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研究生:楊子漢
研究生(外文):Zih-Han Yang
論文名稱:纖維母細胞生長因子23與Klotho在高糖培養NRK-49F細胞及糖尿病大鼠腎臟中的角色
論文名稱(外文):Role of Fibroblast Growth Factor 23 and Klotho in high glucose-cultured NRK-49F cells and diabetic rat kidney
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:碩士
校院名稱:高雄醫學大學
系所名稱:生物化學研究所
學門:生命科學學門
學類:生物化學學類
論文種類:學術論文
論文出版年:2013
畢業學年度:101
語文別:中文
論文頁數:113
中文關鍵詞:纖維母細胞生長因子23Klotho
外文關鍵詞:Fibroblast Growth Factor 23Klotho
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糖尿病腎病變是糖尿病患者常見的嚴重併發症,而糖尿病也在國人十大死因之一。糖尿病腎病特徵主要是腎絲球肥大、腎臟細胞增生,細胞外間質(extracellular matrix,ECM)堆積,造成腎絲球硬化產生腎臟纖維化,最終導致末期腎病變(end-stage renal disease,ESRD)。已知纖維母細胞生長因子23 (Fibroblast growth factor 23,FGF23),在腎臟主要是抑制腎小管對磷酸鹽的吸收,此外,並可抑制1α-hydroxylase之表現進而調節維生素D的活性。FGF23結合於纖維細胞生長因子受體(FGFR)和跨膜蛋白Klotho形成的共同受體,進而活化細胞訊息傳遞。已知FGF23與慢性腎病變(CKD) 有關, 亦發現將Klotho基因過表現於腎臟中可以減緩慢性腎病變,而Klotho基因踢除鼠顯現類似慢性腎病變的特徵。然而FGF23與Klotho在糖尿病腎病變之角色及其相關性尚不清楚。因此本研究首先以正常大鼠腎纖維母細胞(NRK-49F)為對象,發現高糖刺激NRK-49F細胞三天後,利用Western blot及RT-PCR發現FGF23和Klotho蛋白質和mRNA表現皆明顯增加。利用各種訊息傳遞抑制劑研究發現,高糖經由MAPK、MEK1、JNK、TGF-?牷BPI3K和JNK/STAT訊息路徑皆可調控FGF23和Klotho的表現。分別外加FGF23 (50 ng)及Klotho (2 nM)處理NRK-49F細胞,兩者皆促進Fibronectin、Collagen IV、MMP-9和PAI-1產生,且皆呈現劑量效應及時間效應。利用代表TGF-?? promoter及其bioactivity之兩種plasmid轉殖入細胞,發現FGF23和Klotho能促進其轉錄活性。且發現FGF23可促進mTOR、JAK2、STAT3、AKT及Smad2/3之磷酸化,FGF23也會促進Klotho的表現。此外Klotho高濃度 (2 nM)處理下發現可以弱化FGF23所造成Fibronectin之促進現象。高糖處理之細胞外加Klotho (2 nM)和FGF23 (50 ng)共同刺激,發現特定濃度的Klotho (2 nM)和FGF23 (50 ng)可經由逆轉mTOR、JAK2、STAT3、AKT、Erk及Smad2/3磷酸化而逆轉高糖所誘導纖維化表現。
在streptozotocin (STZ)誘導糖尿病腎病變鼠模式中,發現腎臟之Klotho和FGF23的表現亦明顯增加。此外,利用Resveratrol處理NRK-49F細胞,發現呈現劑量效應的逆轉高糖所增加的FGF23及Klotho的表現。因此利用Resveratrol治療STZ鼠之糖尿病腎病變,初步發現FGF23及Klotho明顯減少,並改善腎臟之fibronectin貯積,將進一步利用FGF23 shRNA及Klotho shRNA探討Resveratrol、FGF23及Klotho與糖尿病腎病變之相關性。


