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研究生:吳義勇
研究生(外文):Yee-Yung Ng
論文名稱:經由轉化生長因子訊息標杷治療腎臟疾病
論文名稱(外文):Treatment of Kidney Disease by Targeting TGF-β Signaling Pathway
指導教授:藍輝耀
指導教授(外文):Hui-Yao Lan
學位類別:博士
校院名稱:國立陽明大學
系所名稱:臨床醫學研究所
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:2009
畢業學年度:97
語文別:中文
論文頁數:147
中文關鍵詞:慢性腎臟疾病上皮細胞轉分化為肌纖維母細胞纖維化發炎β型轉化性生長因子Smad
外文關鍵詞:chronic kidney diseaseepithelial-myofibroblast transdifferentiationinflammationrenal fibrosistransforming growth factor-βSmad
相關次數:
  • 被引用被引用:0
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  • 收藏至我的研究室書目清單書目收藏:1
中文摘要
隨著罹患慢性腎臟疾病的人持續增加,因此接受腎臟替代療法(renal replacement therapy)的病人數亦不斷增加,預估未來十年接受腎臟替代療法的病人數會倍增;由於台灣慢性腎臟疾病的盛行率高達11.93%,這種趨勢在台灣會更顯著。因此當病患之慢性腎臟疾病能在早期進行時即加以阻斷,應可達到預防或延緩慢性腎疾病的進行,並降低末期腎疾病的發生率。
不論慢性腎臟疾病是因為何種原因導致,發炎及纖維化被認為是造成人類及動物腎絲球腎炎,長期持續受損的重要決定性因素;因此控制炎症及纖維化的進行,對腎功能的保存極具重要性。
過去我們及其他研究者證實β型轉化性生長因子是眾多會引起腎臟組織纖維化及腎功能惡化的細胞因子中最重要因子。 Smad7的高度表達會抑制Smad2/3的活化,而使腎小管上皮細胞轉化為肌纖維母細胞及腎組織的纖維化被抑制。雖然β型轉化性生長因子及Smad7在腎臟纖維化的角色已充分被確認,但它們在腎臟疾病中的抗炎症反應機轉,卻不是很清楚,Smad7在調控發炎反應的可能角色仍有爭論;因此本研究應用超音波基因轉植技術,將Smad家族中可抑制β型轉化性生長因子信息傳導的 Smad7基因,轉植至5/6腎切除後的大鼠腎臟組織細胞內,以期探討β型轉化性生長因子/Smad7訊息在抑制腎臟炎症反應的可能機轉。在此研究我們發現Smad7可增加NF.kB的抑制劑,IKBα的表達,而抑制了NF.kB /p65的活化及發炎反應。Smad7經由對Smad2/3磷酸化的專一性抑制及NF.kB的交互反應途徑,而同時達到抑制腎臟組織纖維化及發炎反應。因此Smad7抑制腎臟炎症及纖維化的能力可作為治療腎絲球腎炎的新治療方法。
不斷的證據顯示pentoxifylline可經由對炎症及細胞增生的抑制,而減緩包含抗腎絲球基底膜腎炎的多種腎疾病模型,所造成之腎臟功能衰竭。Pentoxifylline也被證實可降低纖維母細胞增生及腎臟纖維化的基因表達及減少間質肌纖維母細胞的數目。在過去我們的研究,發現上皮細胞轉化為肌纖維母細胞,是經由β型轉化性生長因子來調整,而β型轉化性生長因子/Smad訊息途徑是造成上皮細胞肌纖維母細胞轉化的主要途徑,是造成腎臟纖維化的重要過程。因此我們假設pentoxifylline的抗纖維化效果可能是經由對β型轉化性生長因子表達的阻斷,及β型轉化性生長因子/Smad訊息途徑的去活化而達成的。此假設在本研究中獲得支持。在星月體腎絲球腎炎老鼠模型中,上皮細胞轉化為肌纖維母細胞轉化的過程被pentoxifylline抑制,是經由抑制依賴β型轉化性生長因子而活化的Smad2/3訊息達成,而達到抑制腎臟組織纖維化。
結論, Smad7除了有抗纖維化的效果外,亦能經由抑制NFKB/p65的活化,而達到抗炎症作用。Pentoxifylline除了具有抗炎症效果外,它能經由阻斷Smad2/3而抑制腎臟組織纖維化。因此Smad7及pentoxifylline的腎功能保護作用是可以同時阻斷腎炎症及纖維化,所以Smad 7基因治療及pentoxifyline的使用可代表為一種減緩慢性腎疾病進行的治療方向。
The number of patients on renal replacement therapy due to the progression of chronic kidney disease has gradually increased over the last decades, and the number of patients on renal replacement therapy is predicted to double during the next 10 years. This trend is even more pronounced in Taiwan. Therefore, reduction in the incidence of end-stage renal disease by intervention in early stages of chronic kidney disease to prevent or slow the progression of chronic kidney disease has become important and urgently needed.
Regardless of the initial insults leading to the kidney injury, the degree of inflammation and fibrosis have long been considered as crucial determinants in the progression of kidney diseases and in a long-term prognosis of both human and experimental glomerulonephritis. Therefore, controlling the process of inflammation and fibrosis is a critical step for preserving renal function and preventing the development of end-stage kidney diseases.
We and other investigators have demonstrated that transforming growth factor-β (TGF-β), one of the critical cytokines, plays an important role in tubulointerstitial fibrosis and renal function deterioration by activating its downstream mediators called Smad2/3. In contrast, overexpression of its negative regulator Smad7 is able to block the activation of Smad2/3, thereby inhibiting the pathological effects of TGF-β1, including tubular epithelial-myofibroblast transdifferentiation and renal tubulointerstitial fibrosis. Although the role of TGF-β1 and its downstream Smad signaling in renal fibrosis have been firmly established, the signaling mechanisms of its anti-inflammation activities of TGF-β in kidney diseases are poorly understood. In this thesis, we first tested the hypothesis that TGF-β may signal through its downstream regulator Smad7 to exert anti-inflammatory effect