雷公藤甲素急性肾毒性作用机制及抗氧化剂维生素C对肾脏的保护作用的研究
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摘要
[背景]
雷公藤(Tripterygium wilfordii Hook. f. TWHf)属卫矛科,其主要活性成分为二萜类化合物雷公藤甲素(triptolide)。许多研究都已证明,雷公藤甲素有多种功效,如免疫抑制、抗炎、抗肿瘤、抗生育作用等。临床上已经利用多种含有雷公藤甲素的雷公藤提取物进行相关疾病的治疗,并取得了良好效果。然而,雷公藤甲素却有着强烈毒性,会对消化系统、泌尿系统、血液循环系统、生殖系统以及骨髓产生毒性作用,造成不同程度的损害,这严重影响了其使用。此外根据相关研究,在所有雷公藤甲素中毒致死的案例中,肾功能不全/衰竭是最重要的死亡原因,而且肾脏是雷公藤甲素慢性毒性作用最重要的靶器官。然而到目前为止尚不清楚雷公藤甲素所致的肾损伤的机制。因此,从安全角度考虑,必须努力搞清雷公藤甲素肾毒性作用的机制。
[目的]
建立雷公藤甲素致大鼠急性肾损伤模型,研究雷公藤甲素所致大鼠急性肾损伤机制,并对抗氧化剂维生素C对雷公藤甲素急性肾毒性作用的预防效果及可能的机制进行研究。具体内容包括：
1.建立雷公藤甲素致大鼠急性肾损伤模型；
2.研究氧化应激在雷公藤甲素所致大鼠急性肾损伤中的作用；
3.研究细胞凋亡在雷公藤甲素所致大鼠急性肾损伤中的作用及相关机制；
4.研究抗氧化剂维生素C对雷公藤甲素所致大鼠急性肾损伤的预防作用及可能机制。
[方法]
1.将30只雄性SD大鼠完全随机分为1个对照组和2个实验组,对两个实验组大鼠给予腹腔注射剂量分别为lmg/kg和2mg/kg的雷公藤甲素,对照组大鼠则给予相当量的空白对照液。注射后48小时将所有大鼠处死,采集心脏血液并取双侧肾脏固定,检测血浆尿素氮(PUN)与肌酐(Pcr)含量,HE与Masson病理切片染色观察肾组织形态学改变情况；测定肾组织内SOD、GSH-Px活性以及ROS、MDA含量。
2.实验分组、动物处理方法及肾功能检查同1；应用原位末端标记法(TUNEL)检测肾组织细胞凋亡情况；利用免疫组织化学染色法与Western Blot法检测肾组织内凋亡相关蛋白的表达情况,并利用real-time PCR技术测定肾组织内凋亡相关蛋白调控基因的表达量。
3.将40只雄性SD大鼠完全随机分为4组——(1)对照组：在实验第8天,给予对照组大鼠腹腔注射(ip)0.9%的生理盐水；(2)维生素C组：从实验第1天开始,给予本组大鼠灌服剂量为250mg/kg体重的维生素C溶液(蒸馏水溶解)每天一次,连续灌服7天,在实验第8天,给予本组大鼠腹腔注射(ip)0.9%的生理盐水(操作同对照组)；(3)雷公藤甲素组：在实验第8天,给予本组大鼠腹腔注射(ip)剂量为lmg/kg体重的雷公藤甲素溶液；(4)维生素C与雷公藤甲素合用组：从实验第1天开始,给予本组大鼠灌服剂量为250mg/kg体重的维生素C溶液(蒸馏水溶解),每天一次,连续灌服7天,在实验第8天,给予本组大鼠腹腔注射(ip)剂量为1mg/kg体重的雷公藤甲素溶液(操作同雷公藤甲素组)在实验第10天,将所有大鼠处死,抽取心脏血液并取双侧肾脏。测定肾组织内SOD、GSH-Px活性以及ROS、MDA含量；检测血浆尿素氮(PUN)与肌酐(Pcr)含量；观察HE与TUNEL染色切片上肾组织形态学与细胞凋亡情况；Western Blot法检测肾组织内凋亡相关蛋白的表达情况,并利用real-time PCR技术测定肾组织内凋亡相关蛋白调控基因的表达量。
[结果]
1.一次性大剂量注射雷公藤甲素可在短时间内对大鼠肾脏造成严重损伤,剂量越大越显著；经雷公藤甲素处理后,肾组织中SOD与GSH-Px(?)性明显降低,而ROS与MDA含量则明显升高,且均与肾脏的损伤程度密切相关
2.两个雷公藤甲素处理组均可见大量肾小管上皮细胞凋亡,剂量越大越显著,且与肾功能改变相关；经雷公藤甲素处理后,肾组织中Bax、Bid、Bad、Fas以及FasL表达明显增多,且呈剂量依赖性改变；尽管Bcl-2的表达未见明显改变,但Bax/Bcl-2表达量比值却呈剂量依赖性升高。
3.维生素C预处理大鼠1肾组织中抗氧化酶活性比单纯使用雷公藤甲素注射大鼠显著提高,而ROS与MDA含量则明显下降；与单纯注射雷公藤甲素大鼠相比,维生素C预处理大鼠肾功能显著改善；维生素C预处理大鼠肾脏结构损伤程度比单纯注射雷公藤甲素大鼠显著减轻,肾小管上皮细胞凋亡数量明显减少；与雷公藤甲素组相比,维生素C与雷公藤甲素合用组大鼠肾脏中Bax、Bid、Bad表达量以及Bax/Bcl-2表达量比值显著下降,而Fas/FasL表达情况则没有显著差异。
[结论]
1.肾脏是雷公藤甲素急性毒性作用重要的靶器官,氧化应激损伤在雷公藤甲素对肾脏造成的毒性损害中发挥了重要作用。
2.肾小管上皮细胞凋亡是雷公藤甲素所致大鼠急性肾损伤时重要的组织学基础之一,且Bcl-2家族以及Fas/FasL在雷公藤甲素诱导的肾小管上皮细胞凋亡的过程中起到了重要作用。
