基于“肝肾同源”理论探讨柴黄益肾颗粒防治糖尿病肝肾并发症的机制研究
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摘要
糖尿病并发症严重威胁着人类的健康,已经成为失明、终末期肾病、缺血性心脏病、致残、致死的主要原因,其中糖尿病相关肝肾并发症更为广泛、预后较差,中医学从“肝肾同源”理论立足,对其病机认识和诊疗思路有着独特优势。糖尿病肝损伤(Diabetic liver disease, DLD)是在糖尿病的发生发展中出现的肝组织学和/或肝功能异常为主要临床特征,严重者导致肝纤维化和肝硬化。糖尿病肾病作为糖尿病最常见的微血管并发症,已成为导致终末期肾病的主要原因之一。随着糖尿病在我国的广泛流行,20.0%-30.9%的糖尿病患者伴有非特异性肝功能损伤,33.4%的患者伴有肾脏病变。糖尿病引起的肝肾并发症已成为影响国民健康和社会稳定的重大公共卫生问题。现代医学对于糖尿病肝肾并发症的治疗疗效并不理想。中医药在糖尿病并发症的预防和治疗方面有其独特的优势,具有多靶点、整体调节的特点。因此,我们在既往研究基础上,结合中医学整体观,通过对“肝肾同源”理论的梳理与总结,分析探讨该理论对糖尿病肝肾并发症的病机认识和诊疗思路,并观察了在该理论指导下研制的柴黄益肾颗粒(ChaihuangYishen granule, CHYS)对糖尿病大鼠肝肾损伤的改善作用及其共同机制,为糖尿病肝肾并发症的治疗提供药的思路与途径,同时也为中医学“肝肾同源”理论提供了实验依据。
目的：
探讨“肝肾同源”理论在糖尿病肝肾并发症的病机认识和诊疗中的应用,在此基础上通过实验研究阐释该理论指导下的柴黄益肾颗粒在糖尿病大鼠肝肾并发症中的应用及其共同作用机制。
方法：
1.采用文献回顾性研究方法,探讨立足“肝肾同源”论治糖尿病肝肾损伤的理论依据：文献类型包括综合性医书、方书、专书、本草、从书、类书、医案、医论、医话等,以“肝肾”、“肾肝”、“肝肾同源”、“乙癸同源”、“精血同源”、“肾肝同病”、“肝肾相关”、“肝肾同治”等为关键词,通过查阅相关的中医书籍文献,抽取与“肝肾同源”理论相关的文献内容进行整理,以时间顺序为纲,以论述“肝肾同源”理论的代表医家著作为目,综合每个时代中医对“肝肾同源”理论的发展和演变,对中医“肝肾同源”理论的学术源流进行梳理,总结运用“肝肾同源”理论论治疾病的证治规律,并结合糖尿病及其肝肾并发症的病机特征,探讨“肝肾同源”理论对糖尿病肝肾并发症的病机认识和诊疗思路的指导意义。
2.柴黄益肾颗粒对糖尿病大鼠肝肾损伤的保护作用及机制研究：雄性Wistar大鼠以单侧肾切除合并腹腔注射链脲佐菌素(40mg/kg)诱导糖尿病,将造模成功的动物随机分为模型组、CHYS组(2.24g/kg)及蒙话组(1.67mg/kg),另取同周龄大鼠进行假手术并注射柠檬酸缓冲液作为假手术对照组,各组大鼠从造模开始连续给药20周。实验期间每周观察动物状态及体重变化,每4周检测动物血糖及24h尿蛋白水平,实验结束时取血、肝组织及肾组织。血生化分析仪检测肝功能(ALT、AST)及血脂水平(TC、TG)；肝组织称重计算肝重指数,进行HE染色并对其病理改变进行半定量分析,进行PAS、d-PAS染色检测肝糖原蓄积程度变化,肾组织进行PAS染色进行病理改变的半定量分析；RT-PCR方法检测肝、肾组织中TGF-β1、Decorin及GLUT-1表达；Western blot方法检测肝、肾组织中TGF-β1及Decorin蛋白表达,免疫组化法检测肝、肾组织中Ⅰ、Ⅲ型胶原表达。
结果：
1.基于“肝肾同源”论治糖尿病肝肾损伤的理论依据：中医学“肝肾同源”理论源于《黄帝内经》,临床实践丰富于汉唐金元,理论体系形成于明清。该理论认为肝肾在生理上相互滋生,相互促进,病理上相互影响,相互传变,在治疗肝肾相关疾病时应注重肝肾二者的关系和共同发病规律及相互作用。糖尿病能引起肝损伤和肾脏并发症两方面的临床特征。其发病和临床特点符合中医“肝肾同病”的病机特点,因此,立足“肝肾同源”论治糖尿病肝肾并发症,将有助于改进中医治疗糖尿病肝肾并发症的思路。
2.柴黄益肾颗粒对糖尿病大鼠肝损伤的保护作用：与假手术对照组相比,模型组大鼠体重显著降低(p<0.05),随实验周期延长,体重差异逐渐增加,至实验20周差异达到最大。实验期间各时间点模型组大鼠血糖水平均显著高于假手术对照组,均为p<0.01,CHYS及蒙诺对模型大鼠血糖水平均无明显影响。模型组血清ALT、AST与假手术对照组相比,均显著升高(p<0.05),CHYS及蒙诺能显著降低模型大鼠ALT水平(p<0.05)；CHYS组也能显著减少模型大鼠AST水平(p<0.05),模型组大鼠血清TC、TG水平显著高于假手术对照组p<0.01),CHYS组及蒙诺组血清TC、TG水平与假手术组比显著降低(P<0.05),模型组肝重指数及炎症活动度评分与假手术对照组均显著升高p<0.01)；CHYS可显著降低模型大鼠肝重指数p<0.01),CHYS组炎症活动度评分也显著低于模型组(p<0.01)。
3.柴黄益肾颗粒对糖尿病大鼠肾损害的保护作用：模型组大鼠与假手术对照组比24h尿蛋白水平呈渐进性升高,从实验第8周起有统计学意义(p<0.05)；CHYS组从实验12周起与模型组比24h尿蛋白水平显著降低(P<0.05),蒙诺在实验16周和20周能显著降低模型大鼠24h尿蛋白水平(P<0.05)。模型大鼠肾小球系膜基质百分比及肾小管间质纤维化指数显著高于假手术对照组大鼠(p<0.05),CHYS和蒙诺对模型大鼠的肾小球系膜基质百分比和肾小管间质纤维化指数有显著降低作用p<0.05)。
4.柴黄益肾颗粒对耱尿病大鼠肝组织GLUT-1、TGF-β1及Decorin表达的影响：模型大鼠肝组织GLUT-1、TGF-β1、Decorin mRNA表达与假手术对照大鼠比较显著升高(p<0.05),CHYS组肝组织GLUT-1、TGF-β1、Decorin mRNA表达与模型组相比显著下调(p<0.05)；与假手术对照组比,模型组肝组织TGF-β1、Decorin蛋白表达显著增加(p<0.05),CHYS显著抑制模型大鼠肝组织TGF-β1、Decorin蛋白表达水平(p<0.05)；与假手术对照组比较,模型组大鼠肝组织Ⅰ、Ⅲ型胶原表达显著上调(p<0.05),CHYS可显著减少模型大鼠肝组织ⅠⅢ型胶原表达(p<0.05)；与假手术对照组比模型组大鼠肝组织糖原蓄积程度显著增加,CHYS组肝组织糖原蓄积程度与模型组比明显减少。
