隨著近年來西方飲食習慣的普及，肥胖成為了一項重要的議題，肥胖對於疾病治療的影響也愈趨重要。缺血性急性腎損傷是常見的外科手術治療後併發症，並且具有高度的死亡率和發病率。在臨床研究中，肥胖患者經過手術後併發缺血性急性腎損傷的嚴重程度和比例都有增加。細胞趨化素受體CCR5和其配體CCL5在肥胖的患者中有表現量增加的情形，而在肥胖患者中CCL5-CCR5的表現量增加對於缺血性急性腎損傷的影響仍是未知的。我們以C57BL/6小鼠建立飲食誘導肥胖-雙側腎臟缺血再灌流動物模式，來模擬罹患缺血性腎損傷之肥胖病患並進行腎損傷的組織學研究。我們發現，和一般飲食-雙側腎臟缺血再灌流模式相比，腎臟損傷以及纖維化於飲食誘導肥胖-雙側腎臟缺血再灌流模式生物中是增加的。而與一般飲食的雙側腎缺血再灌流模式相比較下，在飲食誘導肥胖-雙側腎在缺血再灌流模式生物的CCL5、CCR5表現量及腎臟中巨噬細胞皆有增加之情形。總結來說，在肥胖的情形下，發生缺血性急性腎損傷時所增加的CCL5-CCR5 軸線反應，在腎臟傷害的病生理機轉當中，扮演著相當重要的角色。

As the population of western diet habit, obesity becomes a critical issue on recent years; in addition, the interaction between obesity and clinical therapy are more important gradually. Ischemic acute kidney injury (ischemic AKI) is a common complication by high mortality and morbidity on patients who have critical ills after surgery. In clinical research revealed that the severity and morbidity of ischemic AKI which complicated after surgery are increased. The expression of C-C motif chemokine receptor 5 (CCR5) and its substrate C-C motif ligand 5 (CCL5) is increased on obesity patient; however, the effect of increased expression of CCL5-CCR5 on ischemic AKI in obese patients is unknown. We used the C57BL/6 mice to build the diet-induced obesity-bilateral ischemia-reperfusion injury (DIO-BIRI) animal model to mimic the AKI-obesity patient. Our investigation reveal that the kidney injury and fibrosis on DIO-BIRI model are significant higher than it on normal chow diet-BIRI (NCD-BIRI) model. Additionally, the expression level of CCL5, CCR5 and macrophage are increased on the kidney of DIO-BIRI animal model. In conclusion, the accumulated CCL5-CCR5 reaction occurred by AKI plays a critical role on increased the renal pathophysiology in AKI patients with obesity.

目錄 ------------------------------------------------------------------------------------------------------------------I
中文摘要 --------------------------------------------------------------------------------------------------------------V
Abstract -------------------------------------------------------------------------------------------------------------VI
名詞縮寫表-----------------------------------------------------------------------------------------------------------VII
第一章 前言 ----------------------------------------------------------------------------------------------------------1
第二章 文獻回顧 ------------------------------------------------------------------------------------------------------3
一、 肥胖與代謝症候群 ----------------------------------------------------------------------------------------------3
1. 代謝症候群概述 ------------------------------------------------------------------------------------------------3
2. 脂肪組織與肥胖 ------------------------------------------------------------------------------------------------5
3. 高脂肪飲食 ----------------------------------------------------------------------------------------------------6
4. 胰島素阻抗 ----------------------------------------------------------------------------------------------------7
二、 肥胖與腎臟疾病 ------------------------------------------------------------------------------------------------9
1. 腎臟構造與生理功能 --------------------------------------------------------------------------------------------9
2. 肥胖導致慢性腎衰竭 -------------------------------------------------------------------------------------------12
3. 肥胖導致慢性腎衰竭之病理現象 ---------------------------------------------------------------------------------14
三、 缺血性急性腎損傷 ---------------------------------------------------------------------------------------------16
1. 缺血性急性腎損傷概述 -----------------------------------------------------------------------------------------16
2. 缺血再灌流傷害 -----------------------------------------------------------------------------------------------18
3. 急性腎損傷與慢性腎衰竭 ---------------------------------------------------------------------------------------20
4. 嗜中性白血球明膠相關性脂質運載蛋白 ---------------------------------------------------------------------------21
四、 趨化素及趨化素受體--------------------------------------------------------------------------------------------22
1. 趨化素及趨化素受體概述 ---------------------------------------------------------------------------------------23
2. 趨化素5 ------------------------------------------------------------------------------------------------------23
