海参虫草复剂对糖尿病大鼠肾脏保护作用及其机制的研究
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摘要
糖尿病肾病(Diabetes nephropathy, DN)是常见的糖尿病慢性微血管并发症,病人晚期出现严重肾功能衰竭,是导致糖尿病患者死亡的主要原因之一。因此,控制和延缓糖尿病肾病的发生和发展过程具有重要的临床意义。
海参自古以来被视为珍贵的滋补品,其味咸性温补,具有补肾益精、养血润燥、滋阴壮阳之功效。海参中含有海参多糖、海参皂苷、胶原多肽、脑苷脂等多种活性物质,具有抗氧化、降血脂、降血压和免疫调节等生理活性。蛹虫草又名北冬虫夏草,其化学成分与冬虫夏草相似,富含虫草多糖、虫草素、虫草酸、超氧化物歧化酶(Superoxide dismutase, SOD)等活性物质,具有降血糖、抗肿瘤、调节免疫和抗衰老等功能。中医认为其味甘性温平,具有补肺益肾、化痰止咳等功能。将二者配药具有大补元气、补肾益肺、养血生精之功效。本研究采用一次性腹腔注射STZ的方法建立糖尿病大鼠模型,在长期高血糖环境下造成肾脏损伤。采用日本刺参(Apostichopus japonicus)和蛹虫草(Cordyceps militaris)配制成的复剂灌胃STZ诱导的糖尿病模型大鼠,研究其对大鼠肾脏的保护作用,并对其作用机理进行了较系统和深入的研究。实验同时设立了海参和虫草单剂组作为比较。主要研究结果如下：
海参虫草复剂具有显著的降血糖和提高肾小球率过功能的作用。实验结果显示：海参虫草复剂能显著降低糖尿病大鼠空腹血糖和肾肥大指数(P<0.05,P<0.01),显著降低血清中尿素氮(Blood urea nitrogen, BUN)、肌酐(Creatinine, Cr)和尿酸(Uric acid, UA)的含量(P<0.05,P<0.01),显著减少尿蛋白、微量白蛋白(Microalbuminuria, mAlb)及N-乙酰-β-D-氨基葡萄糖苷酶(N-acetyl-β-D-Glucosaminidase, NAG)的排泄率(P<0.05,P<0.01)。且海参虫草复剂的效果优于单剂。
海参虫草复剂具有显著的脂质代谢调节作用。结果表明：海参虫草复剂能显著降低糖尿病大鼠血清中总胆固醇(Total cholesterol, TC)、甘油三酯(Triglyceride, TG)和游离脂肪酸(Free fatty acid, FFA)的含量(P<0.05,P<0.01),提高肝脏中饱和脂肪酸(Saturated fatty acid, SFA)比例、降低单不饱和脂肪酸(Mono-unsaturated fatty acid, MUFA)比例,并显著降低肝脏中硬脂酰辅酶A去饱和酶(Stearoyl-CoA desaturase, SCD)活性。提示海参虫草复剂对脂质代谢的调节作用可能是通过降低SCD活性来抑制脂质合成实现的。
海参虫草复剂具有显著的抗氧化功能。实验结果显示,海参虫草复剂能显著降低糖尿病大鼠肾脏中丙二醛(Malondialdehyde, MDA)、一氧化氮(Nobelium, NO)含量(P<0.01),提高肾脏中SOD和过氧化氢酶(Catalase, CAT)活力(P<0.05,P<0.01)。提示海参虫草复剂可通过提高肾脏抗氧化酶活性,清除体内自由基,从而达到肾脏保护作用。海参虫草复剂效果较海参和虫草单剂使用时优。
采用光学显微镜及透射电镜观察,研究了海参虫草复剂对糖尿病大鼠肾脏组织显微和亚显微结构的影响。显微观察结果表明：海参虫草复剂能显著抑制糖尿病大鼠肾小球和肾小管肿大、系膜区扩大和系膜细胞增生。亚显微观察结果显示,海参虫草复剂能显著抑制糖尿病大鼠基底膜节段性增厚,减轻足突细胞融合现象,减少溶酶体在系膜区的聚集。说明海参虫草复剂能显著改善糖尿病大鼠肾脏组织的病理学改变,且海参虫草复剂效果优于单剂。
利用RT-PCR、Western blot和免疫组化等方法研究了海参虫草复剂对糖尿病大鼠肾脏保护的机制。结果表明,海参虫草复剂能显著抑制糖尿病大鼠肾脏中转化生长因子-β1(Transforming growth factor beta, TGF-β1)及其Ⅱ型受体(TypeⅡreceptor of TGF-β, TβRⅡ)、结缔组织生长因子(Connective tissue growth factor, CTGF)的mRNA表达,降低肾脏中TGF-β1及Ⅳ胶原蛋白的表达,提高过氧化物酶体增殖激活受体γ(Peroxisome proliferator activated receptor-γ, PPARγ)的基因表达。TGF-β1与TβRⅡ结合后发挥其生物活性直接造成肾脏损伤,并介导其下游因子CTGF的表达,促进Ⅳ胶原等细胞外基质合成、抑制其降解,导致肾脏肥大。而PPARγ激活可调节体内脂质代谢,减少脂质过氧化物对TGF-β1的刺激。提示海参虫草复剂可通过提高体内PPARγ活性,改善体内脂肪代谢紊乱,并抑制TGF-β1、TβRⅡ和CTGF的表达,从而减少细胞外基质合成,达到保护肾脏的作用。且海参虫草复剂的效果优于海参和虫草单剂使用的效果。
本论文首次全面系统地研究了海参虫草复剂对糖尿病大鼠肾脏的保护作用,并对其机制进行了深入探讨。进一步挖掘了海参和虫草的药用价值,为海参虫草复剂临床推广应用于预防和治疗糖尿病肾病提供了较为全面、深入的分子水平的理论依据。
Diabetic nephropathy(DN) is a major complication of diabetes mellitus and a primary cause of end-stage renal failure. So, it is of improtant clinical significance to prevent the progression toward chronic renal failure in the early stage of diabetic nephropathy.
