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研究生:陳鴻鈞
研究生(外文):Hung-Chun Chen
論文名稱:氧自由基在腎絲球硬化的致病性中所扮演的角色
論文名稱(外文):Role of Reactive Oxygen Species in the Pathogenesis of Glomerulosclerosis
指導教授:賴永勳賴永勳引用關係
指導教授(外文):Yung-Hsiung Lai
學位類別:博士
校院名稱:高雄醫學大學
系所名稱:醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2000
畢業學年度:88
語文別:中文
論文頁數:179
中文關鍵詞:含氧自由基腎絲球硬化局部腎絲球硬化症糖尿病腎絲球硬化症熱休克蛋白
外文關鍵詞:Reactive oxygen speciesGlomerulosclerosisFocal segmental glomerulosclerosisDiabetic glomerulosclerosisHeat shock protein
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腎絲球的硬化現象是進行性腎臟病的共同特徵,其典型的變化在原發性腎臟病以局部腎絲球硬化症(focal segmental glomerulosclerosis, 以下簡稱FSGS)為主,而在續發性腎臟病中又以糖尿病腎絲球硬化症(diabetic glomerulosclerosis, 以下簡稱DGS)最為常見,這兩個疾病也是國人尿毒症的主因;因此腎絲球硬化症可以說是腎衰竭的前身,其重要性自不可言喻,但對於其致病性的了解至今仍是十分缺乏。最近的研究顯示含氧自由基reactive oxygen species, 以下簡稱ROS)與缺血性及毒性腎臟病有密切相關,ROS主要有superoxide, H2O2及hydroxyl radicals,他們是具有高度反應性且極不穩定性的化學物質,可傷害許多細胞及組織,但其與腎絲球硬化症的關係則不明白,因此本研究即探討ROS在腎絲球的硬化過程中所扮演的角色。
本研究首先針對25名原發性FSGS病人及16名DGS病人,檢查其血中、尿中及腎臟內是否有ROS活性增加之情形,其次我們以不同的物質去刺激腎絲球細胞,觀察他們是否確實會產製ROS,接下來我們以ROS刺激腎絲球細胞,觀察ROS對細胞之傷害性,最後我們設法減少ROS的產量,觀察是否就伴隨有適度的保護作用。
本研究結果分為下列4大部份:
1. 首先我們證實在腎絲球硬化症病人確有ROS活性增加現象。我們分別在FSGS及DGS病人的研究均發現病人 血 中、尿中及腎絲球內之脂質過氧化產物malondialdehyde(MDA)均有明顯增加現象,由於直接測定 ROS 並不容易,因此MDA為ROS活性增加的最直接證據之一。另外由於superoxide dismutase(SOD) 的量也有明顯增多,顯示superoxide可能是與疾病有關的主要ROS。
2. 其次我們證明腎絲球細胞確實可以產製ROS。當我們以低密度脂蛋白(low density lipoprotein, 簡稱LDL)刺 激新鮮分離的糖尿病鼠腎絲球時,可見其superoxide產量較正常鼠腎絲球為高。另外我們以由IgA腎病變病 人血中分離的IgA來刺激腎絲球間質細胞時,也可見細胞產製較多量的superoxide及fibronectin;由於糖尿病 腎病變及IgA腎病變均是以腎絲球間質為主要的病變所在,因此腎絲球細胞產生的ROS在致病性上可能有 重要角色。
3. 我們進一步證實ROS可以直接傷害腎絲球細胞。在體外及體內的研究方面,我們都證明ROS可以增加新鮮 分離的糖尿病鼠腎絲球之內皮素-1(endothelin-1, 簡稱ET-1)產量,而ET-1對腎絲球細胞的深切影響則早有 諸多文獻報告。另外我們也證實IgA腎病變病人之血中中性多核白血球以FMLP激活後,可以釋出大量 superoxide而直接促進腎絲球間質細胞的增生及ET-1之分泌,可見ROS確實可以直接傷害腎絲球細胞。
4. 最後我們也證實若能設法減少ROS的產量就可以降低其對腎絲球細胞的傷害。我們使用的第一個方法是誘 發熱休克蛋白70 (heat shock protein 70, 簡稱HSP70),當腎絲球間質細胞被誘發合成HSP70後,再以ROS攻擊 之,則細胞受傷害的程度會大大的減輕。第二個方法使用的是降血脂藥物pravastatin,在模擬糖尿病併高 血脂症的實驗中,我們發現pravastatin可以降低由氧化-LDL及高濃度葡萄糖所誘發之ROS對腎絲球間質細胞 的傷害,因此身為臨床醫師我們應該努力去找出一些可以減少ROS傷害的方法或藥物。
結論:本研究結果顯示腎絲球硬化症病人確有ROS活性增加現象,而腎絲球細胞不但可以產製ROS,ROS也可以直接傷害腎絲球細胞,若減少ROS的產生也確實可以降低腎絲球細胞所受的傷害,因此ROS在腎絲球硬化過程中應扮有重要角色。
Glomerular sclerosis is a common change in patients with progressive renal diseases. Typical changes of glomerular sclerosis are usually found in patients with focal segmental glomerulosclerosis (FSGS) and diabetic glomerulosclerosis (DGS), both are major causes for end stage renal failure in Taiwan. Since glomerulosclerosis is the prerequisite for renal failure, it is important to understand the mechanism of the pathogenesis of glomerulosclerosis, which is still poorly understood. Recent studies indicate that reactive oxygen species (ROS) are involved in the pathogenesis of ischemic and toxic renal diseases. ROS are highly reactive and unstable chemical species that consists of superoxide, hydrogen peroxide, and hydroxyl radicals. The role of ROS in the pathogenesis of glomerulosclerosis, however, is still unknown.
