摘要
背景：
臨床觀察研究發現，台灣慢性腎臟疾病的盛行率和發生率與其他國家相比顯著高出許多，而且台灣的末期腎衰竭發生率為世界最高。此外，越來越多的數據顯示，與僅有心血管疾病或慢性腎臟疾病的患者相比，心腎症候群患者在心血管事件發作後，具有不利的短期和長期臨床結果之發生率有顯著較高。重要的是，儘管現有的治療方式和藥物治療策略的進步，心腎症候群患者的預後仍然不好。因此，為心腎症候群尋找新的、有效的和安全的治療策略不僅對於患者及醫生至關重要，而且對於降低我國的醫療成本也是重要的。

目的：
通常認為心腎症候群惡化的潛在機制包括氧化壓力增加、活性氧化物質增加、發炎反應增加和細胞凋亡/死亡的增加。有趣的是，褪黑激素和艾塞那肽-4可能具有對抗心腎症候群惡化機制的性質。因此，本研究目的是要驗證，於保護心臟和腎臟功能免於心腎症候群的惡化的大鼠模型以及體外研究中，合併使用褪黑激素和艾塞那肽-4治療是優於個別單獨使用的假說。

材料與方法：
實驗包括體外和活體研究。
體外研究包括四組：(1) 對照組：在DMEM培養基中培養24小時的 H9C2 細胞 (編號：CRL-1446TM) (4.0 × 105 個細胞)，(2) 心腎症候群組 (CRS)：H9C2 細胞 + 阿黴素 (50 nM) + 對甲酚 (50 μM) 培養24小時，(3) 心腎症候群-褪黑激素治療組 (CRS-Mel；H9C2 細胞 + 阿黴素 (50 nM) + 對甲酚 (50 μM) + 褪黑激素 (50 μM/mL) 培養24小時，（4）心腎症候群-艾塞那肽-4治療組 (CRS-Ex4；H9C2 細胞 + 阿黴素 (50 nM) + 對甲酚 (50 μM) + 艾塞那肽-4 (200 nM/mL) 培養24小時。然後收集所有細胞用於個別測定。
活體研究則將成年雄性 Sprague Dawley大鼠隨機分組為：(1) 假手術對照組 (SC)，(2) 慢性腎臟疾病組 (CKD；以5/6腎臟切除術來誘導) 或擴張型心肌病組 (DCM) (以阿黴素 7 mg/kg，每5天/ 4次劑量來誘導)，(3) 心腎症候群組 (CRS) (慢性腎臟疾病 + 擴張型心肌病)，(4) 心腎症候群-褪黑激素治療組 (CRS-Mel；20 mg/kg/天)，(5) 心腎症候群-艾塞那肽-4治療組 (CRS-Ex4；10 μg/kg/天) 和 (6) 心腎症候群-褪黑激素-艾塞那肽-4治療組 (CRS-Mel-Ex4)。它們在心腎症候群誘導後第60天安樂死。

