肾舒康对家兔C-BSA膜性肾病模型干预的实验研究
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摘要
目的:膜性肾病(MN)是成人肾病综合征常见的病理类型之一,是一种严重危害人类健康的肾脏常见病。约25%的病人于发病数年后,可逐渐出现肾衰竭。目前治疗多采用糖皮质激素和细胞毒药物治疗,但长期应用毒副作用较大,病情缓解率不高且停药后容易复发。因此,寻找疗效可靠、毒副作用较小的治疗药物具有重要的临床意义。中药复方肾舒康﹙SSK﹚是我们根据慢性肾小球肾炎的发病特点研制的且临床疗效较为肯定的经验方。本研究通过注射阳离子化牛血清白蛋白(C-BSA)复制膜性肾病动物模型,应用肾舒康不同剂量对该模型进行干预性治疗,通过观察C-BSA膜性肾病家兔模型24小时尿蛋白、血浆蛋白、血脂、肾功能、肾脏病理形态学的改变,研究肾舒康对膜性肾病的干预作用及其可能机制,为其临床应用提供可靠的实验基础。
方法:选用健康新西兰种大耳白兔48只,普通饲料适应性喂养1周,两次检测尿蛋白和尿红细胞均为阴性。参照Border方法进行改良,动物采用大肠杆菌内毒素和C-BSA混合溶液进行预免疫,连续注射7天后开始进行正式免疫。6周后取尿蛋白定性为“++”、定量为1g/L及以上者进行实验,随机分为模型组、阳性药物对照组(雷公藤多苷组)、肾舒康高、中、低剂量组每组8只,并设正常对照组每组8只。造模6周后各组均灌胃给药,雷公藤多苷组给予雷公藤多苷10mg/kg/d灌胃,中剂组按人与家兔动物系数折算的等效剂量3.36 g/kg/d灌胃,低剂组和高剂组分别按1.12g/kg/d,10.08g/kg/d灌胃给药,每日1次,连续1个月。模型组和正常组给等容量生理盐水连续1个月。各组动物自由进食、饮水。实验第6、10周各测一次24小时尿蛋白定量。实验第10周末测血清总蛋白(TP)、白蛋白(ALB)、总胆固醇(TC)、甘油三酯(TG)、尿素氮(BUN)、肌酐(Scr)。第10周末实验结束时称家兔体重并全部处死,取双侧肾脏,称湿重,求肾脏系数;取新鲜肾组织送免疫荧光检测,并取肾组织固定于4%戊二醛和4%的多聚甲醛中分送电镜、光镜检查,每例各选5个最大切面的肾小球,计算直径和细胞数,求平均值和标准差。
结果:
1 24小时尿蛋白定量:实验第6周,除正常组外,其余各组均出现大量蛋白尿,与正常组相比均有显著性差异(P<0.01);实验第10周,中剂量、高剂量和雷公藤多苷组尿蛋白定量均明显降低,与模型组相比有显著性差异(P<0.01),低剂量组尿蛋白虽有所下降,但与模型组相比无统计学意义(P>0.05),肾舒康中、高剂量组与雷公藤多苷组相比无统计学意义(P>0.05)。
2实验第10周各组生化指标检测:模型组血清TP、ALB较正常组明显降低(P<0.01);中剂量组、高剂量组和雷公藤多苷组血清TP、ALB与模型组相比明显升高(P<0.01),低剂量组TP、ALB虽比模型组高,但无统计学意义(P>0.05);高剂量组血清TP、ALB高于雷公藤多苷组,但无统计学意义(P>0.05)。模型组与正常组相比,血清TC、TG均明显增高(P<0.01);治疗组与模型组相比,中剂量、高剂量和雷公藤多苷组血清TC、TG明显降低(P<0.01),低剂量组TC、TG虽比模型组高,但无统计学意义(P>0.05);高剂量组血清TC、TG低于雷公藤多苷组,但无统计学意义(P>0.05)。模型组血清BUN、Scr与正常组相比显著升高(P<0.01);各治疗组与模型组相比,中剂量组、高剂量组和雷公藤多苷组血清BUN、Scr明显降低(P<0.01),低剂量BUN、Scr虽比模型组低,但无统计学意义(P>0.05);高剂量组血清BUN、Scr低于雷公藤多苷组,但无统计学意义(P>0.05)。