5.柴黄益肾颗粒对糖尿病大鼠肾组织TGF-β1、Decorin及Ⅰ型胶原表达的影响：与假手术对照组比,模型组肾组织TGF-β1、Decorin蛋白表达显著增加(p<0.05), CHYS显著抑制模型大鼠肾组织TGF-β1、Decorin蛋白表达水平(p<0.05)；与假手术对照组比较,模型组大鼠肾组织Ⅰ型胶原表达显著上调(p<0.05), CHYS可显著减少模型大鼠肾组织Ⅰ型胶原表达(p<0.05)。
结论：
1、“肝肾同源”理论对糖尿病及其并发肝肾损伤的病因病机分析具有重要意义,可用于指导糖尿病肝肾并发症的治疗。
2、柴黄益肾颗粒对糖尿病肝损伤和肾脏病变均显示出良好的保护作用,体现了中药复方整体治疗,多靶点的优势。
3、柴黄益肾颗粒能抑制肝组织和肾组织GLUT-1、TGF-β1及decorin的表达,减轻纤维化形成,这可能是其减轻糖尿病肝肾并发症的共同作用机制。
Diabetic liver disease (DLD) is a hepatic complication of diabetes, which is mainly characterized as abnormality of liver histology or liver function, the serious patients would develop to liver fibrosis or cirrhosis. Diabetic nephropathy(DN) is a common complication of diabetes, which has been one of main cause leading to end-stage renal disease. With the prevalence of diabetes in China, recent epidemiological data revealed20.0-30.9%diabetics suffering from DLD and33.4%diabetic patients complicated with renal impairment. These two complications have been seriously problems of public health. There was few good therapeutic methods in treating the two diabetic complications with modern medicine respectively, which traditional Chinese Medicine(TCM) exhibit some advantages in preventing and treating the two complications dueing to the characteristics of holistic regulation and multiple targets. So we made classification and summary of the theory of homogeny of liver and kidney, then analyzed the application of the theory in recognition of pathogenesis and ideas for diagnosing and treating the two complications based on our previous studies. We also observed the effects of ChaihuangYishen granule(CHYS) on liver injuries and renal impairment in diabetic rats and investigated the common mechanisms of CHYS in treating the two complications, which will be beneficial to develop new drugs of treating the two complications and provide experimental evidences for the theory of homogeny of liver and kidney.
Objective:To investigate the application of the theory of homogeny of liver and kidney in understanding the pathogenesis and ideas of diagnosis and treatment for the two complications. Under the direction of the theory, to study the usage of CHYS in treating liver injuries and renal impairment associated with diabete and clarify the common mechanisms of CHYS in treating the two complications.
Methods:1. We investigated theoretic evidences of treating liver and kidney complications of diabetes based on the theory of homogeny of liver and kidney by utilizing the method of retrospective study of literature. The literature were consulted and arranged from various kinds of literature database and ancient medical classic by using of key words including "kidney and liver","liver and kidney","homoly of liver and kidney","homoly of Yi and Kui","homoly of essence and