結果：
體外結果顯示，在阿黴素及對甲酚處理過的 H9C2細胞中，細胞氧化壓力 (NOX-1/NOX-2/氧化蛋白)、細胞DNA /線粒體損傷 (γ-H2AX/胞質細胞色素-C)、細胞凋亡 (裂解的caspase-3 /裂解的PARP) 和細胞衰老 (β-半乳糖苷酶細胞) 的生物標記蛋白表現量是增加的，且線粒體 ATP 總量是降低的，但在經過褪黑激素和艾塞那肽-4治療後則呈現改善(p <0.001)。到第60天，左心室射出分率方面，SC組最高，CRS組最低，且DCM組顯著低於其他治療組。此外， CRS-Mel治療組和CRS-Ex4治療組之左心室射出分率則低於在CRS-Mel-Ex4治療組，而CRS-Mel治療組則低於CRS-Ex4治療組。但每組別在左心室大小和組織病理學評分結果卻顯示與上述左心室射出分率分析呈相反的模式 (p <0.001)。血漿肌酸酐的總量在CRS組中最高，在SC組中最低，且總量從CRS-Mel治療組，CRS-Ex4治療組，CRS-Mel-Ex4治療組至DCM組是呈現逐漸降低的趨勢 (p <0.0001)。源於左心室心肌之生物標記，包括：心肌發炎 (TNF-α/NF-κB/MMP-2/MMP-9/IL-1β)，心肌凋亡/ DNA損傷 (Bax/c-半胱天冬酶-3/c-PARP/γ-H2AX)，心肌氧化壓力 (NOX-1/NOX-2/NOX-4/氧化蛋白)，心臟肥大/壓力過載 (BNP /β-MHC) 和心臟完整性 (Cx43/α –MHC) 等蛋白的表現量，在每個組別的總量則與上述左心室射出分率分析的結果呈相反的模式 (p <0.001)。
此外，血漿肌酸酐總量，尿蛋白/肌酸酐比值和腎損傷組織病理學評分中，CRS組最高，SC組最低，且上述實驗數值從CKD組，CRS-Mel治療組，CRS-Ex4治療組至CRS-Mel-Ex4治療組是呈現逐漸降低的趨勢 (p <0.0001)。源於腎臟之生物標記，包括：腎臟發炎 (TNF-α/NF-κB/MMP-9/iNOS/RANTES)，腎臟氧化壓力 (NOX-1/NOX-2/NOX-4/氧化蛋白)，腎臟凋亡 (裂解的caspase-3/裂解的PARP / Bax），腎臟DNA損傷 (γ-H2AX）和腎臟纖維化 (p-mad3/TFG-β) 等蛋白的總量則與上述血漿肌酸酐總量分析的結果呈類似的模式 (p <0.0001)。而腎臟GLP-1R蛋白表現從SC組至CRS-Mel-Ex4治療組皆呈現增加的趨勢 (p <0.0001)。源於腎組織中之生物標記，包括：發炎細胞 (CD14/CD68)，DNA損傷/腎損傷 (γ-H2AX/KIM-1) 和足細胞/腎小管功能障礙信號傳導 (β-連環蛋白/ Wnt1/Wnt4) 等蛋白的表現量，在每個組別的總量則與上述血漿肌酸酐總量分析的結果呈類似的模式 (p <0.0001)。足細胞成分(podocin/dystroglycan/p-cadherin/synatopodin) 總量在SC組中最高，CRS組最低，且從CKD組至CRS-Mel-Ex4治療組呈現顯著增加的趨勢 (p <0.0001)。

結論：
為了有效抑制因心腎症候群所造成的左心室功能和重塑的惡化，以及維持腎功能和腎結構之完整性，合併褪黑激素和艾塞那肽-4治療優於個別單獨使用。

Abstract
Background:
Clinical observational studies have reported that the incidence and prevalence of chronic kidney disease (CKD) in Taiwan are more significantly higher as compared with the other countries, and have further identified that the incidence of end-stage renal disease (ESRD) in Taiwan is the highest in the world. Furthermore, growing data showed that as compared with patients with only cardiovascular disease (CVD) or CKD, those of patients with cardiorenal syndrome (CRS) have significantly higher incidence of unfavorable short-term and long-term clinical outcome after cardiovascular event attack. Of important is that although the state-of-the-art therapeutic modality and advancement of drug-therapeutic strategy, the prognosis for patients with CRS remains unfavorable. Accordingly, to find a new, effective and safe strategic management for CRS is not only of the utmost importance for patients, physicians but also important to decrease the medical cost in our country.

Objective:
Commonly considered underlying mechanisms for CRS deterioration include increased oxidative stress, up-regulation of reactive oxygen species (ROS), increased inflammation, and increased cellular apoptosis/death. Interestingly, melatonin (Mel) and exendin-4 (Ex4) might have properties against the proposed mechanisms of CRS. Accordingly, this study tested the hypothesis that combined Mel-Ex4 therapy would be superior to either one alone for protecting the heart and kidney from CRS in a rat model as well as in vitro study.

Materials and Methods:
Experiments consisted in in vitro and in vivo studies.
The in vitro study comprised four groups: (1) Control group: H9C2 cell (ATCC® Number: CRL-1446™) (4.0 x 105 cells) cultured in DMEM culture medium for 24h, (2) CRS group: H9C2 cells + doxorubicine (50 nM) + p-Cresol (50 µM) for culturing 24h, (3) CRS + Mel group: H9C2 cells + doxorubicine (50 nM) + p-Cresol (50 µM) + Mel (50 μM/mL) co-cultured for 24h, (4) CRS + Ex4 group: H9C2 cells + doxorubicine (50 nM) + p-Cresol (50 µM) + Ex-4 (200 nM/mL) co-cultured for 24h. All the cells were then collected for individual assays.
The in vivo study consisted of Male adult Sprague Dawley rats which were randomly and equally divided into (1) sham-control (SC), (2) chronic kidney disease (CKD; induced by 5/6 nephrectomy) or dilated cardiomyopathy (DCM) (doxorubicin 7 mg/kg i.p. every five days/ 4 doses), (3) CRS (CKD + DCM), (4) CRS-Mel (20 mg/kg/day), (5) CRS-Ex4 (10 µg/kg/day) and (6) CRS-Mel-Ex4. They were euthanized by day 60 after CRS induction.