3. 趨化激素受體5 ------------------------------------------------------------------------------------------------24
4. 肥胖與CCL5-CCR5 axis------------------------------------------------------------------------------------------25
5. 趨化因子與急性腎損傷------------------------------------------------------------------------------------------26
第三章 材料與方法 ---------------------------------------------------------------------------------------------------28
一、 究動機與目的 -------------------------------------------------------------------------------------------------28
二、 實驗設計 -----------------------------------------------------------------------------------------------------29
實驗目的(一)：探討不同時間長度雙側腎臟缺血再灌流模式引發急性腎損傷之效應。--------------------------------------------29
實驗目的(二)：探討雙側腎臟缺血再灌流模式引發急性腎損傷存活七天後之腎損傷組織型態學。----------------------------------29
實驗目的(三)：小鼠飲食引發肥胖之動物模式建立。------------------------------------------------------------------------29
實驗目的(四)：小鼠飲食引發肥胖-雙腎缺血再灌流動物模式之建立。---------------------------------------------------------30
實驗目的(五)：觀察高脂肪飲食引發肥胖之小鼠經過急性腎損傷後腎功能指標變化。--------------------------------------------30
實驗目的(六)：觀察高脂肪飲食引發肥胖之小鼠經過急性腎損傷後腎皮質組織組織病理變化。------------------------------------30
實驗目的(七)：觀察高脂肪飲食引發肥胖之小鼠經過急性腎損傷後腎外側髓質外裙帶組織病理變化。------------------------------31
實驗目的(八)：觀察高脂肪飲食引發肥胖之小鼠經過急性腎損傷後腎絲球組織病理變化。----------------------------------------31
實驗目的(九)：觀察正常飲食及高脂肪飲食引發肥胖之小鼠經過急性腎損傷後，CCL5表現之差異。--------------------------------31
實驗目的(十)：觀察正常飲食及高脂肪飲食引發肥胖之小鼠經過急性腎損傷後，CCR5表現之差異。--------------------------------31
實驗目的(十一)：觀察正常飲食及高脂肪飲食引發肥胖之小鼠經過急性腎損傷後，巨噬細胞生物標記F4/80表現之差異。-------------32
三、 實驗方法及流程 -----------------------------------------------------------------------------------------------32
1. 建立兩側腎臟缺血再灌流之動物疾病模式 -------------------------------------------------------------------------32
2. 建立飲食誘導肥胖-兩側腎臟缺血再灌流之動物疾病模式-------------------------------------------------------------33
3. 口服葡萄糖耐受性測試 (Oral glucose tolerance test) -----------------------------------------------------------34
4. 葡萄糖、胰島素及HOMA -----------------------------------------------------------------------------------------34
5. 腎損傷指標檢驗------------------------------------------------------------------------------------------------35
6. 腎臟組織石蠟切片 ---------------------------------------------------------------------------------------------36
7. 腎臟組織冷凍切片 ---------------------------------------------------------------------------------------------37
8. 蘇木紫-伊紅染色法(Hematoxylin and eosin staining, H&E staining)-----------------------------------------------38
9. 過碘酸-戚氏染色法(Periodic acid-Schiff’s staining, PAS staining)---------------------------------------------39
10. 腎小管損傷分數(Tubulointerstitial lesion score, TSI)----------------------------------------------------------41
11. 急性腎小管壞死分數(Acute tubular necrotic score, ATN)---------------------------------------------------------42
12. 腎絲球斑痕化指數(Glomerulosclerosis index, GSI)---------------------------------------------------------------43
13. 免疫化學染色(Immunohistochemistry staining, IHC staining)-----------------------------------------------------43
14. 免疫螢光染色(Immunofluorescence staining, IF staining)--------------------------------------------------------46
15. 苦味酸-天狼星紅染色法(Picro-Sirius red staining, PSR staining)------------------------------------------------48
16. 腎間質纖維化及腎絲球纖維化----------------------------------------------------------------------------------- 50
四、 統計方法----------------------------------------------------------------------------------------------------- 51
五、 實驗材料、藥品、抗體與影像來源--------------------------------------------------------------------------------51
第四章 結果----------------------------------------------------------------------------------------------------------54
一、 不同時間雙側腎臟缺血再灌流損傷存活結果------------------------------------------------------------------------54
二、 雙側腎臟缺血再灌流損傷之腎實質損傷影響------------------------------------------------------------------------54
三、 餵食高脂飼料食之小鼠體重變化、體重成長變化監控及脂肪大小結果--------------------------------------------------55
四、 餵食高脂肪飼料之小鼠口服葡萄糖耐受度測試檢測結果--------------------------------------------------------------56
五、 餵食高脂肪飼料之小鼠空腹血糖、胰島素及HOMA測試檢測結果--------------------------------------------------------56
六、 餵食高脂肪飼料之小鼠於腎缺血再灌流損傷後之血液腎損傷指標變化。------------------------------------------------57
七、 餵食高脂肪飼料之小鼠於腎缺血再灌流損傷後之腎臟皮質組織學型態變化----------------------------------------------58