3肾组织病理形态学观察:模型组与正常组相比,肾小球肿胀明显,细胞增生、细胞数增加,光镜下见肾小球明显增大,球内细胞数显著增多,基底膜增厚和钉突广泛形成,部分肾小球明显萎缩,伴新月体形成;免疫荧光下见基底膜IgG沉积明显增多,荧光强度显著增强+++~++++;电镜下基底膜明显增厚,上皮下大量团块状电子致密物沉积,足突广泛融合。治疗组与模型组相比,肾小球肿胀及细胞增生明显减轻,高、低剂量间差异显著,且有明显剂量相关性;与雷公藤多苷组相比,肾舒康高剂量组作用优于雷公藤多苷组,中剂量组作用类似雷公藤多苷组二者差异无显著性,低剂量组弱于雷公藤多苷组:①光镜下雷公藤多苷组病变相对较轻,球囊内有少量纤维蛋白渗出,钉突形成较少且不典型,上皮下免疫沉积物较少,毛细血管壁增厚程度较轻,毛细血管内未见微血栓形成,部分动物少量新月体形成;肾舒康高剂量组较雷公藤多苷组病变程度更轻。肾舒康中、低剂量组的病变程度略轻于雷公藤多苷组。②免疫荧光见雷公藤多苷组、肾舒康组IgG沉积及荧光强度明显弱于模型组,荧光强度约为+~++,尤以肾舒康高剂量组病变减轻明显。中剂量组及低剂量组的IgG沉积及荧光强度减弱程度均不及高剂量组,但二者均较雷公藤多苷组的病变略轻。③电镜下见雷公藤多苷组与肾舒康组病变相对较轻,上皮下电子致密物沉积程度较模型组明显轻微,基底膜厚亦较模型组轻,钉突形成数量明显不及模型组多且形成不典型,足突融合多为局灶性。肾舒康高剂量组病变更轻,部分融合足突有恢复现象。
结论:
1肾舒康可以减少C-BSA膜性肾病家兔模型的尿蛋白,提高血浆蛋白,改善脂代谢,降低BUN、Scr,具有保护肾功能作用。
2肾舒康可以改善C-BSA膜性肾病家兔模型的肾组织病理形态学损伤,延缓其肾小球硬化及肾间质纤维化的进展。
3肾舒康对C-BSA膜性肾病家兔模型的干预作用与雷公藤多苷基本相似。
Objective: Membranous nephropathy (MN) is one of adult nephrotic syndrome(NS)common pathology types, is one kind of severely impair human health kidney common disease. The approximately 25% patients is taken bad for several years later, may gradually have the renal failure. Now we always treat it by glucocorticoid and the cytotoxic drugs, but the poisonous side effect to be big by long-term used, low remission rate at pathogenetic condition, and easy to recur after drug withdrawal. So seeks for the curative effect reliably, the poisonous side effect small treatment medicine to have the vital clinical significance.The complexpres criptical Chinese medicine—Shenshukang﹙SSK﹚is a good clinical curative effect formula that we according to characteristic of the chronic glomerular nephritis. In this study, membranous nephropathy animal model was made through the C-BSA, different dosage carries on the intervention treatment using Shenshukang to this model, through observes the C-BSA membranous nephropathy rabbit model 24 hour urine protein, the plasma protein, the blood fats, renal function, renal pathology, research the effect of Shenshukang on the membranous nephropathy and the possible mechanism, provides the reliable experiment foundation for its clinical practice.
