------------------------------110
圖七--------------------------------------------------111
圖八--------------------------------------------------112
總結論 -----------------------------------------113
參考文獻 ---------------------------------------120
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