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標題: | 長鏈非編碼核醣核酸Lnc-fibrogen及內質網蛋白TXNDC5在急性腎損傷到慢性腎病變的角色 The role of Lnc-fibrogen and ER protein TXNDC5 in acute kidney injury to chronic kidney disease |
作者: | 趙珮宇 Pei-Yu Jhao |
指導教授: | 楊鎧鍵 Kai-Chien Yang |
關鍵字: | 急性腎損傷,慢性腎病變,腎臟纖維化,內質網蛋白TXNDC5,長鏈非編碼核醣核酸Lnc-fibrogen,TGF-β signaling,小鼠單側缺血再灌流損傷, Acute kidney injury,Chronic kidney disease,Kidney fibrosis,Thioredoxin domain containing 5 (TXNDC5),Long noncoding RNA Lnc-fibrogen,TGF-β signaling,unilateral ischemia injury, |
出版年 : | 2018 |
學位: | 碩士 |
摘要: | 患有急性腎損傷的患者,即使功能完全恢復,也會增加未來發展成慢性腎病(CKD)和腎功能衰竭的風險。然而腎臟纖維化是導致發生CKD的主要因素,發生CKD後不論是死亡率或是發生其他疾病的共病率都很高。在腎臟纖維化最常見的腎小管間質纖維化中,主要是因為腎臟纖維母細胞的活化、累積過量的細胞外基質(ECM)所導致的。然而目前在臨床上並沒有有效的方法來治療或逆轉腎纖維化,因此我們想找到新的有效目標來治療腎臟纖維化。
我們實驗室最近發現了一種長鏈非編碼核醣核酸 Lnc-fibrogen及其宿主基因內質網蛋白TXNDC5是參與心臟纖維化過程的重要因子。因此本研究的目的是想探討Lnc-fibrogen和TXNDC5是否也參與腎纖維化和CKD。本篇主要使用小鼠單側缺血再灌流損傷(uIRI)誘導的CKD模型,發現腎臟損傷14天後Lnc-fibrogen和Txndc5的基因表現都顯著增加,除此之外ECM相關基因表現包括Col1a1,Col3a1,Ctgf和Eln也隨之增加。另外我們也利用Lnc-fibrogen以及Txndc5基因剔除小鼠進行實驗,發現手術過後受損腎臟的纖維化有顯著改善,並且也產生較少的ECM蛋白。此外,我們發現uIRI誘導的TXNDC5表現增加會去影響下游活化JNK、P38 signaling,而剔除Txndc5之後JNK、P38的活化也會受到抑制。綜合實驗結果,可以證明Lnc-fibrogen及其宿主基因TXNDC5是促進損傷後腎纖維化的關鍵因素。TXNDC5主要是透過活化JNK以及P38 signaling活化腎臟纖維母細胞並促進ECM產生。因此,Lnc-fibrogen和TXNDC5可作為腎臟纖維化治療或預防的新型標的。 Patients who had acute kidney injury, even with complete functional recovery, are at increased risk of chronic kidney disease (CKD) and renal failure. CKD is a major cause of morbidity and mortality, and renal fibrosis is an important and common pathway leading to the progression of CKD. Renal fibroblast activation, accumulation and excessive extracellular matrix (ECM) production are the key events leading to renal tubulointerstitial fibrosis. Currently, there is no effective therapy to treat or reverse renal fibrosis, and it is critical to identify novel mediators of renal fibrosis to develop potential new therapeutics. Our laboratory has recently identified a long non-coding RNA Lnc-fibrogen and its host gene thioredoxin domain containing 5 (TXNDC5), an ER-resident protein with the enzyme activity of protein disulfide isomerase, as critical mediators of cardiac fibrosis. The goal of this study was to test the hypothesis that Lnc-fibrogen and TXNDC5 could also be involved in the pathogenesis of renal fibrosis and CKD. Using a mouse model of unilateral ischemia reperfusion injury (uIRI)-induced CKD, we have revealed that Lnc-fibrogen and Txndc5 transcripts were both highly upregulated in mouse fibrotic kidney 14 days after uIRI; the expression levels of Txndc5 also showed strong positive correlation with those of fibrogenic protein genes including Col1a1, Col3a1, Ctgf and ELN. Mice with targeted deletion of Lnc-fibrogen or Txndc5 developed less fibrosis, and produced less ECM proteins in the kidneys following uIRI. Furthermore, we found uIRI-induced increased TXNDC5 levels in renal fibroblasts were accompanied with activated JNK and P38 signaling, whereas Txndc5 knockout abrogated uIRI-induced JNK and P38 activation in renal fibroblasts. Taken together, our data suggest that Lnc-fibrogen and its host gene TXNDC5 are both critical mediators for the development of post-injury renal fibrosis. TXNDC5 promotes renal fibroblast activity and ECM production through activating profibrotic JNK and P38 signaling. Targeting Lnc-fibrogen and TXNDC5, therefore, could be a potential novel therapeutic approach to treat or prevent CKD. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/77553 |
DOI: | 10.6342/NTU201802663 |
全文授權: | 未授權 |
顯示於系所單位: | 藥理學科所 |
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