Method:Forty eight New-Zealand rabbits were selected to our experiment. After one week, they were put into metaboli -sm cage to obtain urine, urine protein and red blood cells were determined. The result was negative. Refer to the Border method to carry on the improvement, the animal used the Bacillus coli endotoxin and the C-BSA mixed solution carried on the pre-immunity, after injected 7 days continuously, carried on the formal immunity. At 6th weekend, those urine protein was“++”and 1g/L or above rabbits were selected to our experiment. Then they were randomly divided into five groups: Model, TWP group and low-dosage SSK group, middle-dosage SSK group, high-dosage SSK group (n=8, in each group), and set up normal control group. Model six weeks after intragastric administration of the group, the TWP group of TWP given 10mg/kg/d gavage; The middle-dosage SSK group according to the person and domestic rabbit animal coefficient conversion's equivalent dosage 3.36g/kg/d, the group of low-SSK group and high-SSK group by 1.12g/kg/d, 10.08g/kg/d gavage for one month. Model group and Normal group, such as the capacity to saline for 1 month. 24h urine protein was determined after6,10 weekend. TP, ALB, TC, TG, BUN, Scr was determined after 10 weekend. At 10th weekend, all rabbits were killed and weight, weigh wet kidney weight, and kidney coefficient; Taken the fresh nephridial tissue for immunofluorescence, and taken the nephridial tissue to fix in 4% glutaric dialdehydes and 4% paraformaldehyde for the electron microscop and the light microscope examination, each example were selected 5 glom -cruluses by the biggest cross section, calculate diameter and cell number and computed mean and standard deviation.
Result:
1 24h urinary protein quantitative analysis showed that: At the 6th weekend, besides the normal group, other each group was significantly higher than Normal group (P<0.01); At the 10th weekend, Model group urine protein compared with four treatment groups had the unusual significant difference except for low-dosage SSK group (P<0.01), though the low-dosage SSK group urine protein was lower than the model group, but there was no significant difference between them (P>0.05). middle-dosage , high-dosage SSK group urine protein compared with TWP group had no statistics significance (P>0.05).
2 At the 10th weekend each group of biochemistry analysis showed that: TP and ALB of the blood serum in Model group was descent significantly than Normal group (P<0.01); TP and ALB in other three treatment groups increased significantly than Model group except for low-dosage SSK group (P<0.05), though the low-dosage SSK group urine protein was higher than the model group, but there was no significant difference between them (P>0.05). There was no significant difference between high-dosage SSK groups and TWP group (P>0.05). TC and TG of the blood serum in Model group increased significantly (P<0.01), TC and TG of the other treatment group was decent than Model group except for low-dosage SSK group (P<0.01), though the low-dosage SSK group TC and TG was higher than the model group, but there was no significant difference between them (P>0.05). There was no significant difference between high-dosage SSK groups and TWP group (P>0.05). BUN and Scr of the blood serum in Model group were higher than Normal group significantly (P<0.01); BUN and Scr of other treatment groups decented significantly than Model group except for low-dosage SSK group (P<0.01), though the low-dosage SSK group BUN and Scr was lower than the model group, but there was no significant difference between them (P>0.05). There was no significant difference between high-dosage SSK groups and TWP group (P>0.05).
3 Nephridial tissue pathomorphology showed that: nephridial tissue pathomorphology: In the model group showed glomcrulus swelling and cell proliferation obviously than Normal group, GBM thickening and rete pegs emerge extensive–ly. In treatment groups lessened significantly than Model group and have dosage relevance obviously, though the low-dosage SSK group effect is lower than the model group, but there was no significant difference between them. There was no significant difference between high-dosage SSK group and TWP group:①the light microscope observation result showed that: In the model group showed glomcrulus and cell number increase obviously than Normal group, and partial glomcrulus obvious atrophy with massive crescent formation. in treatment groups lessened significantly than Model group.②the immunofluores -cence observation showed the IgG deposition under GBM obviously and fluorescence intensity was +++~++++, enhance significantly in the model group; in treatment groups decented significantly than Model group, fluorescence intensity approxi -mately was +~++, especially in high-dosage SSK group.③the electron microscope observation showed that: GBM thickening obviously, and massive electron-dense deposition under EC with foot process confluence extensively in the model group; in treatment groups decented significantly than Model group, the SSK groups were homoioplastic with the TWP group, especially the changes were better than other groups in high-dosage SSK group.