on kidney diseases. This was examined in a rat remnant kidney disease model by using a ultrasound-microbubble-mediated gene transfer of Smad7. In this study, we found that overexpression of renal Smad7 induced IKB-α (a NF.kB inhibitor) expression, thereby inhibiting NF.kB /p65 activation and NF.kB -dependent inflammation, including upregulation of pro-inflammatory cytolines (IL-1β and TNFα) and adhesion molecules (ICAM-1), as well as macrophage and T-cell infiltration, in addition to an inhibition of Smad2/3 phosphorylation and renal fibrosis simultaneously. Thus, the ability of Smad7 to inhibit renal inflammation and fibrosis may represent a new therapeutic strategy for glomerulonephritis.
We also further tested the second hypothesis, that targeting TGF-β/Smad signaling may be a specific and effective therapeutic strategy for chronic kidney disease. This was examined in an immunologically-induced anti-GBM crescentic glomerulonephritis in rats, in which diseased rats were treated with an anti-inflammatory agent-pentoxifylline. In our previous study, we found that epithelial-myofibroblast transition, a critical process in renal fibrosis, was regulated by TGFβ. Therefore, we further hypothesized that the anti-fibrotic effect of pentoxifylline may act by blocking renal TGFβ expression and inactivation of the TGFβ/Smad signaling pathway, a major pathway leading to epithelial-myofibroblast transition and renal fibrosis. Results showed that pentoxifylline treatment blocked the process of epithelial-myofibroblast transition and renal fibrosis in a rat model of anti-GBM crescentic glomerulonephritis. This was associated with inhibition of renal TGFβ expression and inactivation of Smad2/3, demonstrating the TGF-β/Smad signaling pathway as a therapeutic target in kidney diseases.
In conclusion, Smad7 is a therapeutic agent for kidney diseases because Smad7 can inhibit the inflammatory response by inactivating the NF.kB signaling pathway via induction of IkBα, in addition to a protective role in renal fibrosis by blocking the TGF-β/Smad2/3 activation. Pentoxifylline, an anti-inflammatory agent, can also suppress renal fibrosis by blocking the TGF-β/Smad2/3 signaling pathway. Therefore, Smad7 and pentoxifylline may exert their renoprotective effects by blocking both renal inflammation and fibrosis through the TGF-β/Smad signaling pathway. Results from this thesis reveal that targeting the TGF-β/Smad signaling pathway may represent a specific and effective therapeutic strategy for kidney diseases.
Table of Contents

English Abstract -------------------------------------------------------------------------- iii

Chinese Abstract ------------------------------------------------------------------------- vi

List of Abbreviations --------------------------------------------------------------------- viii

Introduction -------------------------------------------------------------------------------- 1

Materials and Methods ----------------------------------------------------------------- 21

Result --------------------------------------------------------------------------------------- 36

Discussion --------------------------------------------------------------------------------- 60

Conclusion --------------------------------------------------------------------------------- 66

Perspectives ------------------------------------------------------------------------------- 68

References --------------------------------------------------------------------------------- 69

Appendix ------------------------------------------------------------------------------------ 86

Publications --------------------------------------------------------------------------------- 117
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