blood","concurrent diseases of liver and kidney"and "concurrent treatment of liver and kidney", which were relevant to homogeny of liver and kidney. We analyzed academic origin, development and evolution of the theory of homogeny of liver and kidney according to firstly time sequence and secondly representative books demonstrating the theory of homogeny of liver and kidney. By these work, we summarize the treatment regularity of treating diseases based on homogeny of liver and kidney. This will be beneficial to the recognition of etiology and pathogenesis of liver and kidney complications of diabetes and guiding therapeutic ideas of the complications with the theory of homogeny of liver and kidney.
2、The effect of Chaihuangyishen Granule (CHYS) on liver injuries and renal demage in diabetic rats:Diabetes was induced by by right-kidney nephrectomy plus peritoneal injection of streptozotocin (40mg/kg) in male Wistar rats, diabetic rats were randomly divided into model group, CHYS group (2.24g/kg) and monopril (1.67mg/kg), Twelve rats with same age and gender were received an sham operation plus peritoneal injection of vehicle and usd as sham group. All animals were orally administrated once daily for20weeks. Body weight and animal behaviors were observed every week, blood glucose and24-h urinary protein were determined every4weeks. The levels of serum lipid(TC, TG) and liver function(ALT, AST) were detected by blood biochemistry meter. Pathological changes of liver and kidney were observed by semiquantitative assessment. The mRNA expression of TGF-β1, decorin and GLUT-1in the liver and kidney were measured by RT-PCR; the protein expression of TGF-β1and decorin in the liver and kidneys were detected by western blot. The expression of collagen I in the liver and kidney and hepatic collagen III expression were analyzed by immunohistochemistry.
Results:
1. Theoretic evidence of treating liver and kidney complications of diabetes based on homogeny of liver and kidney:Theory of homogeny of liver and kidney originated from Inner Canon of Huangdi, Clinical practice replenish and the theory in Han, Tang, Jin and Yuan dynasty, Comlete system of the theory formed in Ming and Qing dynasty. The theory revealed close relation of between liver and kidney, these two organs indidate p physiological promotion each other, while show mutual effect and transmission under pathological condition. Diabetes could induce liver and kidney complications, and clinic features or development of these complications were in line with pathological characteristic of concurrent disearse of live and kidney. So it is helpful for promotion of treating liver and kidney complications of diabetes with TCM under the guideline of the theory of homology of liver and kidney.
