臺灣博碩士論文加值系統

鎳、鎘、砷是現今環境和工業上重要的污染物，對腎臟的系統會產生多變性的影響。這些金屬已被確認為致癌物，但至今鎳、鎘、砷三種重金屬對於腎細胞的作用還不是很清楚。在本研究中，我們探討鎳、鎘、砷對豬腎前曲小管上皮細胞(LLC-PK1細胞)所造成的氧化傷害，凋亡蛋白的表現和細胞內鈣離子濃度變化。LLC-PK1 cells分別以醋酸鎳 (Ni(CH3COO)2)(0-500 μM)、氯化鎘 (CdCl2)(0-8 μM)或亞砷酸鈉 (NaAsO2) (0-8 μM)處理不同時間後觀察細胞的變化。氧化壓力的改變，以測定細胞膜上脂質過氧化與細胞內氧化物含量來評估。經過鎳、鎘、砷處理後LLC-PK1細胞的細胞存活率下降，而細胞內氧化物含量和脂質過氧化增加。當細胞經過鎳處理後，會使得NF-κB, Bax, Bad, Bcl-x表現量增加， Bcl-2表現量下降，而Fas-L沒有差異性，而經由鎘或砷處理的細胞，其NF-κB,Bcl-2, Bad表現量增加而Fas-L, Bax沒有差異性。此外以鎘或砷處理LLC-PK1細胞6小時後，藉由比較細胞核質中NF-κB的蛋白質含量可發現NF-κB的變化，鎳則需要長的時間，但鎳、鎘或砷都會隨著處理時間增長而愈趨顯著。在另一方面，探討細胞在含有鈣離子溶液及外鈣移除後分別經由鎳、鎘、砷處理下，細胞內鈣離子濃度變化的情形。經由鎳與砷處理後，在含有鈣離子溶液中鎳或砷會促進細胞內鈣離子濃度增加，但相反的在外鈣移除時，發現到鎳或砷會抑制細胞內鈣離子的濃度。然而經鎘處理之後，在含有鈣離子溶液及在外鈣移除中都會使得細胞內鈣離子濃度增加。在結果顯示鎳或砷會與鈣離子來競爭鈣離子通道，而鎘則會促進鈣離子的開啟。因此，在氧化壓力與細胞內鈣離子中鎳、鎘、砷所引起腎細胞的分子毒性上扮演一個很重要的角色。

Nickel (Ni), cadmium (Cd) and arsenic (As) are important environmental and industrial contaminants, which will produce varieties of effects on the renal system. These metals are recognized as carcinogen, however, the mechanisms remain unclear. In this study, we investigated the effects of Ni, Cd and As on oxidative stress, expression of apoptic proteins and Ca2+ influx in LLC-PK1 cells. LLC-PK1 cells were treated with nickel (II) acetate (Ni(CH3COO)2) (0-500μM), cadmium chloride (CdCl2 ) (0-8μM) and sodium arsenic (NaAsO2 ) (0-8μM) and then observed their later varcation. The oxidative stress was evaluated by lipid peroxidation and intracellular oxidants. After Ni, Cd or As treatment resulted in the decreasing of the viability, and the increasing of intracellular oxidants and lipid peroxidation. The expression of Bax, Bad, Bcl-x were increased, while Bcl-2 were decreased in Ni-treated LLC-Pk1 cells. In Cd or As treated, the expression of NF-κB, Bcl2 and Bad were increased, while it makes have not significant difference on Fas-L and Bax.As we treat LLP-PK1 cells by ways of Cd or As, we could saw the varcation of NF-κB by comparison of the expression of nuclear for 6hr. The result demonstrates significant expression with the increasing of time treated by any of the three elements.
On the other hand, the intracellular Ca2+ levels ([Ca2+]i) in Ni-, Cd- and As-treated LLC-PK1 cells were explored. [Ca2+]i were measured by using the Ca2+-sensitive dye fura-2. However,in the treatment of Ni or As the Ca2+-contaning buffer of which wrer increased in [Ca2+]i , on the contrary, it was found the inhibit of [Ca2+]i in Ca2+-free buffer. With the treatment of Cd, it increased either in Ca2+-contaning buffer or Ca2+-free buffer. The results may indicate that Ni or As resulted inhibitor, while Cd play as enhancer of calcium entry pathway. The oxidative stress and intracellular Ca2+ may play important role in Ni-, Cd- or As-induced renal molecule cytotoxicity.

