硫代硫酸鈉在慢性腎臟病與腎血管性高血壓之治療及保護效果
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2019
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慢性腎臟疾病（Chronic kidney disease，CKD）是一種持續腎功能喪失的疾病，通常在初期沒有顯著的症狀，當發現罹患疾病時，其損傷可能已無法逆轉及修復。腎血管性高血壓（Renovascular hypertension，RVHT）之發病機制主要為供給腎臟的動脈狹窄，造成腎素-血管張力素-醛固酮系統(Renin-angiotensin-aldosterone system，RAAS)異常，導致高血壓，進一步對腎功能造成損傷。兩者皆會引起腎臟功能異常及損傷。
硫代硫酸鈉（Sodium thiosulfate，STS）是目前在人體醫學上已使用在治療氰化物中毒和預防鈣化的藥物，根據先前研究表示，硫代硫酸鈉具有抗氧化、減緩氧化壓力之功能，能夠有效降低自由基的累積，不僅減少細胞釋放過氧化氫，還能保留超氧化物歧化酶的活性，甚至可減低血管張力素II誘導的腎臟損害和尿蛋白。然而，硫代硫酸鈉是否能夠有效降低慢性腎病便和腎血管性高血壓造成之腎損害，目前尚未證實。
本實驗的目的，針對硫代硫酸鈉目前臨床的研究成果用於兩種腎臟疾病的治療評估。於Wistar大鼠上手術誘發類似於慢性腎臟疾病與腎血管性高血壓的疾病模式和傷害，並且給予腹腔注射硫代硫酸鈉，評估硫代硫酸鈉是否有改善疾病所造成的損傷。同時參考衛生福利部全國解毒劑儲備網氰化物中毒之硫代硫酸鈉靜脈注射劑量，成人靜脈注射劑量12.5 g，經換算後0.2 g/kg，再以各劑量濃度測試硫代硫酸鈉最佳抗氧化之劑量，經測試硫代硫酸鈉抗氧化能力之結果表明，0.2 g/kg與0.1 g/kg之抗氧化能力相當，所以實驗治療劑量選擇低於衛生福利部之安全劑量上限，採用0.1 g/kg (最高劑量之1/2)做為治療劑量。本研究結果顯示，在慢性腎臟疾病與腎血管性高血壓動物模式，硫代硫酸鈉確實能降低血液中自由基的含量與腎臟組織氧化產物4-HNE的表現，減少腎臟中性白血球浸潤腎臟組織、減緩腎臟纖維化程度、降低Bax/Bcl-2 比值而減少腎臟皮質與髓質之細胞凋亡且有效改善慢性腎臟疾病所導致的血清尿素氮(Blood urine nitrogen，BUN)和血清肌酸酐(Creatinine)。這些結果表明，硫代硫酸鈉透過抗氧化、抗纖維化與抗凋亡效應可改善慢性腎臟疾病與腎血管性高血壓造成之腎損傷。在未來臨床應用治療，具有潛在的改善效果。
關鍵字：硫代硫酸鈉、慢性腎臟疾病、腎血管性高血壓、自由基
Chronic kidney disease (CKD) is a gradual process of renal dysfunction. CKD is divided into five stages by the efficacy of renal function. In the early stages of CKD, it is hard to identify the disease induction for the uncertain signs or symptoms. Moreover, patients are usually informed about coming down with CKD while the kidney damage has resulted in renal dysfunction and irreversible consequences. On the other hand, the main pathogenesis of renovascular hypertension (RH) is due to the production of arterial stenosis. Arterial stenosis leads to activation abnormalities of the renin-angiotensin-aldosterone system (RAAS), which can result in renal hypertension. Additionally, renal hypertension always causes serious damage to kidneys. Both of these two diseases can lead to kidney dysfunction and damage. Sodium thiosulfate (STS) is currently applied to treat cyanide poisoning and to prevent calcification in clinical trials. According to previous studies, STS is a developed antioxidant which can retard oxidative stress. STS can effectively reduce the accumulation of free radicals by the action of decreasing the release of hydrogen peroxide and retaining the activity of superoxide dismutase. In this study, we induced two kinds of disease models which are similar to CKD and RH diseases in Wistar rats. In addition, intraperitoneal administration of STS is applied to evaluate whether STS can improve renal damage, renal dysfunction and systemic hypertension in these chronic kidney injury models. We first evaluated the dosage of STS by the antioxidant activity evaluation. We adapted the dosage of STS at the value of 0.1 g/kg which is a safe dosage lower the maximal dose 0.2 g/kg. Additionally, the antioxidant activity was similar between 0.1 g/kg and 0.2 g/kg according to our data. Our results further showed that STS can actually reduce the amount of free radicals in blood, the level of renal 4 HNE lipid peroxidation expression, the degree of neutrophil infiltration into the kidney, the degree of renal fibrosis, Bax/Bcl-2 ratio, renal apoptosis formation and effectively depress the elevated level of blood urine nitrogen (BUN) and creatinine in the 5/6 kidney removal induced CKD and RVHT models. In conclusion, our results suggest that STS treatment may be a potentially therapeutic strategy in ameliorating CKD and RH through the action of antioxidant, anti-fibrosis and anti-apoptosis. Key Words：sodium thiosulfate,chronic kidney disease, renal hypertension, free radical
Chronic kidney disease (CKD) is a gradual process of renal dysfunction. CKD is divided into five stages by the efficacy of renal function. In the early stages of CKD, it is hard to identify the disease induction for the uncertain signs or symptoms. Moreover, patients are usually informed about coming down with CKD while the kidney damage has resulted in renal dysfunction and irreversible consequences. On the other hand, the main pathogenesis of renovascular hypertension (RH) is due to the production of arterial stenosis. Arterial stenosis leads to activation abnormalities of the renin-angiotensin-aldosterone system (RAAS), which can result in renal hypertension. Additionally, renal hypertension always causes serious damage to kidneys. Both of these two diseases can lead to kidney dysfunction and damage. Sodium thiosulfate (STS) is currently applied to treat cyanide poisoning and to prevent calcification in clinical trials. According to previous studies, STS is a developed antioxidant which can retard oxidative stress. STS can effectively reduce the accumulation of free radicals by the action of decreasing the release of hydrogen peroxide and retaining the activity of superoxide dismutase. In this study, we induced two kinds of disease models which are similar to CKD and RH diseases in Wistar rats. In addition, intraperitoneal administration of STS is applied to evaluate whether STS can improve renal damage, renal dysfunction and systemic hypertension in these chronic kidney injury models. We first evaluated the dosage of STS by the antioxidant activity evaluation. We adapted the dosage of STS at the value of 0.1 g/kg which is a safe dosage lower the maximal dose 0.2 g/kg. Additionally, the antioxidant activity was similar between 0.1 g/kg and 0.2 g/kg according to our data. Our results further showed that STS can actually reduce the amount of free radicals in blood, the level of renal 4 HNE lipid peroxidation expression, the degree of neutrophil infiltration into the kidney, the degree of renal fibrosis, Bax/Bcl-2 ratio, renal apoptosis formation and effectively depress the elevated level of blood urine nitrogen (BUN) and creatinine in the 5/6 kidney removal induced CKD and RVHT models. In conclusion, our results suggest that STS treatment may be a potentially therapeutic strategy in ameliorating CKD and RH through the action of antioxidant, anti-fibrosis and anti-apoptosis. Key Words：sodium thiosulfate,chronic kidney disease, renal hypertension, free radical
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硫代硫酸鈉, 慢性腎臟疾病, 腎血管性高血壓, 自由基, sodium thiosulfate, chronic kidney disease, renal hypertension, free radical