2. Improving effects of CHYS on live injuries in diabetic rats. Body weight of model group was significantly lower than that of sham group at weeks4(p<0.05), the difference reached an peaking at weeks20. There was significant difference in the level of blood glucose between model group and sham group during the whole experiment period(p<0.01); treatment with CHYS or monopril didn't effect the levels of body weight and blood glucose. Serum levels of TC, TG, ALT and AST in model group showed obvious raise compared to those in sham group, while there was remarkable reduction of serum AST, TC and TG levels in CHYS group and monopril group. Index of liver weight and hepatic histologic active scores of inflammatory in model group were significantly higher than those in sham group, treatment with CHYS could alleviate these parameters(p<0.05).
3. Attenuation of CHYS on renal impairments in diabetic rats. The level of24-h urinary protein of model group exhibited progressive elevation at weeks8(p<0.05), CHYS exerted significant decreasement of24-h urinary protein from weeks12(p<0.05), and monopril could reduce the level of24-h urinary protein at weeks16and weeks20(p<0.05). Percentage of mesangial matrix and tubulo-interstitial fibrosis index in model group were obviously higher than that in sham group(p<0.01), CHYS and monopril improved the abnormalities of the indices in diabetic rats(p<0.05).
4. Effects of CHYS on expression of TGF-β1、decorin及GLUT-1in the liver and kidney of diabetic rats. Compared to that of sham group, hepatic expression of TGF-β1, decorin and GLUT-1mRNA were significantly increased; while CHYS group were statistically lower than that of model group(p<0.01). The increased expression of TGF-β1and decorin protein in the liver and kidney of diabetic rats were inhibited by CHYS or monopril treatment(p<0.05). The results of immunohistochemistry revealed the upregulation of collagen I expression in the liver and kidneys of diabetic rats(p<0.01), hepatic collagen III expression also remarkably raised in model group(p<0.05), and these changes were reversed by CHYS treatment; By PAS staining and d-PAS staining, we also observed accumulation of hepatic glycogen in model group, and CHYS could reduce hepatic glycogen storage in diabetic rats.
Conclusion:
1. The theory of homogeny of liver and kidney is important to understand etiology and pathogenesis of liver and kidney complications of diabetes and could be used for guiding the treatment of the two complications.
2. CHYS exhibited good therapeutic effects on both liver injury and renal impairment associated with diabetes, which reflect the advantages of multiple targets and holistic regulation of TCM.
3.CHYS could inhibit expression of TGF-β1and decorin in the liver and kidney of diabetic rats and reduce the degree of fibrosis, which involves the common machanisms of CHYS in treating liver and kidney complications of diabetes.