3.维生素C能够显著抑制雷公藤甲素对大鼠肾脏造成的结构与功能损害,这与其抗氧化活性密切相关；维生素C能通过对Bcl-2家族成员表达的调控抑制雷公藤甲素诱导的肾小管上皮细胞凋亡
4.抗氧化剂有可能成为我们预防和治疗雷公藤甲素所造成的肾脏损害的有效药物。
[Backgound]
Triptolide is a diterpenoid isolated from the plant Tripterygium wilfordii Hook. f (TWHf), a member of the Celastraceae family and it is one of the main active components in TWHf. Many studies have shown that triptolide has various functions including immunosuppressive, anti-cancer, and contraceptive activities. The ethanol extract, ethyl acetate extract, and other extracts of TWHf containing triptolide have been used for the treatment of rheumatoid arthritis and autoimmune diseases clinically and triptolide was deemed to account for the immunosuppressive activity of the extracts. However, triptolide has severe toxicities on digestive, urogenital, blood circulatory, reproductive system and bone marrow, which have largely limited its clinical application. Furthermore, among acute poisoning of triptolide cases which result in fatal consequences, acute renal dysfunction/failure is the most important cause of death, and a subchronic toxicological study on mice also suggested that kidney is one of the most common target organs of triptolide-induced toxicity. However, the mechanism of renal injury caused by triptolide remains unclear. Therefore, elucidation of the possible mechanisms of nephrotoxicity is essential from a safety point of view.
[Aims]
We want to set up a model of triptolide-induced acute renal injury in SD rats, and study the possible mechanisms of triptolide-induced acute nephrotoxicity, as well as the preventive effect of antioxidant vitamin C on triptolide-induced acute nephrotoxicity in rats. It consists of the following:
1. Set up the model of triptolide-induced acute renal injury in SD rats.
2. Study on the role of oxidative stress in triptolide-induced acute nephrotoxicity in rats.
3. Study the role of apoptosis of renal tubular cells in triptolide-induced acute nephrotoxicity and possible mechanisms in rats.
4. Study the preventive function of vitamin C on triptolide-induced acute nephrotoxicity and possible mechanisms in rats.