誌謝 ----------------------------------------------------------------------------------------------------------------------- i
中文摘要 ---------------------------------------------------------------------------------------------------------------- ii
英文摘要----------------------------------------------------------------------------------------------------------------- iv
目錄----------------------------------------------------------------------------------------------------------------------- vi
表目錄------------------------------------------------------------------------------------------------------------------ viii
圖目錄------------------------------------------------------------------------------------------------------------------ viii
縮寫表---------------------------------------------------------------------------------------------------------------------ix
第一章 緒論------------------------------------------------------------------------------------------------------------- 1
第二章 文獻探討------------------------------------------------------------------------------------------------------- 5
第一節 鎳、鎘、砷化物之簡介------------------------------------------------------------------------------------ 5
一 鎳化物之簡介------------------------------------------------------------------------------------------------------- 5
二 鎘化物之簡介------------------------------------------------------------------------------------------------------- 6
三 砷化物之簡介------------------------------------------------------------------------------------------------------- 8
第二節 鎳、鎘、砷化物之毒理機制---------------------------------------------------------------------------- 10
一 活化型氧原子(ROS)的形成------------------------------------------------------------------------------------ 10
二 細胞的tyrosine磷酸化(phosphorylation)影響--------------------------------------------------------------- 11
三 對細胞的訊息傳遞之影響--------------------------------------------------------------------------------------12
四 對細胞週期之影響----------------------------------------------------------------------------------------------- 15
五 對細胞的細胞凋亡(apoptosis)之影響------------------------------------------------------------------------17
第三節 鈣離子與細胞生理-----------------------------------------------------------------------------------------21
一 鈣離子在細胞中扮演的角色-----------------------------------------------------------------------------------21
二 細胞鈣訊號的作用機轉-----------------------------------------------------------------------------------------22
三 鈣與細胞的凋亡和毒殺-----------------------------------------------------------------------------------------25
第三章 材料與方法---------------------------------------------------------------------------------------------------26
第一節 實驗材料------------------------------------------------------------------------------------------------------26
一 細胞株----------------------------------------------------------------------------------------------------------------26
二 培養基(Medium) ---------------------------------------------------------------------------------------------------26
三 實驗藥品-------------------------------------------------------------------------------------------------------------26
四 其他實驗材料------------------------------------------------------------------------------------------------------ 30
五 實驗儀器------------------------------------------------------------------------------------------------------------ 32
第二節 實驗方法------------------------------------------------------------------------------------------------------ 35
一 細胞培養------------------------------------------------------------------------------------------------------------ 35
二 重金屬的處理------------------------------------------------------------------------------------------------------ 35
三 細胞毒性之測定--------------------------------------------------------------------------------------------------- 36
四 脂質過氧化測定--------------------------------------------------------------------------------------------------- 37
五 細胞內氧化物含量測定------------------------------------------------------------------------------------------39
六 全蛋白質之萃取--------------------------------------------------------------------------------------------------- 40
七 細胞核蛋白之萃取------------------------------------------------------------------------------------------------ 40
八 蛋白質濃度測定--------------------------------------------------------------------------------------------------- 41
九 蛋白質之膠體電泳分析------------------------------------------------------------------------------------------42
十 蛋白質轉漬及西方墨點法---------------------------------------------------------------------------------------43
十一 細胞週期分析--------------------------------------------------------------------------------------------------- 44
十二 [Ca2+]i的測定--------------------------------------------------------------------------------------------------- 46
第四章 研究結果------------------------------------------------------------------------------------------------------ 48
一 鎳、鎘、砷對豬腎細胞株（LLC-PK1）的細胞存活率之分析----------------------------------------48
二 鎳、鎘、砷對豬腎細胞株（LLC-PK1）的脂質過氧化物含量之分析------------------------------49
三 鎳、鎘、砷對豬腎細胞株（LLC-PK1）的細胞內氧化物含量之分析------------------------------49
四 鎳、鎘、砷在時間上對豬腎細胞株（LLC-PK1）的細胞內過氧化物含量表現-----------------50
五 鎳、鎘、砷會改變豬腎細胞株（LLC-PK1）的apoptotic protein 表現------------------------------51
六 鎳、鎘、砷對豬腎細胞株（LLC-PK1）所造成的NF-κB 活性改變的影響------------------------52
七 鎳、鎘、砷會影響LLC PK-1 cells的細胞週期-------------------------------------------------------------52
八 鎳、鎘、砷所誘發之鈣離子濃度的變化--------------------------------------------------------------------54
九 外鈣移除時鎳、鎘、砷所誘發之鈣離子濃度的變化----------------------------------------------------54
第五章 討論與結論--------------------------------------------------------------------------------------------------- 56
參考文獻 參考文獻--------------------------------------------------------------------------------------------------- 68
附表 -----------------------------------------------------------------------------------------------------------------------82
附圖 -----------------------------------------------------------------------------------------------------------------------85

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