Sea cucumber, an important food and medicine resource, has lots of bioactive substances, such as sea cucumber polysaccharide, saponins, collagen proteins and cerebrosides. These substances have been proved to possess anti-oxidation, hypolipidemic, antihypertensive and immunomodulatory activities. Cordyceps militaris, one of the most valued traditional Chinese medicines, which contains polysaccharide, cordycepin, cordycepic acid and SOD, has the activities of hypoglycemic, anti-tumour, anti-aging and kidney protection. In this study, the mixture of Apostichopus japonicus and Cordyceps militaris (AC) was used to investigate the protection effect and mechanisms in diabetes nephropathy rat which was induced by a single intraperitoneal injection of Streptozotocin. Results are shown as follows:
AC has remarkable suppress hyperglycemia and promote glomerular filtration rate in diabetic rats. And it could decreased the renal index (p<0.05, p<0.01), the level of BUN, Cr and UA (p<0.05,p<0.01) in serum, and decreased excretion of protein, mAlb and NAG (p<0.05, p<0.01) in urine. The AC was more effective than Apostichopus japonicus and Cordyceps militaris.
The effect of AC on rugulate lipid metabolism in DN rats was detected. The results showed that AC could significantly reduce the serum TC, TG and FFA contents (p<0.05,p<0.01) and improve the ratio of hepatic SFA. It also reduced the activities of SCD and the ratio of MUFA in the liver tissue. It is suggested that AC could inhibit the synthesis of fatty acid wich attribute to the protection of renal injury in diabetic rats.
Comparative investigation on the effect of AC on the anti-oxidation possibility in DN rats was also conducted. The results showed that AC could reduce the content of MDA and NO (P<0.01), increase the activities of CAT(P<0.05, P<0.01) and SOD(P<0.01) remarkably in the kidney. Therefore, AC could downregulate the level of fasting blood glucose, improve lipid metabolism and promote the activities of endogenous anti-oxidation enzymes, which attribute to the impact of preventing DN. The AC was more effective than Apostichopus japonicus and Cordyceps militaris. The AC was more effective than Apostichopus japonicus and Cordyceps militaris.
The changes of renal tissue morphology in diabetic rats were observed by optical microscope and electric microscope. The results showed that AC could lessen the glomerular hypertrophy and the extracellar matrix expansion, inhibit the mesangial hyperplasia and extension; AC could also reduce glomerular basement membrane thickness, decrease the deposition of immunocomplex and lysosomes aggregation in mesangium,witch were observed under electromicroscopy. The results presented here indicated that AC could raise the pathological change of diabetic rats
The investigation of the protection of diabetes nephropathy mechanisms of AC were conducted by RT-PCR, immunohistochemistry or western blot analysis. The results demonstrated that the TGF-β1, TβRⅡand CTGF mRNA expression were markedly increased in the kidney of diabetic rats, which were effectively suppressed by AC treatment (P<0.05, P<0.01); AC could also improve the mRNA expression level of PPARy (P<0.05, P<0.01); Western blot and immunohistochemistry analysis showed that the expression of TGF-β1 and CollagenⅣprotein was reduced significantly by AC treatment. All these rusults suggested that the beneficial effect of AC might result from its inhibiting TGF-β1, TβRⅡand CTGF expression and activating PPARy.