Conclusion:
1 Shenshukang could decrease the C-BSA membranous nephropathy rabbit's proteinuria, enhances the plasma protein, improvement lipid metabolism, reduces BUN, Scr, and protection renal function.
2 Shenshukang could improve the C-BSA membranous nephropathy rabbit's renal pathology morphology damage, delay it's glomerular sclerosis and renal interstitium fibrosis progress.
3 Shenshukang maybe similar to Tripterygium wilfordii in the effect of treating C-BSA membranous nephropathy rabbit model
方法:选用健康新西兰种大耳白兔48只,普通饲料适应性喂养1周,两次检测尿蛋白和尿红细胞均为阴性。参照Border方法进行改良,动物采用大肠杆菌内毒素和C-BSA混合溶液进行预免疫,连续注射7天后开始进行正式免疫。6周后取尿蛋白定性为“++”、定量为1g/L及以上者进行实验,随机分为模型组、阳性药物对照组(雷公藤多苷组)、肾舒康高、中、低剂量组每组8只,并设正常对照组每组8只。造模6周后各组均灌胃给药,雷公藤多苷组给予雷公藤多苷10mg/kg/d灌胃,中剂组按人与家兔动物系数折算的等效剂量3.36 g/kg/d灌胃,低剂组和高剂组分别按1.12g/kg/d,10.08g/kg/d灌胃给药,每日1次,连续1个月。模型组和正常组给等容量生理盐水连续1个月。各组动物自由进食、饮水。实验第6、10周各测一次24小时尿蛋白定量。实验第10周末测血清总蛋白(TP)、白蛋白(ALB)、总胆固醇(TC)、甘油三酯(TG)、尿素氮(BUN)、肌酐(Scr)。第10周末实验结束时称家兔体重并全部处死,取双侧肾脏,称湿重,求肾脏系数;取新鲜肾组织送免疫荧光检测,并取肾组织固定于4%戊二醛和4%的多聚甲醛中分送电镜、光镜检查,每例各选5个最大切面的肾小球,计算直径和细胞数,求平均值和标准差。
结果:
1 24小时尿蛋白定量:实验第6周,除正常组外,其余各组均出现大量蛋白尿,与正常组相比均有显著性差异(P<0.01);实验第10周,中剂量、高剂量和雷公藤多苷组尿蛋白定量均明显降低,与模型组相比有显著性差异(P<0.01),低剂量组尿蛋白虽有所下降,但与模型组相比无统计学意义(P>0.05),肾舒康中、高剂量组与雷公藤多苷组相比无统计学意义(P>0.05)。
2实验第10周各组生化指标检测:模型组血清TP、ALB较正常组明显降低(P<0.01);中剂量组、高剂量组和雷公藤多苷组血清TP、ALB与模型组相比明显升高(P<0.01),低剂量组TP、ALB虽比模型组高,但无统计学意义(P>0.05);高剂量组血清TP、ALB高于雷公藤多苷组,但无统计学意义(P>0.05)。模型组与正常组相比,血清TC、TG均明显增高(P<0.01);治疗组与模型组相比,中剂量、高剂量和雷公藤多苷组血清TC、TG明显降低(P<0.01),低剂量组TC、TG虽比模型组高,但无统计学意义(P>0.05);高剂量组血清TC、TG低于雷公藤多苷组,但无统计学意义(P>0.05)。模型组血清BUN、Scr与正常组相比显著升高(P<0.01);各治疗组与模型组相比,中剂量组、高剂量组和雷公藤多苷组血清BUN、Scr明显降低(P<0.01),低剂量BUN、Scr虽比模型组低,但无统计学意义(P>0.05);高剂量组血清BUN、Scr低于雷公藤多苷组,但无统计学意义(P>0.05)。
3肾组织病理形态学观察:模型组与正常组相比,肾小球肿胀明显,细胞增生、细胞数增加,光镜下见肾小球明显增大,球内细胞数显著增多,基底膜增厚和钉突广泛形成,部分肾小球明显萎缩,伴新月体形成;免疫荧光下见基底膜IgG沉积明显增多,荧光强度显著增强+++~++++;电镜下基底膜明显增厚,上皮下大量团块状电子致密物沉积,足突广泛融合。治疗组与模型组相比,肾小球肿胀及细胞增生明显减轻,高、低剂量间差异显著,且有明显剂量相关性;与雷公藤多苷组相比,肾舒康高剂量组作用优于雷公藤多苷组,中剂量组作用类似雷公藤多苷组二者差异无显著性,低剂量组弱于雷公藤多苷组:①光镜下雷公藤多苷组病变相对较轻,球囊内有少量纤维蛋白渗出,钉突形成较少且不典型,上皮下免疫沉积物较少,毛细血管壁增厚程度较轻,毛细血管内未见微血栓形成,部分动物少量新月体形成;肾舒康高剂量组较雷公藤多苷组病变程度更轻。肾舒康中、低剂量组的病变程度略轻于雷公藤多苷组。②免疫荧光见雷公藤多苷组、肾舒康组IgG沉积及荧光强度明显弱于模型组,荧光强度约为+~++,尤以肾舒康高剂量组病变减轻明显。中剂量组及低剂量组的IgG沉积及荧光强度减弱程度均不及高剂量组,但二者均较雷公藤多苷组的病变略轻。③电镜下见雷公藤多苷组与肾舒康组病变相对较轻,上皮下电子致密物沉积程度较模型组明显轻微,基底膜厚亦较模型组轻,钉突形成数量明显不及模型组多且形成不典型,足突融合多为局灶性。肾舒康高剂量组病变更轻,部分融合足突有恢复现象。
结论:
1肾舒康可以减少C-BSA膜性肾病家兔模型的尿蛋白,提高血浆蛋白,改善脂代谢,降低BUN、Scr,具有保护肾功能作用。
2肾舒康可以改善C-BSA膜性肾病家兔模型的肾组织病理形态学损伤,延缓其肾小球硬化及肾间质纤维化的进展。
3肾舒康对C-BSA膜性肾病家兔模型的干预作用与雷公藤多苷基本相似。