[Methods]
1.30 male SD rats were randomly divided into a control group and two testing groups (triptolide a and triptolide b). The rats of two testing groups received peritoneal injection of triptolide solution at doses of lmg/kg of body weight and 2mg/kg of body weight respectively, and the rats of the control received peritoneal injection of 0.9% physiological saline instead. Testing rats were killed 48h after injection; blood samples were collected and both kidneys were removed. The PUN and Pcr concentrations were measured, and renal histology was examined by HE and Masson's trichrome staining. The activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), as well as renal content of reactive oxygen species (ROS) and malondialdehyde (MDA) were measured.
2. The experimental design and the methods for the detection of PUN and Pcr concentrations did not differ compared with the first part. TUNEL staining was performed to evaluate apoptosis of renal tissue. Renal expression of apoptosis related proteins Bcl-2, Bax, Bid, Bad, Fas and FasL, as well as corresponding regulating genes were assessed by immunohistochemical staining, Western Blotting and real-time PCR.
3.40 male SD rats were randomly divided into four groups:the first group (control group) received a single peritoneal injection of 0.9% physiological saline on day 8; the second group (vitamin C group) first received an oral administration of vitamin C (dissolved in distilled water) at a dose of 250 mg/kg of body weight per day for 7 days continually, and then received a single peritoneal injection of 0.9% physiological saline on day 8 as the first group; the third group (triptolide group) received a single peritoneal injection of triptolide solution at a dose of 1 mg/kg of body weight on day 8; the forth group (Vitamin C+triptolide group) first received an oral administration of vitamin C (dissolved in distilled water) at a dose of 250 mg/kg of body weight per day for 7 days continually, and then received a single peritoneal injection of triptolide solution at a dose of 1 mg/kg of body weight on day 8 as the third group. All the rats were killed by cervical dislocation on day 10. The renal superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities, as well as renal ROS and malondialdehyde (MDA) content were measured to evaluate oxidative damage level. Blood samples were collected for biochemical analysis, and both kidneys were removed. Plasma creatinine (Pcr) concentrations and plasma urea nitrogen (PUN) concentrations were measured to assess renal function. Histological examination of renal tissue was done by H&E staining and viewed under common light microscope. TUNEL staining was performed to assess apoptosis of renal tubular cells. Renal expression of apoptosis related proteins Bcl-2, Bax, Bid, Bad, Fas and FasL, as well as corresponding regulating genes were assessed by Western Blotting and real-time PCR.
[Results]
1. A single large dose injection of triptolide resulted in both morphological and functional injury dose dependently in a short time; furthermore, triptolide shock could lead to depletion of renal SOD and GSH-Px activities and increases of renal ROS and MDA content in a dose dependent manner, which correlated well with the degree of renal injury.
2. After injection of triptolide, rats presented increased number of apoptotic tubular cells corresponding to the increases of PUN and Pcr concentrations. Furthermore, increased expression of Bax, Bid, Bad, Fas and FasL was detected at both protein and mRNA levels, but the expression of Bcl-2 did not differ around the three groups; nevertheless, the ratio of Bax to Bcl-2 increased at both protein and mRNA levels.
3. Pretreatment with the antioxidant vitamin C significantly ameliorated triptolide-induced depletion in renal SOD and GSH-Px activities, caused marked normalization of renal ROS and MDA content and also inhibited the triptolide-induced apoptosis of renal tubular cells and renal injury. Compared with the triptolide group, the expression patterns of Bax, Bid and Bad, as well as the ratio of Bax to Bcl-2 at both protein and mRNA levels were decreased; however, there were no statistical differences of the expression patterns of Fas and FasL between the two groups.
[Conclusion]
1. Kidney is an important target organ of triptolide-induced toxicities, and oxidative stress contributes to the mechanism of triptolide-induced acute nephrotoxicity.
2. Apoptosis of tubular cells plays a key role in the pathogenesis of triptolide-induced acute nephrotoxicity, and Bcl-2 family, as well as Fas and FasL, are involved in this process.
3. Pretreatment with the antioxidant, oral administration of vitamin C (250 mg/kg of body weight, dissolved in distilled water) per day for 7 days continually, significantly reduced the generation of oxidative stress and effectively inhibited the triptolide-induced apoptosis of renal tubular cells and renal injury by regulating the expression patterns of Bcl-2 family members.
