臺灣博碩士論文加值系統

慢性腎臟疾病會導致腎功能惡化且造成不可逆的損害，氧化壓力及纖維化和慢性腎病的發展關係非常密切。臨床上，低血鉀及高血壓是導致慢性腎病病患，罹患心血管疾病及死亡的重要因子。慢性腎病所引發的長期性低血鉀及高血壓，將促使左心室肥大發生，進而提升心因性疾病的發病率及死亡率，是導致心臟衰竭的重要風險因子。腎素-血管收縮素系統所活化的絲裂原活化蛋白激酶及氧化壓力，在左心室肥大的病理發展過程中扮演重要的角色。芝麻油是天然又營養豐富的抗氧化物，能保護腎臟免於多種腎病損傷，且具有抗高血壓的潛力。本研究探討芝麻油治療慢性腎病引發之心肌肥大的功效及其機轉。老鼠給予單側腎臟切除，持續五週每週兩次，注射醋酸去氧皮脂酮 (15 毫克/毫升/千克體重，溶於礦物油中)，並在飲用水中添加1%氯化鈉，來誘導慢性腎病引發左心室肥大的動物模式；由於誘導動物模式的第四週開始產生腎功能下降及高血壓，自第五週開始連續一週給予動物芝麻油(0.5，1 毫升/千克體重/天)，第五週結束取得老鼠血液、心臟及腎臟組織，評估芝麻油對慢性腎病鼠的腎功能及左心室肥大的治療效果。結果顯示，芝麻油顯著降低慢性腎病鼠的血中尿素氮、肌酸酐、排尿量、蛋白尿、腎臟羥基自由基、過氧亞硝酸、脂質過氧化、骨橋蛋白及膠原蛋白的沉積；增加肌酸酐清除率及核內Nrf2的表現；有效抑制慢性腎病鼠的收縮壓及舒張壓、心電圖異常、心臟重量、左心室厚度、心肌細胞大小；提升血中鉀鎂離子濃度；降低慢性腎病鼠的心臟中腎素-血管收縮素系統、氧化壓力及絲裂原活化蛋白激酶的活化。總結，芝麻油能透過降低腎臟氧化壓力及纖維化，改善慢性腎病鼠的腎功能缺失；並且經由抑制低血鉀、心臟中腎素-血管收縮素系統調控的絲裂原活化蛋白激酶的活化及氧化壓力，達到改善慢性腎病鼠左心室肥大的功效。

Chronic kidney disease (CKD) causes a progressive and irreversible loss of renal function. Oxidative stress and fibrosis are highly related to the progression of CKD. Hypokalemia and hypertension in CKD patients are common manifestation of preclinical cardiovascular conditions that have a predictive value for cardiovascular morbidity and mortality. Left ventricular hypertrophy (LVH), an important risk factor in heart failure, is attributed to long-term hypokalemia and hypertension in CKD. The renin-angiotensin system (RAS) is involved in the development of LVH by which increases cardiac morbidity and mortality. Activation of mitogen-activated protein kinases (MAPKs) and oxidative stress are important in RAS-mediated cardiac hypertrophy. Sesame oil, a natural nutrient-rich and potent antioxidant protects the kidney in many renal disorders, and possesses potent anti-hypertensive activities. We examined the efficacy and mechanism of sesame oil on cardiac hypertrophy in CKD. We induced LVH using a CKD model by subcutaneously injecting deoxycorticosterone acetate (DOCA; 15 mg/ml/kg in mineral oil; twice weekly for 5 weeks) and supplementing with 1% sodium chloride drinking water (DOCA/salt) to uni-nephrectomized rats. Sesame oil was gavaged (0.5 or 1 ml/kg/day for 7 days) after 4 weeks of DOCA/salt treatment. Sesame oil significantly decreased blood urea nitrogen, creatinine, urine volume, and albuminuria in DOCA/salt-treated rats. Sesame oil significantly decreased renal hydroxyl radical, peroxynitrite level, lipid peroxidation, osteopontin, and collagen deposition, but increased creatinine clearance rate and nuclear Nrf2 expression in DOCA/salt-treated rats. In addition, sesame oil effectively reduced the SP/DP and ECG abnormality, the heart mass, the thickness of left ventricle, and the size of cardiomyocytes, and increased the serum levels of K+ and Mg2+ in DOCA/salt-treated rats. Furthermore, sesame oil significantly decreased the levels of cardiac RAS, oxidative stress, and down-regulated the expression of MAPKs in DOCA/salt-treated rats. We conclude that sesame oil mitigates renal dysfunction by inhibiting renal oxidative stress and fibrosis; attenuates LVH by regulating hypokalemia and decreasing cardiac RAS-mediated MAPK activation in CKD rats.