Objective: Membranous nephropathy (MN) is one of adult nephrotic syndrome(NS)common pathology types, is one kind of severely impair human health kidney common disease. The approximately 25% patients is taken bad for several years later, may gradually have the renal failure. Now we always treat it by glucocorticoid and the cytotoxic drugs, but the poisonous side effect to be big by long-term used, low remission rate at pathogenetic condition, and easy to recur after drug withdrawal. So seeks for the curative effect reliably, the poisonous side effect small treatment medicine to have the vital clinical significance.The complexpres criptical Chinese medicine—Shenshukang﹙SSK﹚is a good clinical curative effect formula that we according to characteristic of the chronic glomerular nephritis. In this study, membranous nephropathy animal model was made through the C-BSA, different dosage carries on the intervention treatment using Shenshukang to this model, through observes the C-BSA membranous nephropathy rabbit model 24 hour urine protein, the plasma protein, the blood fats, renal function, renal pathology, research the effect of Shenshukang on the membranous nephropathy and the possible mechanism, provides the reliable experiment foundation for its clinical practice.
Method:Forty eight New-Zealand rabbits were selected to our experiment. After one week, they were put into metaboli -sm cage to obtain urine, urine protein and red blood cells were determined. The result was negative. Refer to the Border method to carry on the improvement, the animal used the Bacillus coli endotoxin and the C-BSA mixed solution carried on the pre-immunity, after injected 7 days continuously, carried on the formal immunity. At 6th weekend, those urine protein was“++”and 1g/L or above rabbits were selected to our experiment. Then they were randomly divided into five groups: Model, TWP group and low-dosage SSK group, middle-dosage SSK group, high-dosage SSK group (n=8, in each group), and set up normal control group. Model six weeks after intragastric administration of the group, the TWP group of TWP given 10mg/kg/d gavage; The middle-dosage SSK group according to the person and domestic rabbit animal coefficient conversion's equivalent dosage 3.36g/kg/d, the group of low-SSK group and high-SSK group by 1.12g/kg/d, 10.08g/kg/d gavage for one month. Model group and Normal group, such as the capacity to saline for 1 month. 24h urine protein was determined after6,10 weekend. TP, ALB, TC, TG, BUN, Scr was determined after 10 weekend. At 10th weekend, all rabbits were killed and weight, weigh wet kidney weight, and kidney coefficient; Taken the fresh nephridial tissue for immunofluorescence, and taken the nephridial tissue to fix in 4% glutaric dialdehydes and 4% paraformaldehyde for the electron microscop and the light microscope examination, each example were selected 5 glom -cruluses by the biggest cross section, calculate diameter and cell number and computed mean and standard deviation.
