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研究生:林中成
研究生(外文):Chung-Cheng Lin
論文名稱:P-glycoprotein在第一型及第二型糖尿病小鼠腎臟表現量及功能之探討
論文名稱(外文):P-glycoprotein expression and function in kidney of inbred mice with type 1 or type 2 diabetes
指導教授:林君榮
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:藥學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2008
畢業學年度:97
語文別:中文
論文頁數:90
中文關鍵詞:糖尿病腎臟P-gp轉運蛋白
外文關鍵詞:DiabetesKidneyP-glycoprotein
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糖尿病是一種多樣性的代謝症候群,會造成全身性的代謝疾病,進而引起視網膜、腎臟、神經和心血管方面的病變。研究指出P-glycoprotein豐富地存在於腎臟中,且與藥物等異質體的代謝有密切關係。本篇研究主要是探討在糖尿病的情形下,P-gp蛋白質的表現量與功能是否會受到影響,而先前的研究指出,在腦部caveolin-1、2蛋白質的表現會影響P-gp的表現量與功能性,因此我們也探討caveolin-1、2蛋白質是否會對腎臟中的P-gp造成影響。
本研究所使用的自發性第一型和第二型糖尿病動物模式分別為NOD (non-obese diabetic) 和NZO (New Zealand obese) 小鼠,而對照組則是使用NON (non-obese, non-diabetic) 小鼠。從西方墨點法與組織免疫染色的結果顯示不論在第一型糖尿病NOD母鼠或是第二型糖尿病NZO公鼠的腎臟,其P-gp表現量皆明顯低於對照組NON小鼠。 針對caveolin-1、2蛋白質而言,其西方墨點法的結果顯示,不論在NOD母鼠或是NZO公鼠,其表現量也呈現減少的趨勢,就其組織免疫染色結果,我們可以觀察到caveolin-1、2主要分布在微血管和腎遠端小管基底側,其表現位置與P-gp並無相關,因此推論在腎臟中caveolin-1、2對於P-gp的表現量與功能可能沒有太大的影響性。我們進行小鼠腎臟刷狀絨毛膜微粒 (BBMV)的萃取,加以研究P-gp受質digoxin與腎臟BBMV攝取量的多寡,分析糖尿病對腎臟P-gp功能的影響性。實驗結果顯示糖尿病小鼠腎臟的BBMV對於P-gp受質digoxin攝取量有顯著的上升,顯示出糖尿病小鼠腎臟中P-gp的功能是下降的。
在後續的實驗中,我們使用經過基因轉殖MDR1之犬腎小管上皮細胞MDCK-MDR1,作為研究糖尿病與腎臟細胞P-gp表現量之體外試驗,研究在高血糖和高胰島素環境下,是否會造成腎臟細胞株P-gp表現量的改變。將萃取的細胞膜蛋白作西方墨點法試驗,其結果顯示給予高濃度葡萄糖和胰島素皆會造成MDCK-MDR1細胞株P-gp表現量下降。
本篇研究的結果顯示,不論在自發性第一型或是第二型糖尿病小鼠的腎臟中,P-gp的表現量與功能是顯著下降的,而就體外細胞試驗的結果顯示,高血糖的環境下會降低P-gp蛋白質的表現量,但詳細機轉與調控因子則需更進一步的研究。
Diabetes mellitus is a systematic metabolic disease and is related to a number of complications including retinopathy, nephropathy, neuropathy, and vascular diseases. Recent studies showed that diabetic nephropathy is a leading cause of end-stage kidney disease. Some reports indicated that P-gp is abundant in the kidney, and is closely related to the excretion and metabolism of xenobiotics and drugs. Moreover, previous studies showed that the levels of caveolin affect the expression and function of P-gp in the brain. Therefore, the current study is to investigate the relationship between caveolin and P-gp in the kidney of diabetes mellitus.
Inbred non-obese diabetic (NOD) and New Zealand obese (NZO) mice were used as the models of type 1 and type 2 diabetes, respectively, and non-obese non-diabetic (NON) mice were used as control. Western blots and immunohistochemical staining showed that protein expressions of P-gp and caveolin were both significantly lower in the kidney of male NZO and female NOD mice than that of male and female NON mice. In addition, immunohistochemical staining indicated that P-gp is localized to the apical membrane of proximal tubule, while caveolin is localized to the endothelial cells and the basolateral membrane of the distal tubular. These results suggested that P-gp expression in the kidny may not be directly affected by caveolin. Then, we assessed the function of P-gp by using mice renal brush-border membrane vesicles (BBMVs) and digoxin was used as a substrate of P-gp. The result indicated that the uptake of digoxin in diabetic mice were higher than that in NON mice. Thus, we concluded that the activity of P-gp is decreased in the kidney of diabetic mice.
To investigate the correlation between P-gp and hyperglycimia, MDCK-MDR1 cells were used as an in vitro renal model and treated with high concentration of glucose and insulin. The results showed that high concentration of glucose and insulin can reduce the expression of P-gp.
In conclusion, the expression and activity of P-gp are decreased in the diabetic mice. Further studies are required to understand the regulatory pathway and mechanism of renal P-gp.