八、 餵食高脂肪飼料之小鼠於腎缺血再灌流損傷後之腎臟OSOM組織學型態變化----------------------------------------------59
九、 餵食高脂肪飼料之小鼠於腎缺血再灌流損傷後之腎臟腎絲球組織學型態變化--------------------------------------------61
十、 餵食高脂肪飼料之小鼠於腎缺血再灌流損傷後腎臟CCL5表現量變化結果------------------------------------------------62
十一、 餵食高脂肪飼料之小鼠於腎缺血再灌流損傷後腎臟CCR5表現量變化結果------------------------------------------------63
十二、 餵食高脂肪飼料之小鼠於腎缺血再灌流損傷後腎臟免疫浸潤生物標記F4/80表現量變化結果-------------------------------64
第五章 討論----------------------------------------------------------------------------------------------------------65
第六章 結論----------------------------------------------------------------------------------------------------------70
第七章 參考文獻------------------------------------------------------------------------------------------------------71
第八章 附表----------------------------------------------------------------------------------------------------------77
表一 慢性腎疾病階段區分及診斷指標-------------------------------------------------------------------------------------77
表二 RIFLE急性腎損傷階段區分及診斷指標--------------------------------------------------------------------------------78
表三 AKIN急性腎損傷階段區分及診斷指標---------------------------------------------------------------------------------79
表四 KDIGO急性腎損傷階段區分及診斷指標------------------------------------------------------------------------------- 80
第九章 附圖--------------------------------------------------------------------------------------------------------- 81
圖一 以過碘酸-戚氏染色法判斷腎臟組織構造------------------------------------------------------------------------------81
圖二 小鼠雙側腎臟缺血再灌流手術操作流程-------------------------------------------------------------------------------82
圖三 腎小管傷害類型圖示-----------------------------------------------------------------------------------------------83
圖四 8～10週齡小鼠於BIRI手術後腎皮質H&E染色型態觀察-------------------------------------------------------------------84
圖五 8～10週齡小鼠於BIRI手術後腎皮質損傷PAS染色之計數-----------------------------------------------------------------85
圖六 8~10週齡小鼠於BIRI手術後OSOM H&E染色型態觀察---------------------------------------------------------------------86
圖七 8～10週齡小鼠於BIRI手術後OSOM損傷PAS染色之計數-------------------------------------------------------------------87
圖八 不同飲食餵食之小鼠體重及攝食情形---------------------------------------------------------------------------------88
圖九 不同飲食餵食後小鼠之脂肪重量情形---------------------------------------------------------------------------------89
圖十 不同飲食餵食4週後小鼠之OGTT結果----------------------------------------------------------------------------------90
圖十一 不同飲食餵食10週後小鼠之空腹葡萄糖及胰島素結果-----------------------------------------------------------------91
圖十二 不同飲食餵食小鼠手術前之體重分配-------------------------------------------------------------------------------92
圖十三 不同飲食之小鼠BIRI手術後血漿肌酸酐濃度-------------------------------------------------------------------------93
圖十四 不同飲食之小鼠BIRI手術後尿素氮濃度-----------------------------------------------------------------------------94
圖十五 不同飲食之小鼠BIRI手術後腎皮質H&E染色型態觀察------------------------------------------------------------------95
圖十六 不同飲食之小鼠BIRI手術後腎皮質PAS染色之計數--------------------------------------------------------------------96
圖十七 不同飲食之小鼠BIRI手術後腎皮質纖維化之情形---------------------------------------------------------------------98
圖十八 不同飲食之小鼠BIRI手術後腎皮質NGAL表現之情形------------------------------------------------------------------100
圖十九 不同飲食之小鼠BIRI手術後OSOM H&E染色型態觀察------------------------------------------------------------------102
圖二十 不同飲食之小鼠BIRI手術後OSOM PAS染色之計數--------------------------------------------------------------------103
圖二十一 不同飲食之小鼠BIRI手術後OSOM纖維化之情形--------------------------------------------------------------------105
圖二十二 不同飲食之小鼠BIRI手術後OSOM NGAL表現之情形-----------------------------------------------------------------107
圖二十三 不同飲食之小鼠BIRI手術後腎絲球外觀及大小--------------------------------------------------------------------109
圖二十四 不同飲食之小鼠BIRI手術後腎絲球瘢痕化之情形------------------------------------------------------------------111
圖二十五 不同飲食之小鼠BIRI手術後腎絲球纖維化之情形------------------------------------------------------------------113
圖二十六 不同飲食之小鼠BIRI手術後腎臟CCL5表現之情形------------------------------------------------------------------115
圖二十七 不同飲食之小鼠BIRI手術後腎臟CCR5表現之情形------------------------------------------------------------------116
圖二十八 不同飲食之小鼠BIRI手術後腎臟F4/80表現之情形-----------------------------------------------------------------117

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