目的：
探讨“肝肾同源”理论在糖尿病肝肾并发症的病机认识和诊疗中的应用,在此基础上通过实验研究阐释该理论指导下的柴黄益肾颗粒在糖尿病大鼠肝肾并发症中的应用及其共同作用机制。
方法：
1.采用文献回顾性研究方法,探讨立足“肝肾同源”论治糖尿病肝肾损伤的理论依据：文献类型包括综合性医书、方书、专书、本草、从书、类书、医案、医论、医话等,以“肝肾”、“肾肝”、“肝肾同源”、“乙癸同源”、“精血同源”、“肾肝同病”、“肝肾相关”、“肝肾同治”等为关键词,通过查阅相关的中医书籍文献,抽取与“肝肾同源”理论相关的文献内容进行整理,以时间顺序为纲,以论述“肝肾同源”理论的代表医家著作为目,综合每个时代中医对“肝肾同源”理论的发展和演变,对中医“肝肾同源”理论的学术源流进行梳理,总结运用“肝肾同源”理论论治疾病的证治规律,并结合糖尿病及其肝肾并发症的病机特征,探讨“肝肾同源”理论对糖尿病肝肾并发症的病机认识和诊疗思路的指导意义。
2.柴黄益肾颗粒对糖尿病大鼠肝肾损伤的保护作用及机制研究：雄性Wistar大鼠以单侧肾切除合并腹腔注射链脲佐菌素(40mg/kg)诱导糖尿病,将造模成功的动物随机分为模型组、CHYS组(2.24g/kg)及蒙话组(1.67mg/kg),另取同周龄大鼠进行假手术并注射柠檬酸缓冲液作为假手术对照组,各组大鼠从造模开始连续给药20周。实验期间每周观察动物状态及体重变化,每4周检测动物血糖及24h尿蛋白水平,实验结束时取血、肝组织及肾组织。血生化分析仪检测肝功能(ALT、AST)及血脂水平(TC、TG)；肝组织称重计算肝重指数,进行HE染色并对其病理改变进行半定量分析,进行PAS、d-PAS染色检测肝糖原蓄积程度变化,肾组织进行PAS染色进行病理改变的半定量分析；RT-PCR方法检测肝、肾组织中TGF-β1、Decorin及GLUT-1表达；Western blot方法检测肝、肾组织中TGF-β1及Decorin蛋白表达,免疫组化法检测肝、肾组织中Ⅰ、Ⅲ型胶原表达。
结果：
1.基于“肝肾同源”论治糖尿病肝肾损伤的理论依据：中医学“肝肾同源”理论源于《黄帝内经》,临床实践丰富于汉唐金元,理论体系形成于明清。该理论认为肝肾在生理上相互滋生,相互促进,病理上相互影响,相互传变,在治疗肝肾相关疾病时应注重肝肾二者的关系和共同发病规律及相互作用。糖尿病能引起肝损伤和肾脏并发症两方面的临床特征。其发病和临床特点符合中医“肝肾同病”的病机特点,因此,立足“肝肾同源”论治糖尿病肝肾并发症,将有助于改进中医治疗糖尿病肝肾并发症的思路。
2.柴黄益肾颗粒对糖尿病大鼠肝损伤的保护作用：与假手术对照组相比,模型组大鼠体重显著降低(p<0.05),随实验周期延长,体重差异逐渐增加,至实验20周差异达到最大。实验期间各时间点模型组大鼠血糖水平均显著高于假手术对照组,均为p<0.01,CHYS及蒙诺对模型大鼠血糖水平均无明显影响。模型组血清ALT、AST与假手术对照组相比,均显著升高(p<0.05),CHYS及蒙诺能显著降低模型大鼠ALT水平(p<0.05)；CHYS组也能显著减少模型大鼠AST水平(p<0.05),模型组大鼠血清TC、TG水平显著高于假手术对照组p<0.01),CHYS组及蒙诺组血清TC、TG水平与假手术组比显著降低(P<0.05),模型组肝重指数及炎症活动度评分与假手术对照组均显著升高p<0.01)；CHYS可显著降低模型大鼠肝重指数p<0.01),CHYS组炎症活动度评分也显著低于模型组(p<0.01)。
3.柴黄益肾颗粒对糖尿病大鼠肾损害的保护作用：模型组大鼠与假手术对照组比24h尿蛋白水平呈渐进性升高,从实验第8周起有统计学意义(p<0.05)；CHYS组从实验12周起与模型组比24h尿蛋白水平显著降低(P<0.05),蒙诺在实验16周和20周能显著降低模型大鼠24h尿蛋白水平(P<0.05)。模型大鼠肾小球系膜基质百分比及肾小管间质纤维化指数显著高于假手术对照组大鼠(p<0.05),CHYS和蒙诺对模型大鼠的肾小球系膜基质百分比和肾小管间质纤维化指数有显著降低作用p<0.05)。
4.柴黄益肾颗粒对耱尿病大鼠肝组织GLUT-1、TGF-β1及Decorin表达的影响：模型大鼠肝组织GLUT-1、TGF-β1、Decorin mRNA表达与假手术对照大鼠比较显著升高(p<0.05),CHYS组肝组织GLUT-1、TGF-β1、Decorin mRNA表达与模型组相比显著下调(p<0.05)；与假手术对照组比,模型组肝组织TGF-β1、Decorin蛋白表达显著增加(p<0.05),CHYS显著抑制模型大鼠肝组织TGF-β1、Decorin蛋白表达水平(p<0.05)；与假手术对照组比较,模型组大鼠肝组织Ⅰ、Ⅲ型胶原表达显著上调(p<0.05),CHYS可显著减少模型大鼠肝组织ⅠⅢ型胶原表达(p<0.05)；与假手术对照组比模型组大鼠肝组织糖原蓄积程度显著增加,CHYS组肝组织糖原蓄积程度与模型组比明显减少。
5.柴黄益肾颗粒对糖尿病大鼠肾组织TGF-β1、Decorin及Ⅰ型胶原表达的影响：与假手术对照组比,模型组肾组织TGF-β1、Decorin蛋白表达显著增加(p<0.05), CHYS显著抑制模型大鼠肾组织TGF-β1、Decorin蛋白表达水平(p<0.05)；与假手术对照组比较,模型组大鼠肾组织Ⅰ型胶原表达显著上调(p<0.05), CHYS可显著减少模型大鼠肾组织Ⅰ型胶原表达(p<0.05)。
结论：
1、“肝肾同源”理论对糖尿病及其并发肝肾损伤的病因病机分析具有重要意义,可用于指导糖尿病肝肾并发症的治疗。
2、柴黄益肾颗粒对糖尿病肝损伤和肾脏病变均显示出良好的保护作用,体现了中药复方整体治疗,多靶点的优势。
3、柴黄益肾颗粒能抑制肝组织和肾组织GLUT-1、TGF-β1及decorin的表达,减轻纤维化形成,这可能是其减轻糖尿病肝肾并发症的共同作用机制。
