臺灣博碩士論文加值系統

慢性腎病變病患發生心血管疾病的危險性大幅上升，慢性腎病變患者多死於心血管疾病。隨著國人飲食習慣西化及生活形態的改變，根據美國腎臟病登錄系統《末期腎臟病2007年年報》顯示，台灣末期腎臟病發生率（新生病例）和盛行率（累積總病人數），都是世界第一。動脈血管粥狀硬化是造成心臟血管疾病最重要的致病機轉。若長期暴露於心臟血管疾病的危険因子會損傷血管內皮細胞，導致血管內皮細胞功能異常，喪失了保護血管的功能，可能導致單核球細胞與血小板容易粘著於受傷的血管壁上，以及引發血管內層平滑肌細胞的過度增生，之後血管壁即逐漸形成所謂的動脈硬化瘢塊（atherosclerotic plaque）。因此，探討慢性腎衰竭如何造成血管內皮細胞功能失調與釐清其分生機轉是避免慢性腎衰竭病患發生動脈粥狀硬化相當重要的關鍵。
微小核糖核酸（MicroRNAs/miRNAs）是一22個核苷酸、無法編碼出蛋白質的單股RNA，具有負向調控基因表現功能。miRNAs調控基因表現的機制與RNAi類似，成熟的miRNAs為一小片段的單股RNA，藉由結合至RISC複合體可以去辨認與其序列互補的標的mRNA，依據與標的mRNA完全互補與否，而將有標的mRNA降解或阻擋其進行蛋白質轉譯的機制。近期有研究指出miRNAs調控基因包含了內皮細胞生長、爬行與入侵能力等，因此，當miRNAs表現失衡時將會影響細胞的行為，但到目前為止關於miRNAs再慢性腎病變是如何影響內皮細胞發炎進而導致血管動脈硬化病不是非常清楚。
本研究希冀釐清當發生腎損傷與慢性腎病變時血中miRNAs之變化，同時探討其中的作用機轉，首先我們將檢測急性腎損傷下血中miRNAs的變化，希望找到早期偵測的生物標劑。接著檢視腎毒素如何影響miRNAs進而引發血管內皮發炎，另外我們亦針對洗腎動靜脈廔管栓塞的機轉做探討。期能對於未來臨床應用治療時能提供重要資料。

Chronic kidney disease (CKD) is a common and serious public health problem globally. Taiwan has the highest prevalence of end-stage renal disease (ESRD) in the world with 12% of adults affected by CKD. Numerous clinical studies have demonstrated excess cardiovascular risk is associated with CKD, and about half of CKD patients die from cardiovascular diseases. Novel therapeutic strategies showed some promising results, but morbidity and mortality of ESRD patients throughout the last decade did not decrease markedly. Therefore, exploring the underlying mechanisms for vasculopathy in CKD patients is essential to improve clinical outcomes.
MicroRNAs (miRs) are endogenous 20-22 nucleotides noncoding small RNAs that can act as endogenous RNA interference. MiRs are key regulators in cell function including endothelial cells, through regulating nitric oxide via eNOS, angiogenesis, and inflammation. For example, endothelial miR-126 and miR-483 are important regulators in angiogenesis and are required in endothelial repair and homeostasis. In addition to their intracellular functions, miRs can also be secreted through microparticles (MPs) for intercellular communication. An increase in endothelium-derived circulating MPs have been demonstrated in patients with ESRD and these MPs impair the NO-dependent vasodilation of rat aorta.
We tried to script the miRs roles in CKD patients through our study. First we will investigate circulating miRs in kidney injury mice model and patients. We wanted to identify possible miRs for kidney injury biomarker for clinicians to start treatment earlier. Second, given the prevalence of oxidative stress and endothelial dysfunction resulted from uremia in CKD, we will investigate whether miRs plays a pivotal role linking CKD and endothelial dysfunction. Finally we will investigate miR rols in neointimal hyperplasia in arterial-venous fistula for hemodialysis. These experiments may extend current knowledge and provide important information in clinical treatment.

Table of Contents
中文摘要 I
Abstract II
Table of Cotents III
List of Figures V
List of Tables VII

Chapter 1 Introduction 1
1.1: Specific aim 1
Chapter 2 Background 3
2.1: Biomarkers for kidney injury 3
2.2: Endothelial function-related microRNAs in chronic kidney disease 6
2.3: Arterial-venous fistula 9
Chapter 3 Methods 13
3.1 Biomarkers for kidney injury 13
3.1.1 Explore the transmission of remote ischemic preconditioning signals through circulation 13
3.1.2 Investigation kidney specific microRNA changes in 5/6 nephrectomy mice model and liver recipients 21
3.2 Endothelial function related microRNA in chronic kidney disease 23
3.3 Arterial-venous fistula neointimal hyperplasia 27
3.3.1 Screening of the microRNA changes in arterial venous fistula of mice without chronic kidney disease 27
3.3.2 Vasculopathy in AVF mice model 29
3.3.3 Circulating levels of candidate microRNAs and their origin 30
3.3.4 Verification candidate microRNAs roles in endotheliopathy 32
Chapter 4 Results 35
4.1 Biomarkers for kidney injury 35
4.1.1 Remote ischemic preconditioning mechanism 35
4.1.2 Identify kidney specific microRNA for kidney injury 40
4.2 Endothelial function-related microRNAs in chronic kidney disease 43
4.2.1 Identification of microRNAs expression in chronic kidney disease patients 43
4.2.2 Verifying our findings in cell experiments 45
4.2.3 To verify the results in CKD mice 48
4.2.4 verifying our findings in chronic kidney disease patients 49
4.3 Arterial venous fistula neointimal hyperplasia 52
4.3.1 Arterial venous fistula mice model 52
4.3.2 TGF- pathway activation in neointimal hyperplasia 52
4.3.3 Small RNAseq for neointimal hyperplasia 53
Chapter 5 Discussion 57
5.1 Kidney injury biomarkers 57
5.2 Endothelial function related microRNAs in chronic kidney disease 59
5.3 microRNA and modulating pathwaysin arterial venous fistula neointimal hyperplasia 63
Chapter 6 Future work 64
6.1 Biomarkers for kidney injury 64
6.1.1 Verify CYR61 role in remote ischemic preconditioning 64
6.1.2 Predicting organ damage by CYR61 and tissue specific microRNA 64
6.2 Endothelial function related microRNAs 64
6.3 Arterial venous fistula neointimal hyperplasia 65

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