In the present study, we evaluated the in vivo activities of ROS in the plasma, urine and renal biopsy samples of 25 FSGS and 16 DGS patients. The measurement was followed by in vitro studies that evaluated the ability of generating ROS by freshly isolated glomeruli and cultured glomerular mesangial cells, under various conditions. The noxious effects of endogenous and exogenous ROS on glomeruli and mesangial cells were evaluated thereafter, and we also tried to save them by inducing endogenous heat shock protein 70 (HSP70), or by exogenous supplement of the lipid-lowering drug pravastatin. The results are shown below:
1. ROS activities were enhanced in patients with glomerulosclerosis. We had demonstrated that the concentrations of malondialdehyde (MDA), a major product of lipid peroxidation induced by ROS, were elevated in plasma, urine, and renal glomeruli of patients with FSGS and DGS. Superoxide dismutase (SOD), instead of glutathione peroxidase (GPX), was also elevated in both groups of patients, indicating that superoxide is the major species of ROS that is involved in the pathogenesis of glomerulosclerosis.
2. Glomerular cells produced ROS under various stimulations. We had demonstrated that low density lipoprotein (LDL) and oxidized-LDL enhanced superoxide production by freshly isolated diabetic rat glomeruli. In addition, the circulating IgA isolated from patients with IgA nephropathy, a disease characterized by mesangial proliferation, had differential effects on the production of superoxide and fibronectin by glomerular mesangial cells.
3. Both endogenous and exogenous ROS damaged glomerular cells. We had demonstrated in vitro and in vivo that both endogenous and exogenous ROS were tonic regulator of endothelin-1 (ET-1) production by freshly isolated diabetic rat glomeruli. ET-1 induced vasoconstriction and mitogenesis that in turn induced profound effects on glomerular cells. The ET-1 production of mesangial cells could also be induced by FMLP-activated neutrophils through the release of superoxide.
4. Glomerular cells can be protected by suppressing the ROS activities. We had demonstrated that induction of heat shock protein 70 (HSP70), an endogenous protein that affords protection against many stresses, protected mesangial cells against ROS injury. When mesangial cells were stimulated with oxidized-LDL and high concentration of glucose that induced ROS, the cell damage was also greatly attenuated in the presence of pravastatin, a potent lipid-lowering drug with a potential of antioxidation. Therefore, suppression of ROS activities can protect glomerular cells against oxidative injury.
In conclusion, we have demonstrated that ROS activities are enhanced in patients with FSGS and DGS. ROS can be produced by glomerular cells after various stimulations, and the glomerular cells are also susceptible to ROS damage, which can be prevented by endogenous HSP70 or exogenous pravastatin. Our results indicate that ROS is closely related to glomerulosclerosis.
封面
目錄
誌謝 Acknowledgement
中文摘要 Abstract(Chinese)
英文摘要Abstract(English)
第一章 緒論
General Introduction
第二章 腎絲球硬化症病人自由基活性增加之證據
Part I-局部腎絲球硬化症病人脂質過氧化物及抗氧化酵素濃度之測量
Measurement of Lipid Peroxides and Antioxidant Ezzyme Concentrations in Patients with Focal Segmental Glomerulosclerosis
Part II-糖反病腎絲球硬化症病人脂質過氧化物及抗氧化酵素濃度之測量
Measurement fo Lipid Peroxides and Antioxidant Enzyme Concentrations in Patients with Diabetic Glomerulosclerosis
第三章 腎絲球細胞在疾病狀況下可產生自由基之證據
Part I-低密度及氧化低密脂蛋白對糖反病鼠腎絲球產生Superoxide之影響-體內及體外實驗
Effects of Native and Oxidized-Low Density Lipoprotein(LDL)on the Superoxide Production of Diabetic Rat Glomeruli in vivo and in vito
Part II-IgA腎病變病人血中 IgA 可刺激腎絲球間質細胞產生較多量的 Superoxide 及 fibronectin
Differential Effects of Circulating IgA Isolated from Patients with IgA Nephropathy on Superoxide and Fibronectin Production of Glomerular Mesangial Cells
第四章 在疾病狀況下所產生之自由基可傷害腎絲球細胞之證據
Part I-含氧自由基在體外及體內實驗均可增 加糖反病鼠腎絲球之內皮素-1產量
Reactive Oxygen Species Enhanced Endothelin-1 Production of Diabetic Rat Glomeruli in vivo and in vitro
Part II-受FMLP激活之中性多核白血球可釋出Superoxide促進腎絲球間質細胞的增生及內皮素-1之分泌
Superoxide Released from FMLP-Activated Neutrophils Enhanced Proliferation and Endothelin-1 Secretion of Glomerular Mesangial Cells
第五章 降低自由基對腎絲球細胞的傷害之對策
Part I-誘發熱休克蛋白 70可以保護腎絲球間質細胞降低自由基所導致之傷害
Induction of Heat Shock Protein 70 Protects Glomerular Mesangial Cells Against Oxidative Injury
Part II-Pravastatin 可以保護腎絲球間質細胞降低由氧化低密度脂蛋白及高濃度葡萄糖誘發自由基所導致之傷害
Pravastatin Protects Glomerular Mesangial Cells Against Oxidative Injury Induced by Oxidized-Low Density Lipoprotein and High Glucose
第六章 總結論與未來研究方向
Conclusion and Future Researches
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