Diabetic liver disease (DLD) is a hepatic complication of diabetes, which is mainly characterized as abnormality of liver histology or liver function, the serious patients would develop to liver fibrosis or cirrhosis. Diabetic nephropathy(DN) is a common complication of diabetes, which has been one of main cause leading to end-stage renal disease. With the prevalence of diabetes in China, recent epidemiological data revealed20.0-30.9%diabetics suffering from DLD and33.4%diabetic patients complicated with renal impairment. These two complications have been seriously problems of public health. There was few good therapeutic methods in treating the two diabetic complications with modern medicine respectively, which traditional Chinese Medicine(TCM) exhibit some advantages in preventing and treating the two complications dueing to the characteristics of holistic regulation and multiple targets. So we made classification and summary of the theory of homogeny of liver and kidney, then analyzed the application of the theory in recognition of pathogenesis and ideas for diagnosing and treating the two complications based on our previous studies. We also observed the effects of ChaihuangYishen granule(CHYS) on liver injuries and renal impairment in diabetic rats and investigated the common mechanisms of CHYS in treating the two complications, which will be beneficial to develop new drugs of treating the two complications and provide experimental evidences for the theory of homogeny of liver and kidney.
Objective:To investigate the application of the theory of homogeny of liver and kidney in understanding the pathogenesis and ideas of diagnosis and treatment for the two complications. Under the direction of the theory, to study the usage of CHYS in treating liver injuries and renal impairment associated with diabete and clarify the common mechanisms of CHYS in treating the two complications.
Methods:1. We investigated theoretic evidences of treating liver and kidney complications of diabetes based on the theory of homogeny of liver and kidney by utilizing the method of retrospective study of literature. The literature were consulted and arranged from various kinds of literature database and ancient medical classic by using of key words including "kidney and liver","liver and kidney","homoly of liver and kidney","homoly of Yi and Kui","homoly of essence and blood","concurrent diseases of liver and kidney"and "concurrent treatment of liver and kidney", which were relevant to homogeny of liver and kidney. We analyzed academic origin, development and evolution of the theory of homogeny of liver and kidney according to firstly time sequence and secondly representative books demonstrating the theory of homogeny of liver and kidney. By these work, we summarize the treatment regularity of treating diseases based on homogeny of liver and kidney. This will be beneficial to the recognition of etiology and pathogenesis of liver and kidney complications of diabetes and guiding therapeutic ideas of the complications with the theory of homogeny of liver and kidney.