Diabetes mellitus (DM) is the 5th leading cause in Taiwan in 2012 while diabetic nephropathy (DN) is a common complication of DM. DN is characterized by renal hypertrophy, cell proliferation and extracellular matrices accumulation which results in glomerulosclerosis and renal fibrosis and finally end-stage renal disease. Fibroblast growth factor 23 (FGF23) is phosphaturic because it inhibits renal tubular reabsorption of phosphate. It also inhibits 1??-hydroxylase to inhibit the formation of active 1,25-vitamin D. FGF23 binds to the complex of FGF receptor (FGFR) and klotho to activate signal transduction. Additionally, FGF23 has been associated with chronic kidney disease (CKD) and overexpression of klotho has been found to attenuate animal CKD. Conversely, klotho knockout mice developed features of CKD. However, the roles of FGF23 and klotho in DN remain unknown. Thus, the purpose of this study is to study the roles of FGF23 and klotho in high glucose-cultured normal rat kidney fibroblast (NRK-49F) cells and streptozotocin (STZ)-diabetic rats.
We found that high glucose (30 mM) increased FGF23 and klotho mRNA and protein expression at 3 days while PD98059 (ERK1/2 inhibitor), SP600125 (JNK inhibitor), AG490 (JAK/STAT inhibitor), SB431542 (type 1 TGF-?? receptor inhibitor) and LY294002 (PI3 kinase inhibitor) attenuated high glucose-induced FGF23 and Klotho mRNA and protein expression at 3 days. Exogenous FGF23 and klotho dose-dependently (10 ng to 50 ng and 400 pM to 2 nM, respectively) increased fibronectin, collagen IV, matrix metalloproteinase-9 (MMP-9)and plasminogen activator inhibitor-1 (PAI-1) protein expression at 3 days. Exogeneous FGF23 and klotho also increased TGF-?? transcriptional activity and TGF-???涀ioactivity. FGF23 increased phosphorylations of mammalian target of rapamycin (mTOR), Janus kinase2 (JAK2), signal transducers and activators of transcription3 (STAT3), Akt and Smad2/3. FGF23 increased klotho protein expression whereas klotho (2 nM) attenuated FGF23-induced fibronectin protein expression. Combined treatment of FGF23 (50 ng) and high dose klotho (2 nM) attenuated high glucose-induced extraceuular matrices via attenuating high glucose-induced phosphorylations of mTOR, JAK2, STAT3, Akt, ERK1/2 and Smad2/3. Finally, resveratrol dose-dependently attenuated high glucose-induced FGF23 and klotho protein expression. FGF23 and klotho protein expression increased at 8 weeks in the STZ-diabetic rats whereas resveratrol attenuated fibronectin, FGF23 and klotho protein expression in the STZ-diabetic rats.
We concluded that FGF23 and klotho expression are increased in high glucose-cultured NRK-49F cells and the STZ-diabetic rats. FGF23 or klotho alone were detrimental in high glucose-cultured NRK-49F cells. However, combined treatment of FGF23 and high dose klotho (2 nM) was beneficial. We are going to study the separate and combined effects of resveratrol, FGF23 shRNA and klotho shRNA on high glucose-cultured NRK-49F cells and the STZ-diabetic rats in future studies.


目錄 5
中文摘要 8
英文摘要 11
縮寫表 14
緒論 18
研究目的 41
實驗材料 44
實驗方法 48
細胞實驗 49
蛋白質含量測定(Protein assay) 51
西方點墨法 (Western blotting) 52
啟動子報導基因表現分析 (Luciferase assay) 55
即時定量聚合酶鍊鎖反應(Real-time quantitative polymerase chain reactcion) 59
動物實驗 60
動物犧牲 60
免疫組織化學染色法 (Immunohistochemistry, IHC) 61
實驗結果 63
討論 72
圖表 77
Figure 1. Time-dependent of FGF23 and Klotho mRNA and protein in high glucose treated NRK-49F cells. 78
Figure 2. Time-dependent effects of high gluecose on fibronectin and FGF23 protein expression in NRK-49F cells. 79
Figure 4. High glucose increased FGF23 protein expression via the p38 kinase、JNK、TGF-bRI、PI3K and JAK2/STAT pathways in NRK-49F cells. 81
Figure 5. FGF23 induced TGF- b bioactivity and promoter transactivation in NRK-49F cells . 82
Figure 6. Klotho induced TGF- b bioactivity and promoter transactivation in NRK-49F cells . 83
Figure 7. Dose-dependent effects of FGF23 on ECM , PAI-1 and MMP-9 protein expression in NRK-49F cells. 84
Figure 8. Time-dependent effects of FGF23 on phospho- signaling pathway expression in NRK-49F cells. 86
Figure 9. Dose-dependent effects of FGF23 on Klotho protein expression in NRK-49F cells. 87
Figure 10. Effects of FGF23 and Klotho(KL) on fibronectin protein expression in NRK-49F cells. 88

Figure 11. Dose-dependent effects of Klotho on fibronectina and MMP-9 protein expression in NRK-49F cells. 89
Figure 12. Time-dependent effects of Klotho phospho-signaling pathway expression in NRK-49F cells. 90
Figure 13. Effects of high glucose, Klotho and FGF23 on fibronectin protein expression in NRK-49F cells. 91
Figure 14. High glucose, FGF23 and Klotho induced phospho-signaling pathway expression in NRK-49F cells. 92
Figure 15. Resveratrol attenuated high glucose-induced FGF23 and Klotho protein expression in NRK-49F cells. 94
Figure 16. Fibronectin expression was increased in the kidneys of STZ induced diabetic rats. 95
Figure 17. FGF23 expression was increased in the kidneys of STZ-induced diabetic rats. 96
Figure 18. Klotho expression was increased in the kidneys of STZ-induced diabetic rats. 97
Figure 19. A hypothetical scheme for the effects of high glucose, FGF23, Klotho, FGF23+Klotho and Reveratrol on TGF-b and the signaling pathway in NRK-49F cells. 98
參考文獻 99


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