4. The protective effect of vitamin C could provide a new insight into the potential therapeutic solution to triptolide-induced renal injury.
雷公藤(Tripterygium wilfordii Hook. f. TWHf)属卫矛科,其主要活性成分为二萜类化合物雷公藤甲素(triptolide)。许多研究都已证明,雷公藤甲素有多种功效,如免疫抑制、抗炎、抗肿瘤、抗生育作用等。临床上已经利用多种含有雷公藤甲素的雷公藤提取物进行相关疾病的治疗,并取得了良好效果。然而,雷公藤甲素却有着强烈毒性,会对消化系统、泌尿系统、血液循环系统、生殖系统以及骨髓产生毒性作用,造成不同程度的损害,这严重影响了其使用。此外根据相关研究,在所有雷公藤甲素中毒致死的案例中,肾功能不全/衰竭是最重要的死亡原因,而且肾脏是雷公藤甲素慢性毒性作用最重要的靶器官。然而到目前为止尚不清楚雷公藤甲素所致的肾损伤的机制。因此,从安全角度考虑,必须努力搞清雷公藤甲素肾毒性作用的机制。
[目的]
建立雷公藤甲素致大鼠急性肾损伤模型,研究雷公藤甲素所致大鼠急性肾损伤机制,并对抗氧化剂维生素C对雷公藤甲素急性肾毒性作用的预防效果及可能的机制进行研究。具体内容包括：
1.建立雷公藤甲素致大鼠急性肾损伤模型；
2.研究氧化应激在雷公藤甲素所致大鼠急性肾损伤中的作用；
3.研究细胞凋亡在雷公藤甲素所致大鼠急性肾损伤中的作用及相关机制；
4.研究抗氧化剂维生素C对雷公藤甲素所致大鼠急性肾损伤的预防作用及可能机制。
[方法]
1.将30只雄性SD大鼠完全随机分为1个对照组和2个实验组,对两个实验组大鼠给予腹腔注射剂量分别为lmg/kg和2mg/kg的雷公藤甲素,对照组大鼠则给予相当量的空白对照液。注射后48小时将所有大鼠处死,采集心脏血液并取双侧肾脏固定,检测血浆尿素氮(PUN)与肌酐(Pcr)含量,HE与Masson病理切片染色观察肾组织形态学改变情况；测定肾组织内SOD、GSH-Px活性以及ROS、MDA含量。
2.实验分组、动物处理方法及肾功能检查同1；应用原位末端标记法(TUNEL)检测肾组织细胞凋亡情况；利用免疫组织化学染色法与Western Blot法检测肾组织内凋亡相关蛋白的表达情况,并利用real-time PCR技术测定肾组织内凋亡相关蛋白调控基因的表达量。
3.将40只雄性SD大鼠完全随机分为4组——(1)对照组：在实验第8天,给予对照组大鼠腹腔注射(ip)0.9%的生理盐水；(2)维生素C组：从实验第1天开始,给予本组大鼠灌服剂量为250mg/kg体重的维生素C溶液(蒸馏水溶解)每天一次,连续灌服7天,在实验第8天,给予本组大鼠腹腔注射(ip)0.9%的生理盐水(操作同对照组)；(3)雷公藤甲素组：在实验第8天,给予本组大鼠腹腔注射(ip)剂量为lmg/kg体重的雷公藤甲素溶液；(4)维生素C与雷公藤甲素合用组：从实验第1天开始,给予本组大鼠灌服剂量为250mg/kg体重的维生素C溶液(蒸馏水溶解),每天一次,连续灌服7天,在实验第8天,给予本组大鼠腹腔注射(ip)剂量为1mg/kg体重的雷公藤甲素溶液(操作同雷公藤甲素组)在实验第10天,将所有大鼠处死,抽取心脏血液并取双侧肾脏。测定肾组织内SOD、GSH-Px活性以及ROS、MDA含量；检测血浆尿素氮(PUN)与肌酐(Pcr)含量；观察HE与TUNEL染色切片上肾组织形态学与细胞凋亡情况；Western Blot法检测肾组织内凋亡相关蛋白的表达情况,并利用real-time PCR技术测定肾组织内凋亡相关蛋白调控基因的表达量。
[结果]
1.一次性大剂量注射雷公藤甲素可在短时间内对大鼠肾脏造成严重损伤,剂量越大越显著；经雷公藤甲素处理后,肾组织中SOD与GSH-Px(?)性明显降低,而ROS与MDA含量则明显升高,且均与肾脏的损伤程度密切相关
2.两个雷公藤甲素处理组均可见大量肾小管上皮细胞凋亡,剂量越大越显著,且与肾功能改变相关；经雷公藤甲素处理后,肾组织中Bax、Bid、Bad、Fas以及FasL表达明显增多,且呈剂量依赖性改变；尽管Bcl-2的表达未见明显改变,但Bax/Bcl-2表达量比值却呈剂量依赖性升高。
3.维生素C预处理大鼠1肾组织中抗氧化酶活性比单纯使用雷公藤甲素注射大鼠显著提高,而ROS与MDA含量则明显下降；与单纯注射雷公藤甲素大鼠相比,维生素C预处理大鼠肾功能显著改善；维生素C预处理大鼠肾脏结构损伤程度比单纯注射雷公藤甲素大鼠显著减轻,肾小管上皮细胞凋亡数量明显减少；与雷公藤甲素组相比,维生素C与雷公藤甲素合用组大鼠肾脏中Bax、Bid、Bad表达量以及Bax/Bcl-2表达量比值显著下降,而Fas/FasL表达情况则没有显著差异。
[结论]
1.肾脏是雷公藤甲素急性毒性作用重要的靶器官,氧化应激损伤在雷公藤甲素对肾脏造成的毒性损害中发挥了重要作用。
2.肾小管上皮细胞凋亡是雷公藤甲素所致大鼠急性肾损伤时重要的组织学基础之一,且Bcl-2家族以及Fas/FasL在雷公藤甲素诱导的肾小管上皮细胞凋亡的过程中起到了重要作用。