In summary, the protective effect and its mechanism of AC on the renal in the DN rats was systemically investigated for the first time, which could further the pharmaceuticals applications of AC and supplied comprehensive and intensive theoretical basis for the clinic trial on the DN.
海参自古以来被视为珍贵的滋补品,其味咸性温补,具有补肾益精、养血润燥、滋阴壮阳之功效。海参中含有海参多糖、海参皂苷、胶原多肽、脑苷脂等多种活性物质,具有抗氧化、降血脂、降血压和免疫调节等生理活性。蛹虫草又名北冬虫夏草,其化学成分与冬虫夏草相似,富含虫草多糖、虫草素、虫草酸、超氧化物歧化酶(Superoxide dismutase, SOD)等活性物质,具有降血糖、抗肿瘤、调节免疫和抗衰老等功能。中医认为其味甘性温平,具有补肺益肾、化痰止咳等功能。将二者配药具有大补元气、补肾益肺、养血生精之功效。本研究采用一次性腹腔注射STZ的方法建立糖尿病大鼠模型,在长期高血糖环境下造成肾脏损伤。采用日本刺参(Apostichopus japonicus)和蛹虫草(Cordyceps militaris)配制成的复剂灌胃STZ诱导的糖尿病模型大鼠,研究其对大鼠肾脏的保护作用,并对其作用机理进行了较系统和深入的研究。实验同时设立了海参和虫草单剂组作为比较。主要研究结果如下：
海参虫草复剂具有显著的降血糖和提高肾小球率过功能的作用。实验结果显示：海参虫草复剂能显著降低糖尿病大鼠空腹血糖和肾肥大指数(P<0.05,P<0.01),显著降低血清中尿素氮(Blood urea nitrogen, BUN)、肌酐(Creatinine, Cr)和尿酸(Uric acid, UA)的含量(P<0.05,P<0.01),显著减少尿蛋白、微量白蛋白(Microalbuminuria, mAlb)及N-乙酰-β-D-氨基葡萄糖苷酶(N-acetyl-β-D-Glucosaminidase, NAG)的排泄率(P<0.05,P<0.01)。且海参虫草复剂的效果优于单剂。
海参虫草复剂具有显著的脂质代谢调节作用。结果表明：海参虫草复剂能显著降低糖尿病大鼠血清中总胆固醇(Total cholesterol, TC)、甘油三酯(Triglyceride, TG)和游离脂肪酸(Free fatty acid, FFA)的含量(P<0.05,P<0.01),提高肝脏中饱和脂肪酸(Saturated fatty acid, SFA)比例、降低单不饱和脂肪酸(Mono-unsaturated fatty acid, MUFA)比例,并显著降低肝脏中硬脂酰辅酶A去饱和酶(Stearoyl-CoA desaturase, SCD)活性。提示海参虫草复剂对脂质代谢的调节作用可能是通过降低SCD活性来抑制脂质合成实现的。
海参虫草复剂具有显著的抗氧化功能。实验结果显示,海参虫草复剂能显著降低糖尿病大鼠肾脏中丙二醛(Malondialdehyde, MDA)、一氧化氮(Nobelium, NO)含量(P<0.01),提高肾脏中SOD和过氧化氢酶(Catalase, CAT)活力(P<0.05,P<0.01)。提示海参虫草复剂可通过提高肾脏抗氧化酶活性,清除体内自由基,从而达到肾脏保护作用。海参虫草复剂效果较海参和虫草单剂使用时优。
采用光学显微镜及透射电镜观察,研究了海参虫草复剂对糖尿病大鼠肾脏组织显微和亚显微结构的影响。显微观察结果表明：海参虫草复剂能显著抑制糖尿病大鼠肾小球和肾小管肿大、系膜区扩大和系膜细胞增生。亚显微观察结果显示,海参虫草复剂能显著抑制糖尿病大鼠基底膜节段性增厚,减轻足突细胞融合现象,减少溶酶体在系膜区的聚集。说明海参虫草复剂能显著改善糖尿病大鼠肾脏组织的病理学改变,且海参虫草复剂效果优于单剂。
利用RT-PCR、Western blot和免疫组化等方法研究了海参虫草复剂对糖尿病大鼠肾脏保护的机制。结果表明,海参虫草复剂能显著抑制糖尿病大鼠肾脏中转化生长因子-β1(Transforming growth factor beta, TGF-β1)及其Ⅱ型受体(TypeⅡreceptor of TGF-β, TβRⅡ)、结缔组织生长因子(Connective tissue growth factor, CTGF)的mRNA表达,降低肾脏中TGF-β1及Ⅳ胶原蛋白的表达,提高过氧化物酶体增殖激活受体γ(Peroxisome proliferator activated receptor-γ, PPARγ)的基因表达。TGF-β1与TβRⅡ结合后发挥其生物活性直接造成肾脏损伤,并介导其下游因子CTGF的表达,促进Ⅳ胶原等细胞外基质合成、抑制其降解,导致肾脏肥大。而PPARγ激活可调节体内脂质代谢,减少脂质过氧化物对TGF-β1的刺激。提示海参虫草复剂可通过提高体内PPARγ活性,改善体内脂肪代谢紊乱,并抑制TGF-β1、TβRⅡ和CTGF的表达,从而减少细胞外基质合成,达到保护肾脏的作用。且海参虫草复剂的效果优于海参和虫草单剂使用的效果。
本论文首次全面系统地研究了海参虫草复剂对糖尿病大鼠肾脏的保护作用,并对其机制进行了深入探讨。进一步挖掘了海参和虫草的药用价值,为海参虫草复剂临床推广应用于预防和治疗糖尿病肾病提供了较为全面、深入的分子水平的理论依据。
Diabetic nephropathy(DN) is a major complication of diabetes mellitus and a primary cause of end-stage renal failure. So, it is of improtant clinical significance to prevent the progression toward chronic renal failure in the early stage of diabetic nephropathy.