Abstract in Chinese............I
Abstract.............III
Acknowledgement............V
Contents...........VI
Figure contents............XI
Abbreviation...........XIII
1. Introduction.............1
1.1. Chronic kidney disease (CKD) .........1
1.2. Renal oxidative stress in CKD.........1
1.3. Renal fibrosis in CKD.........2
1.4. Left ventricular hypertrophy (LVH) in CKD.....3
1.5. Hypokalemia in CKD-induced LVH.......3
1.6. Activation of renin-angiotensin system (RAS) in CKD-induced LVH....4
1.7. Sesame oil............5
1.8. The aim of the study...........6
2. Experimental design..........7
2.1. Time-course study of DOCA/salt-induced CKD in rats......7
2.2. Effect of sesame oil on LVH in DOCA/salt-treated rats......7
3. Materials and methods...........9
3.1. Materials...........9
3.1.1. Animals............9
3.1.2. Chemicals...........9
3.1.3. Antibodies...........11
3.1.4. ELISA assay kits........12
3.1.5. Expendables..........13
3.1.6. Equipment..........13
3.1.7. Computer software.........15
3.2. Methods...........15
3.2.1. Uninephrectomy.........15
3.2.2. Inducing LVH...........15
3.2.3. Assessing renal function........16
3.2.4. Hemodynamic and functional measurements......16
3.2.5. Assessing electrolyte levels.......16
3.2.6. Estimating heart weight/100 g body weight ratio.....17
3.2.7. Histological evaluation of renal injury and cardiac hypertrophy....17
3.2.8. Measuring hydroxyl radical, peroxynitrite, and superoxide anion in renal and heart tissue.........18
3.2.9. Measuring renal and heart lipid peroxidation....18
3.2.10. Measuring heart nitric oxide levels......19
3.2.11. Immunohistochemical staining of Nrf2.....19
3.2.12. Determining renal OPN expression......19
3.2.13. Evaluating renal fibrosis.......20
3.2.14. Quantifying Nrf2, renin, ACE, Ang II, AT1R, p47-phox, ERK, JNK, p38, and ASK1 expression.........20
3.2.15. Measuring c-Fos and c-Jun mRNA expression......21
3.2.16. Protein assay..........22
3.2.17. Statistical analyses.........22
4. Results.............23
4.1. Time course of DOCA/salt-induced renal dysfunction and hypertension in rats...........23
4.2. Therapeutic effects of sesame oil on renal dysfunction in DOCA/salt-treated rats...........23
4.3. Therapeutic effects of sesame oil on renal histological change in DOCA/salt-treated rats............23
4.4. Therapeutic effects of sesame oil on renal oxidative stress in DOCA/salt-treated rats..........24
4.5. Therapeutic effects of sesame oil on renal Nrf2 expression in DOCA/salt-treated rats............24
4.6. Therapeutic effects of sesame oil on OPN expression in DOCA/salt-treated rats............25
4.7. Therapeutic effects of sesame oil on renal fibrosis in DOCA/salt-treated rats............25
4.8. Therapeutic effects of sesame oil on cardiac function in DOCA/salt-treated rats ...........25
4.9. Therapeutic effects of sesame oil on serum K+ and Mg2+ levels in DOCA/salt-treated rats..........25
4.10. Therapeutic effects of sesame oil on cardiac hypertrophy in DOCA/salt-treated rats...........26
4.11. Therapeutic effects of sesame oil on systemic RAS in DOCA/salt-treated rats............26
4.12. Therapeutic effects of sesame oil on cardiac RAS in DOCA/salt-treated rats............27
4.13. Therapeutic effects of sesame oil on cardiac AT1R expression in DOCA/salt-treated rats...........27
4.14. Therapeutic effects of sesame oil on cardiac MAPK signal transduction in DOCA/salt-treated rats.........28
4.15. Therapeutic effects of sesame oil on cardiac c-Fos and c-Jun mRNA expression in DOCA/salt-treated rats.......28
4.16. Therapeutic effects of sesame oil on cardiac oxidative stress in DOCA/salt-treated rats...........28
4.17. Therapeutic effects of sesame oil on the expression of ASK1 in DOCA/salt-treated rats...........29
5. Discussion...........30
6. Conclusion............37
7. References............38
Table ＆ Figures...........51
Publication list..............75
Publications...........76

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