3.维生素C能够显著抑制雷公藤甲素对大鼠肾脏造成的结构与功能损害,这与其抗氧化活性密切相关；维生素C能通过对Bcl-2家族成员表达的调控抑制雷公藤甲素诱导的肾小管上皮细胞凋亡
4.抗氧化剂有可能成为我们预防和治疗雷公藤甲素所造成的肾脏损害的有效药物。
[Backgound]
Triptolide is a diterpenoid isolated from the plant Tripterygium wilfordii Hook. f (TWHf), a member of the Celastraceae family and it is one of the main active components in TWHf. Many studies have shown that triptolide has various functions including immunosuppressive, anti-cancer, and contraceptive activities. The ethanol extract, ethyl acetate extract, and other extracts of TWHf containing triptolide have been used for the treatment of rheumatoid arthritis and autoimmune diseases clinically and triptolide was deemed to account for the immunosuppressive activity of the extracts. However, triptolide has severe toxicities on digestive, urogenital, blood circulatory, reproductive system and bone marrow, which have largely limited its clinical application. Furthermore, among acute poisoning of triptolide cases which result in fatal consequences, acute renal dysfunction/failure is the most important cause of death, and a subchronic toxicological study on mice also suggested that kidney is one of the most common target organs of triptolide-induced toxicity. However, the mechanism of renal injury caused by triptolide remains unclear. Therefore, elucidation of the possible mechanisms of nephrotoxicity is essential from a safety point of view.
[Aims]
We want to set up a model of triptolide-induced acute renal injury in SD rats, and study the possible mechanisms of triptolide-induced acute nephrotoxicity, as well as the preventive effect of antioxidant vitamin C on triptolide-induced acute nephrotoxicity in rats. It consists of the following:
1. Set up the model of triptolide-induced acute renal injury in SD rats.
2. Study on the role of oxidative stress in triptolide-induced acute nephrotoxicity in rats.
3. Study the role of apoptosis of renal tubular cells in triptolide-induced acute nephrotoxicity and possible mechanisms in rats.
4. Study the preventive function of vitamin C on triptolide-induced acute nephrotoxicity and possible mechanisms in rats.