Sea cucumber, an important food and medicine resource, has lots of bioactive substances, such as sea cucumber polysaccharide, saponins, collagen proteins and cerebrosides. These substances have been proved to possess anti-oxidation, hypolipidemic, antihypertensive and immunomodulatory activities. Cordyceps militaris, one of the most valued traditional Chinese medicines, which contains polysaccharide, cordycepin, cordycepic acid and SOD, has the activities of hypoglycemic, anti-tumour, anti-aging and kidney protection. In this study, the mixture of Apostichopus japonicus and Cordyceps militaris (AC) was used to investigate the protection effect and mechanisms in diabetes nephropathy rat which was induced by a single intraperitoneal injection of Streptozotocin. Results are shown as follows:
AC has remarkable suppress hyperglycemia and promote glomerular filtration rate in diabetic rats. And it could decreased the renal index (p<0.05, p<0.01), the level of BUN, Cr and UA (p<0.05,p<0.01) in serum, and decreased excretion of protein, mAlb and NAG (p<0.05, p<0.01) in urine. The AC was more effective than Apostichopus japonicus and Cordyceps militaris.
The effect of AC on rugulate lipid metabolism in DN rats was detected. The results showed that AC could significantly reduce the serum TC, TG and FFA contents (p<0.05,p<0.01) and improve the ratio of hepatic SFA. It also reduced the activities of SCD and the ratio of MUFA in the liver tissue. It is suggested that AC could inhibit the synthesis of fatty acid wich attribute to the protection of renal injury in diabetic rats.
Comparative investigation on the effect of AC on the anti-oxidation possibility in DN rats was also conducted. The results showed that AC could reduce the content of MDA and NO (P<0.01), increase the activities of CAT(P<0.05, P<0.01) and SOD(P<0.01) remarkably in the kidney. Therefore, AC could downregulate the level of fasting blood glucose, improve lipid metabolism and promote the activities of endogenous anti-oxidation enzymes, which attribute to the impact of preventing DN. The AC was more effective than Apostichopus japonicus and Cordyceps militaris. The AC was more effective than Apostichopus japonicus and Cordyceps militaris.
The changes of renal tissue morphology in diabetic rats were observed by optical microscope and electric microscope. The results showed that AC could lessen the glomerular hypertrophy and the extracellar matrix expansion, inhibit the mesangial hyperplasia and extension; AC could also reduce glomerular basement membrane thickness, decrease the deposition of immunocomplex and lysosomes aggregation in mesangium,witch were observed under electromicroscopy. The results presented here indicated that AC could raise the pathological change of diabetic rats
The investigation of the protection of diabetes nephropathy mechanisms of AC were conducted by RT-PCR, immunohistochemistry or western blot analysis. The results demonstrated that the TGF-β1, TβRⅡand CTGF mRNA expression were markedly increased in the kidney of diabetic rats, which were effectively suppressed by AC treatment (P<0.05, P<0.01); AC could also improve the mRNA expression level of PPARy (P<0.05, P<0.01); Western blot and immunohistochemistry analysis showed that the expression of TGF-β1 and CollagenⅣprotein was reduced significantly by AC treatment. All these rusults suggested that the beneficial effect of AC might result from its inhibiting TGF-β1, TβRⅡand CTGF expression and activating PPARy.
In summary, the protective effect and its mechanism of AC on the renal in the DN rats was systemically investigated for the first time, which could further the pharmaceuticals applications of AC and supplied comprehensive and intensive theoretical basis for the clinic trial on the DN.
引文
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