Title

胞外超氧歧化酶:糖尿病腎病變進展之相關性與於高血壓及糖尿病腎病變動物模式功效評估

Translated Titles

Extracellular Superoxide Dismutase : Association with Progression of Diabetic Nephropathy and Effects on Hypertension and Diabetic Nephropathy Animal Model

Authors

郭嘉文

Key Words

胞外超氧化物歧化酶 ; 重組人類胞外超氧歧化酶 ; 糖尿病腎病變 ; 高血壓 ; extracellular superoxide dismutase ; human recombinant extracellular superoxide dismutase ; diabetic nephropathy ; hypertension

PublicationName

中興大學生命科學系所學位論文

Volume or Term/Year and Month of Publication

2018年

Academic Degree Category

博士

Advisor

陳全木

Content Language

英文

Chinese Abstract

許多疾病及器官損傷的肇因為氧化壓力。有一群氧化還原酶作為保護細胞及面對消除超氧陰離子的第一線稱為超氧歧化酶。但是因為它的生理化學特質,包含半衰期短及不易細胞附著等,限制了他在臨床上的應用。為了增加在臨床上的使用性,也努力運用包含生物化學方式修飾或以分子生物技術等方式來改變。我們團隊也運用經基因轉殖嗜甲基酵母菌大量產出重組人類胞外超氧歧化酶。為了瞭解它在臨床運用上的效能以及人體血中及尿中胞外超氧歧化酶濃度所代表的意義及其特性及是否可為另一生物標記,我們執行了這些研究。首先,我們先針對不同時期的糖尿病腎病變患者進行一橫斷性研究,觀察其血中及尿中胞外超氧化物歧化酶濃度於各階段的變化及相關性。發現,血中胞外超氧化物歧化酶濃度與腎功能有高度相關性反應,也許可以反映出血管內皮的受損情形。因為,血中胞外超氧歧化酶濃度,在已發生腎臟疾病族群表現較高,而且可被血中肌酸酐濃度預測的相關性。而尿中的胞外超氧歧化酶濃度則與其他尿中的生物標的物質呈明顯相關,如尿中血管張力素原、血管內皮生長因子;但與血中胞外超氧歧化酶濃度並無相關性。尿中胞外超氧歧化酶可能代表腎小管本身受損脫落而非來自腎絲球過濾所得。而且,尿中胞外超氧歧化酶也許可以如同尿中血管張力素原一樣成為尿中反應腎臟病變的生物標的,成為腎臟病變的風險評估及腎衰竭進展預測的生物標地。另外,我們探討經腹腔注射補充重組人類胞外超氧歧化酶是否可避免或延緩鏈佐黴素引發的糖尿病大鼠的糖尿病腎病變進展。我們發現,補充的重組人類胞外超氧歧化酶可以藉由其肝素接合位吸附於組織或增加其組織的表現並清除超氧陰離子。可以減緩糖尿病腎病變、疾病大鼠死亡率、腎臟肥大及纖維化情形。可以降低phox47及opn基因的表現,進而減少轉化生長因子及血管張力素受體第一型表現。最重要是可藉由下降細胞外超氧陰離子,使得胞內超氧陰離子表現活化受到抑制,抑制此惡性循環,使氧化壓力下降。然而,如由口服補充此類胜肽或酶,可能因腸道降解而失去作用,本試驗亦作一系列的體外模擬胃腸道消化試驗及動物體內的功效試驗。我們觀察自發性高血壓大鼠經口服補充重組人類胞外超氧歧化酶的降血壓效果。發現口服補充重組人類胞外超氧歧化酶可以清除超氧陰離子並達到降壓效果。一開始降壓效果發生與血中一氧化氮上升有相關性。但經七日治療降壓效果仍然持續且與劑量相關,可能歸因於血管平滑肌細胞內的超氧陰離子獲得清除的關係。體外模擬胃腸液消化實驗也證實重組人類胞外超氧歧化酶,雖會被截切為較小片段,但仍有少量雙偶體存在且其他小分子的活性仍然存在。

English Abstract

Oxidative stress is the culprit of the development of multiple diseases and organ damage. Superoxide dismutases (SODs), a group of oxido-reductase, are in the frontline and the major cellular defense on scavenging the O2•−. However, its unfavorable physicochemical properties including short half-life and poor cellular adherence limited its clinical application. Several efforts including biochemical modifications and molecular approaches had been made to improve its clinical utility. Our team also harvested human recombinant extracellular superoxide dismutase (rhEC-SOD) efficiently from gene transformed methylotrophic yeast Pichia pastoris. In order to clarify it’s clinical utility and to understand the representations and characteristics of serum and urinary extracellular sueroxide dismutase (EC SOD, SOD3) levels, especially in the progression of diabetic nephropathy, we conducted these studies. We firstly performed a cross-sectional study to observe the changes in the serum and urine levels of SOD3 in diabetic patients with and without diabetic nephropathy in different stages. We noted that the serum SOD3 level may reflect the extent of damage of the vascular endothelium and was strongly affected by the renal function. The serum SOD3 level was higher in the groups of patients with kidney disease and can be significantly predicted by the serum creatinine level. The urinary levels of SOD3 were significantly correlated with the other urinary biomarkers, such as urinary angiotensinogen (ANG) and vascular endothelial growth factor but not the serum SOD3 level. The urinary SOD3 may come from the damaged renal tubules rather than glomerulus filtration. The urinary SOD3 level may act like the urinary ANG level, which has been considered as a biomarker in the urine used for risk stratification and kidney disease progression prediction. Further, we investigated whether intra-peritoneal rhEC-SOD supplement can prevent diabetic nephropathy in the streptozotocin-induced diabetic rat model. We found that rhEC-SOD can bind to the heparan domain of the tissue or enhance its expression and act as a superoxide scavenger. Treatment with rhEC-SOD can reverse the changes caused by diabetic nephropathy, leading to reduced death rates, kidney weight/body weight ratio, fibrosis changes and TGF-β1 expression through the down-regulation of the phox47 and opn genes and the AT1 receptors. Most importantly, the vicious circle and feedback between superoxide and intracellular superoxide activation can be broken by rhEC-SOD treatment, resulting in decreased ROS levels. However, the challenge of peptide or enzyme enteral administration is the biodegradation in the gastrointestinal system. We performed the study to elucidate the effect of rhEC-SOD given orally on blood pressure in spontaneous hypertensive rats (SHRs) and to identify the function of rhEC-SOD after digestion in vitro. We found that the rhEC-SOD given orally can exert its effects of superoxide scavenger and lower the systolic blood pressure. In the beginning, the blood pressure lowering effects may come form the avoidance of nitric oxide (NO) degradation and the sustaining effects observed for 7 days may be ascribed to the superoxide scavenging effect in the vascular smooth muscle cell. In vitro digestion test, though the rhEC-SOD will be cleaved to smaller pieces and loss most of the higher-molecular-mass monomer, there were still great SOD activities and dimmer remenance reserved.

Topic Category 生命科學院 > 生命科學系所
生物農學 > 生物科學
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