[Methods]
1.30 male SD rats were randomly divided into a control group and two testing groups (triptolide a and triptolide b). The rats of two testing groups received peritoneal injection of triptolide solution at doses of lmg/kg of body weight and 2mg/kg of body weight respectively, and the rats of the control received peritoneal injection of 0.9% physiological saline instead. Testing rats were killed 48h after injection; blood samples were collected and both kidneys were removed. The PUN and Pcr concentrations were measured, and renal histology was examined by HE and Masson's trichrome staining. The activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), as well as renal content of reactive oxygen species (ROS) and malondialdehyde (MDA) were measured.
2. The experimental design and the methods for the detection of PUN and Pcr concentrations did not differ compared with the first part. TUNEL staining was performed to evaluate apoptosis of renal tissue. Renal expression of apoptosis related proteins Bcl-2, Bax, Bid, Bad, Fas and FasL, as well as corresponding regulating genes were assessed by immunohistochemical staining, Western Blotting and real-time PCR.
3.40 male SD rats were randomly divided into four groups:the first group (control group) received a single peritoneal injection of 0.9% physiological saline on day 8; the second group (vitamin C group) first received an oral administration of vitamin C (dissolved in distilled water) at a dose of 250 mg/kg of body weight per day for 7 days continually, and then received a single peritoneal injection of 0.9% physiological saline on day 8 as the first group; the third group (triptolide group) received a single peritoneal injection of triptolide solution at a dose of 1 mg/kg of body weight on day 8; the forth group (Vitamin C+triptolide group) first received an oral administration of vitamin C (dissolved in distilled water) at a dose of 250 mg/kg of body weight per day for 7 days continually, and then received a single peritoneal injection of triptolide solution at a dose of 1 mg/kg of body weight on day 8 as the third group. All the rats were killed by cervical dislocation on day 10. The renal superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities, as well as renal ROS and malondialdehyde (MDA) content were measured to evaluate oxidative damage level. Blood samples were collected for biochemical analysis, and both kidneys were removed. Plasma creatinine (Pcr) concentrations and plasma urea nitrogen (PUN) concentrations were measured to assess renal function. Histological examination of renal tissue was done by H&E staining and viewed under common light microscope. TUNEL staining was performed to assess apoptosis of renal tubular cells. Renal expression of apoptosis related proteins Bcl-2, Bax, Bid, Bad, Fas and FasL, as well as corresponding regulating genes were assessed by Western Blotting and real-time PCR.
[Results]
1. A single large dose injection of triptolide resulted in both morphological and functional injury dose dependently in a short time; furthermore, triptolide shock could lead to depletion of renal SOD and GSH-Px activities and increases of renal ROS and MDA content in a dose dependent manner, which correlated well with the degree of renal injury.
2. After injection of triptolide, rats presented increased number of apoptotic tubular cells corresponding to the increases of PUN and Pcr concentrations. Furthermore, increased expression of Bax, Bid, Bad, Fas and FasL was detected at both protein and mRNA levels, but the expression of Bcl-2 did not differ around the three groups; nevertheless, the ratio of Bax to Bcl-2 increased at both protein and mRNA levels.
3. Pretreatment with the antioxidant vitamin C significantly ameliorated triptolide-induced depletion in renal SOD and GSH-Px activities, caused marked normalization of renal ROS and MDA content and also inhibited the triptolide-induced apoptosis of renal tubular cells and renal injury. Compared with the triptolide group, the expression patterns of Bax, Bid and Bad, as well as the ratio of Bax to Bcl-2 at both protein and mRNA levels were decreased; however, there were no statistical differences of the expression patterns of Fas and FasL between the two groups.
[Conclusion]
1. Kidney is an important target organ of triptolide-induced toxicities, and oxidative stress contributes to the mechanism of triptolide-induced acute nephrotoxicity.
2. Apoptosis of tubular cells plays a key role in the pathogenesis of triptolide-induced acute nephrotoxicity, and Bcl-2 family, as well as Fas and FasL, are involved in this process.
3. Pretreatment with the antioxidant, oral administration of vitamin C (250 mg/kg of body weight, dissolved in distilled water) per day for 7 days continually, significantly reduced the generation of oxidative stress and effectively inhibited the triptolide-induced apoptosis of renal tubular cells and renal injury by regulating the expression patterns of Bcl-2 family members.
4. The protective effect of vitamin C could provide a new insight into the potential therapeutic solution to triptolide-induced renal injury.
引文
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