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研究生:吳家賢
研究生(外文):Chia-Hsien Wu
論文名稱:XBP1 在急性腎損傷到慢性腎臟病扮演之角色
論文名稱(外文):Role of XBP1 in acute kidney injury to chronic kidney disease transition
指導教授:姜至剛姜至剛引用關係
指導教授(外文):Chih-Kang Chiang
口試委員:劉興華楊榮森許美鈴
口試委員(外文):Shing-Hwa LiuRong-Sen YangMeei-Ling Sheu
口試日期:2016-07-22
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:毒理學研究所
學門:醫藥衛生學門
學類:其他醫藥衛生學類
論文種類:學術論文
論文出版年:2016
畢業學年度:104
語文別:英文
論文頁數:90
中文關鍵詞:急性腎衰竭慢性腎臟病腎小管細胞未折疊蛋白反應細胞週期停滯
外文關鍵詞:acute kidney injurychronic kidney diseaserenal tubular cellsunfolded protein responsecell cycle arrest
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慢性腎臟病所造成沉重的財政負擔已成為世界各國迫切解決之問題。而急性腎損傷發生後,腎臟未正確修復損傷的結果已被認為是導致慢性腎臟病的主因之一。近年來已有許多研究旨在探討急性腎損傷到慢性腎臟病進程間可能參與的機轉,而腎小管細胞之細胞週期因損傷而停滯在G2/M時期被認為參與其中。另一方面,過去十年已有許多研究發現未折疊蛋白質反應 (unfolded protein response, UPR)會參與在急性腎損傷 (acute kidney injury, AKI) 或慢性腎臟病 (chronic kidney disease, CKD) 中,但其是否也會參與在急性腎損傷到慢性腎臟病的進程則是未被確定。在本研究中,使用小鼠之單邊腎臟缺血再灌流受損(unilateral ischemia/reperfusion injury, UIRI) 模式模擬急性腎損傷到慢性腎臟病之變化。我們首先確立此模式是否符合AKI到CKD間腎臟病理變化,在此模式中,我們可以藉由H & E染色看到腎小管在UIRI第五天後因受到傷害而擴張,且經由Periodic Acid-Schiff 染色指出死亡細胞的殘骸大量累積在腎小管空腔中。另外,以即時聚合酶鏈鎖反應 (Real-time polymerase chain reaction) 得知,作為判斷AKI之生物標記的其中一種蛋白質―KIM-1之表現在UIRI後第一天相較對照組有大於200倍之顯著上升。另一方面,以Masson’s trichrome染色指出腎臟纖維化的程度隨UIRI經過的天數而上升,並且在15天時達到30%左右之纖維化比例,腎臟纖維化相關蛋白―α-SMA (alpha-smooth muscle actin) 表現量也隨之上升。在腎臟功能方面,經由在UIRI第11天後切除小鼠健康腎臟後也可以看到血清中creatinine、BUN有顯著上升。綜合以上可以說明在我們的UIRI模式中的確可以模擬AKI到CKD之進程。在UPR表現方面,IRE1 (inositol-requiring enzyme 1) 與PERK (protein kinase RNA-like endoplasmic reticulum kinase) 這兩個作為未折疊蛋白質反應啟始因子的蛋白均會在慢性腎臟病的進程間持續被活化,然而,作為IRE1下游被活化的分子XBP1的表現卻反而隨之下降,因此我們假設XBP1的表現可能和慢性腎臟病的進程有所關連。經由相關性係數檢驗,剪切型XBP1的表現的確和腎臟纖維化比例(Pearson’s r = -0.6525, r < 0.0001)或是細胞週期停滯相關因子p21 (Pearson’s r
= -0.3986, r < 0.05)有負相關的情形。因此我們進一步假設若腎小管細胞缺乏XBP1可能會導致其細胞週期停滯在G2/M時期。實驗結果顯示,在HK-2細胞內以基因表現減量技術減少XBP1之表現的確可以使細胞增值速度明顯減慢,並使細胞週期停滯在G2/M時期,且伴隨著細胞週期調控相關因子Wee1的上升。總結來說,我們提供了一個未折疊蛋白質反應參與在急性腎損傷到慢性腎臟病進程間的新途徑,並且此途徑可能是經由缺失XBP1所導致腎小管細胞週期停滯而造成。