Result:
1 24h urinary protein quantitative analysis showed that: At the 6th weekend, besides the normal group, other each group was significantly higher than Normal group (P<0.01); At the 10th weekend, Model group urine protein compared with four treatment groups had the unusual significant difference except for low-dosage SSK group (P<0.01), though the low-dosage SSK group urine protein was lower than the model group, but there was no significant difference between them (P>0.05). middle-dosage , high-dosage SSK group urine protein compared with TWP group had no statistics significance (P>0.05).
2 At the 10th weekend each group of biochemistry analysis showed that: TP and ALB of the blood serum in Model group was descent significantly than Normal group (P<0.01); TP and ALB in other three treatment groups increased significantly than Model group except for low-dosage SSK group (P<0.05), though the low-dosage SSK group urine protein was higher than the model group, but there was no significant difference between them (P>0.05). There was no significant difference between high-dosage SSK groups and TWP group (P>0.05). TC and TG of the blood serum in Model group increased significantly (P<0.01), TC and TG of the other treatment group was decent than Model group except for low-dosage SSK group (P<0.01), though the low-dosage SSK group TC and TG was higher than the model group, but there was no significant difference between them (P>0.05). There was no significant difference between high-dosage SSK groups and TWP group (P>0.05). BUN and Scr of the blood serum in Model group were higher than Normal group significantly (P<0.01); BUN and Scr of other treatment groups decented significantly than Model group except for low-dosage SSK group (P<0.01), though the low-dosage SSK group BUN and Scr was lower than the model group, but there was no significant difference between them (P>0.05). There was no significant difference between high-dosage SSK groups and TWP group (P>0.05).
3 Nephridial tissue pathomorphology showed that: nephridial tissue pathomorphology: In the model group showed glomcrulus swelling and cell proliferation obviously than Normal group, GBM thickening and rete pegs emerge extensive–ly. In treatment groups lessened significantly than Model group and have dosage relevance obviously, though the low-dosage SSK group effect is lower than the model group, but there was no significant difference between them. There was no significant difference between high-dosage SSK group and TWP group:①the light microscope observation result showed that: In the model group showed glomcrulus and cell number increase obviously than Normal group, and partial glomcrulus obvious atrophy with massive crescent formation. in treatment groups lessened significantly than Model group.②the immunofluores -cence observation showed the IgG deposition under GBM obviously and fluorescence intensity was +++~++++, enhance significantly in the model group; in treatment groups decented significantly than Model group, fluorescence intensity approxi -mately was +~++, especially in high-dosage SSK group.③the electron microscope observation showed that: GBM thickening obviously, and massive electron-dense deposition under EC with foot process confluence extensively in the model group; in treatment groups decented significantly than Model group, the SSK groups were homoioplastic with the TWP group, especially the changes were better than other groups in high-dosage SSK group.
Conclusion:
1 Shenshukang could decrease the C-BSA membranous nephropathy rabbit's proteinuria, enhances the plasma protein, improvement lipid metabolism, reduces BUN, Scr, and protection renal function.
2 Shenshukang could improve the C-BSA membranous nephropathy rabbit's renal pathology morphology damage, delay it's glomerular sclerosis and renal interstitium fibrosis progress.
3 Shenshukang maybe similar to Tripterygium wilfordii in the effect of treating C-BSA membranous nephropathy rabbit model
引文
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