2、The effect of Chaihuangyishen Granule (CHYS) on liver injuries and renal demage in diabetic rats:Diabetes was induced by by right-kidney nephrectomy plus peritoneal injection of streptozotocin (40mg/kg) in male Wistar rats, diabetic rats were randomly divided into model group, CHYS group (2.24g/kg) and monopril (1.67mg/kg), Twelve rats with same age and gender were received an sham operation plus peritoneal injection of vehicle and usd as sham group. All animals were orally administrated once daily for20weeks. Body weight and animal behaviors were observed every week, blood glucose and24-h urinary protein were determined every4weeks. The levels of serum lipid(TC, TG) and liver function(ALT, AST) were detected by blood biochemistry meter. Pathological changes of liver and kidney were observed by semiquantitative assessment. The mRNA expression of TGF-β1, decorin and GLUT-1in the liver and kidney were measured by RT-PCR; the protein expression of TGF-β1and decorin in the liver and kidneys were detected by western blot. The expression of collagen I in the liver and kidney and hepatic collagen III expression were analyzed by immunohistochemistry.
Results:
1. Theoretic evidence of treating liver and kidney complications of diabetes based on homogeny of liver and kidney:Theory of homogeny of liver and kidney originated from Inner Canon of Huangdi, Clinical practice replenish and the theory in Han, Tang, Jin and Yuan dynasty, Comlete system of the theory formed in Ming and Qing dynasty. The theory revealed close relation of between liver and kidney, these two organs indidate p physiological promotion each other, while show mutual effect and transmission under pathological condition. Diabetes could induce liver and kidney complications, and clinic features or development of these complications were in line with pathological characteristic of concurrent disearse of live and kidney. So it is helpful for promotion of treating liver and kidney complications of diabetes with TCM under the guideline of the theory of homology of liver and kidney.
2. Improving effects of CHYS on live injuries in diabetic rats. Body weight of model group was significantly lower than that of sham group at weeks4(p<0.05), the difference reached an peaking at weeks20. There was significant difference in the level of blood glucose between model group and sham group during the whole experiment period(p<0.01); treatment with CHYS or monopril didn't effect the levels of body weight and blood glucose. Serum levels of TC, TG, ALT and AST in model group showed obvious raise compared to those in sham group, while there was remarkable reduction of serum AST, TC and TG levels in CHYS group and monopril group. Index of liver weight and hepatic histologic active scores of inflammatory in model group were significantly higher than those in sham group, treatment with CHYS could alleviate these parameters(p<0.05).
3. Attenuation of CHYS on renal impairments in diabetic rats. The level of24-h urinary protein of model group exhibited progressive elevation at weeks8(p<0.05), CHYS exerted significant decreasement of24-h urinary protein from weeks12(p<0.05), and monopril could reduce the level of24-h urinary protein at weeks16and weeks20(p<0.05). Percentage of mesangial matrix and tubulo-interstitial fibrosis index in model group were obviously higher than that in sham group(p<0.01), CHYS and monopril improved the abnormalities of the indices in diabetic rats(p<0.05).
4. Effects of CHYS on expression of TGF-β1、decorin及GLUT-1in the liver and kidney of diabetic rats. Compared to that of sham group, hepatic expression of TGF-β1, decorin and GLUT-1mRNA were significantly increased; while CHYS group were statistically lower than that of model group(p<0.01). The increased expression of TGF-β1and decorin protein in the liver and kidney of diabetic rats were inhibited by CHYS or monopril treatment(p<0.05). The results of immunohistochemistry revealed the upregulation of collagen I expression in the liver and kidneys of diabetic rats(p<0.01), hepatic collagen III expression also remarkably raised in model group(p<0.05), and these changes were reversed by CHYS treatment; By PAS staining and d-PAS staining, we also observed accumulation of hepatic glycogen in model group, and CHYS could reduce hepatic glycogen storage in diabetic rats.
Conclusion:
1. The theory of homogeny of liver and kidney is important to understand etiology and pathogenesis of liver and kidney complications of diabetes and could be used for guiding the treatment of the two complications.
2. CHYS exhibited good therapeutic effects on both liver injury and renal impairment associated with diabetes, which reflect the advantages of multiple targets and holistic regulation of TCM.
3.CHYS could inhibit expression of TGF-β1and decorin in the liver and kidney of diabetic rats and reduce the degree of fibrosis, which involves the common machanisms of CHYS in treating liver and kidney complications of diabetes.
引文
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