Chronic kidney disease (CKD) has become a public health burden all over the world. Acute kidney injury (AKI), one of the major causes that lead to CKD has been recognized as an irreversible insult due to maladaptive repair process. There are numbers of studies focus on the underlining mechanisms of post-AKI maladaptive repair process recently, and renal tubular cell cycle arrest in G2/M is thought to contribute to this mechanism. On the other hand, unfolded protein response (UPR), an endogeneous cellular response that triggered by the accumulation of unfolded proteins in ER luman, has been revealed to participate in both AKI and CKD progression depending on numerous publications in the past decade. However, whether UPR participates in the transition state from AKI to CKD progression and what is its role during transition is not been well discussed. In our present study, we mimic AKI to CKD transition in mice model using renal unilateral ischemia/reperfusion injury (UIRI). As pathological section present, we saw renal tubular dilation at day 5 after UIRI and accumulation of cell debris in the tubular lumen. One of the AKI biomarker - KIM-1 (Kidney Injury Molecule-1) has over 200 fold upregulation compare to sham operation control at day 1 after UIRI. On the other hand, Masson’s thrichrome showed that fibrotic area kept rising upon UIRI induction, and had about 30% fibrosis tissue area at day 15 after UIRI. Also, α-SMA (alpha-smooth muscle actin) was rising along with fibrosis. Serum creatinine and BUN have significant rising after conduct nephrectomy to the contralateral kidney, indicated that renal function was impaired. In conclusion, we successfully perform the AKI to CKD transition in our UIRI model. In the aspect of UPR expression pattern, we found that two of the UPR initiators, both IRE1 (inositol-requiring enzyme 1) and PERK (protein kinase RNA-like endoplasmic reticulum kinase) continue activation during post-AKI transition state. Surprisingly, expression level of IRE1 downstream molecule XBP1 (X-box binding protein 1) was decrease. We then hypothesis that XBP1 might contribute to the CKD progression. To confirm our hypothesis, we evaluated the correlation efficiency between XBP1 expression and post-AKI fibrosis or the expression of cell cycle arrest marker - p21. According to the results, sliced XBP1 (XBP1s) have a strong negative correlation with fibrosis progression (Pearson’s r = -0.6525, r < 0.0001), and with p21 expression level (Pearson’s r = -0.3986, r < 0.05) as well. We further hypothesis that losing XBP1 will lead to tubular cell cycle arrest at G2/M phase. And depends on the in vitro knock-down experiments, losing XBP1 inhibit HK-2 cells proliferation that is results from cell cycle arrested at G2/M phase, accompanied with upregulation of Wee1 expression. In conclusion, we established a possible connection between UPR and post-AKI CKD progression, which may through cell cycle arrest result from losing XBP1 in renal tubular cells.

口試委員會審定書 I
誌謝 II
Content IV
摘要 VII
Abstract IX
Abbreviations XII
Introduction 1
Kidney disease 1
Acute kidney injury 1
Pathophysiology of acute kidney injury 2
Postrenal causes 3
Prerenal causes 3
Intrinsic causes 4
Clinical phase of ischemia-induced AKI 5
Initiation phase 6
Extension phase 7
Maintenance and recovery phases 8
Characteristics of tubular injury 9
Maladaptive repair after AKI lead to CKD progression 10
Activation of fibroblast 11
EMT processing of tubular epithelial cells 12
Cell cycle arrest of proximal tubule epithelial cells (PTECs) contribute to fibrosis progression 13
Fundamental roles of ER stress and unfolded protein responses 15
ER stress in renal disease 17
Renal unilateral ischemia/reperfusion as an in vivo model for AKI to CKD 19
Aim 21
Materials and Methods 22
Animal studies 22
Induction of renal unilateral ischemia-reperfusion injury (UIRI) 22
Nephrectomy 24
Renal function and histology 24
Cell culture 25
In vitro XBP1 knock-down and cell cycle analysis 25
Immunoblotting 26
Quantification of mRNA by real-time quantitative reverse transcription PCR 27
Antibodies 29
Statistical analyses 29
Results 31
Induction of AKI 31
CKD progression after AKI 32
Expression pattern of UPR molecules after UIRI 33
IRE1-XBP1 pathway 33
BiP expression and PERK pathway 34
Cell cycle arrest in G2/M phase along with CKD progression 34
Correlation between XBP1 expression and fibrosis progression or p21 expression 35
In vitro experiment 36
In vitro knock-down of XBP1 36
Knock-down XBP1 in HK-2 cells leads to cell cycle arrest in G2/M phase 37
Discussions 39
Future perspectives 46
References 49
Figures 71

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