中文摘要 i
Abstract iii
目錄 v
圖目錄 x
表目錄 xii
第1章 序論 1
1.1 糖尿病 (Diabetes Mellitus) 1
1.1.1 糖尿病簡介 1
1.2 糖尿病實驗動物簡介 3
1.3 腎臟與藥物代謝 5
1.3.1 腎臟的簡介 5
1.3.2 藥物排泄 5
1.3.3 糖尿病與腎病變 7
1.4 P-glycoprotein之簡介 8
1.4.1 P-glycoprotein的發現與分布 8
1.4.2 P-gp的結構 9
1.4.3 P-gp的功能 9
1.4.4 P-gp 與糖尿病之關係 10
1.5 Caveolin之簡介 11
1.5.1 Caveolin的分布 11
1.5.2 Caveolin的結構 11
1.5.3 Caveolin的功能介紹 12
1.5.4 Caveolin與糖尿病之關係 13
1.6 腎臟藥物動力學研究 14
第2章 研究目的 18
第3章 實驗材料 19
3.1 實驗動物 19
3.2 血糖監測試驗 19
3.3 膠體電泳及西方墨點法 19
3.3.1 試劑 19
3.3.2 材料與設備 21
3.3.3 一級抗體 21
3.4 免疫組織化學染色 21
3.4.1 試劑 21
3.4.2 儀器設備 22
3.4.3 一級抗體 22
3.4.4 二級抗體 22
3.5 溶液配方 22
3.6 分離小鼠小腸刷狀外緣細胞膜微粒(BBMV) 24
3.6.1 試劑 24
3.6.2 設備 24
3.7 蛋白質濃度測定 25
3.7.1 試劑 25
3.7.2 設備 25
3.8 鹼性磷酸酶之活性測定 25
3.8.1 試劑 25
3.8.2 設備 25
3.9 鈉鉀腺苷三磷酸水解酶之活性測定 25
3.9.1 試劑 25
3.10 放射性物質攝取量之測定 26
3.10.1 試劑 26
3.10.2 設備 26
3.11 MDCK細胞培養 26
3.11.1 試劑 26
3.11.2 材料 27
3.11.3 設備 27
第4章 研究方法 28
4.1 實驗動物血糖監測 28
4.2 小鼠腎組織細胞膜粹取 28
4.3 蛋白質濃度測定 (Bio-Rad DC protein assay) 29
4.3.1 Loery methood 29
4.3.2 Coomassive blue 29
4.4 蛋白質表現量分析 30
4.4.1 SDS Page配置 30
4.4.2 Runnig 30
4.4.3 SDS-PAGE蛋白質轉漬與西方墨點法 30
4.5 免疫組織化學染色 31
4.5.1 4P福馬林灌流 31
4.5.2 石蠟包埋 32
4.5.3 玻片鍍膜 (coating): 32
4.5.4 切片及貼片 32
4.5.5 免疫組織化學染色 (Immunohistochemistry) 32
4.5.6 蘇木精染色 34
4.5.7 封片與攝影 34
4.6 分離小鼠腎臟小管刷狀外緣細胞膜微粒 (BBMV): 34
4.7 鹼性磷酸酶活性測定 (Alkaline phosphatase activity) 36
4.8 鈉-鉀腺苷三磷酸水解酶活性測定 37
4.9 放射性物質攝取量測定 38
4.9.1 Digoxin與時間相依性研究 38
4.9.2 糖尿病鼠和digoxin攝取量之研究 39
4.10 MDCK細胞株的培養 39
4.11 高濃度葡萄糖與胰島素處理MDCK-MDR1細胞株 40
4.12 MDCK細胞株細胞膜的粹取 41
第5章 實驗結果 44
5.1 小鼠生理數據監測 44
5.1.1 年齡 44
5.1.2 體重監測 44
5.1.3 血糖監測 44
5.2 糖尿病與腎臟特定蛋白表現量之研究 44
5.2.1 糖尿病影響腎臟caveolin-1蛋白質表現量之研究 45
5.2.2 糖尿病影響腎臟caveolin-2蛋白質表現量之研究 45
5.3 糖尿病影響腎臟上特定蛋白質表現量之研究 46
5.3.1 糖尿病影響P-gp在腎臟表現量之研究 46
5.3.2 糖尿病影響caveolin-1在腎臟表現量之研究 46
5.3.3 糖尿病影響caveolin-2在腎臟表現量之研究 47
5.4 糖尿病影響腎臟P-gp功能性之研究 47
5.4.1 腎臟BBMV (brush-border membrane vesicles)純化結果 47
5.4.2 腎臟BBMV與Digoxin攝取量之研究結果 47
5.5 MDCK cell lines西方墨點法之結果 48
5.6 高濃度glucose以及insulin處理之MDCK-MDR1對於P-gp之影響 48
第6章 結果討論 65
6.1 糖尿病與P-gp的相關性 65
6.2 糖尿病影響P-gp功能與表現量之探討 66
6.3 Caveolin表現量與影響P-gp功能之探討 68
6.4 糖尿病影響腎臟功能之探討 70
6.5 糖尿病與影響腎臟P-gp表現的因子探討 71
第7章 結論 76
第8章 參考資料 78
附錄………………………………………………………86
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