Results:
In-vitro results showed protein expressions of oxidative-stress (NOX-1/NOX-2/oxidized protein), DNA/mitochondrial-damaged (γ-H2AX/cytosolic cytochrome-C) and apoptotic (cleaved caspase-3/PARP) biomarkers, and senescence (β-galactosidase cells) were upregulated, whereas mitochondrial ATP level was decreased in doxorubicin/ p-Cresol-treated H9C2 cells that were revised by Mel and Ex4 treatments (all p<0.001). By day 60, LVEF was highest in SC and lowest in CRS, significantly lower in DCM than in other treatment groups, lower in CRS-Mel and CRS-Ex4 than in CRS-Mel-Ex4, and lower in CRS-Mel than in CRS-Ex4, whereas LV chamber size and histopathology score showed a pattern opposite to that of LVEF among all groups (all p<0.001). Plasma creatinine level was highest in CRS and lowest in SC, and progressively decreased from CRS-Mel, CRS-Ex4, CRS-Mel-Ex4 to DCM (p<0.0001). Protein expressions of inflammation (TNF-α/NF-κB/MMP-2/MMP-9/IL-1β), apoptosis/DNA-damage (Bax/c-caspase-3/c-PARP/γ-H2AX), fibrosis (Samd3/TGF-β), oxidative-stress (NOX-1/NOX-2/NOX-4/oxidized protein), cardiac-hypertrophy/pressure-overload (BNP/β-MHC), and cardiac integrity (Cx43/α-MHC) biomarkers in LV myocardium showed an opposite pattern compared to that of LVEF among all groups (all p<0.001). Fibrotic area, DNA-damage (γ-H2AX+/53BP1+CD90+/XRCC1+CD90+), and inflammation (CD14+/CD68+) biomarkers in LV myocardium displayed a pattern opposite to that of LVEF among all groups (all p<0.001).
Furthermore, plasma creatinine level, urine protein/creatinine ratio and kidney injury histopathology score were highest in CRS, lowest in SC, and progressively decreased from CKD, CRS-Mel, CRS-Ex4 to CRS-Mel-Ex4 (all p<0.0001). The kidney protein expressions of inflammation (TNF-α/NF-κ/MMP-9/iNOS/RANTES), oxidative stress (NOX-1/NOX-2/NOX-4/oxidized protein), apoptosis (cleaved caspase-3/cleaved PARP/Bax), NDA-damaged marker (γ-H2AX) and fibrosis (p-mad3/TFG-β) showed identical patterns of creatinine level, whereas kidney protein expressions of GLP-1R showed a progressive increase from SC to CRS-Mel-Ex4 (all p<0.0001). Cellular expressions of inflammatory (CD14/CD68), DNA/kidney-damaged (γ-H2AX/KIM-1) and podocyte/renal tubule dysfunction signaling (β-catenin/Wnt1/Wnt4) biomarkers in kidney tissue exhibited an identical pattern of creatinine level (all p<0.0001). Podocyte components (podocin/dystroglycan/p-cadherin/synatopodin) were highest in SC, lowest in CRS, and significantly progressively increased from CKD to CRS-Mel-Ex4 (all p<0.0001).

Conclusions:
Combined Mel-Ex4 therapy was superior to either one alone in suppressing deterioration of LV function and LV remodeling as well as preserving renal function and kidney architectural integrity in the setting of CRS.

目錄
論文審定書………………………………………………………………………………i
致謝……………………………………………………………………………..….……ii
中文摘要…………………………………………………………………………..……iii
Abstract…………………………………………………………………………....…...vi
目錄……………………………………………………………………………….…….xi
INTRODUCTION………………………..…………...…………………………………1
Cardiorenal Syndrome (CRS)……………….…………..……………….……...……2
Classification of CRS………………………….………….…….………………….…..3
Oxidative Stress and Inflammation in CRS……….………….….…………………..4
Biological Role of Melatonin…………………….…………….….…………..…….…8
Biological Role of Exendin-4…………………….…………….….…………...….….11
RATIONALE………………………………...…………………………………….……14
STUDY DESIGN…………………………………...…………………….…………….18
Experiment 1: In Vitro Study………………….……………………..…….…….……19
Experiment 2: In Vivo Study…………………….………………………….…...…….21
MATERIALS AND METHODS………………………......…………..…………....….24
RESULTS……………………………………………...………...………………....…..36
DISCUSSION…………………………………...………………...……………………52
Study Limitations……………………………….…………………..…..…………...…60
CONCLUSIONS AND FUTURE WORKS…………...………………….....…..……61
FIGURES AND LEGENDS…………………………………………....………...……64
TABLE……………………………………………………………………………....…114
REFERENCES…………………………………………....……...………..……...….116

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