益肾活血中药肾康灵干预阿霉素肾病大鼠与NF-κB关系的实验研究
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摘要
目的：通过观察益肾活血中药肾康灵对AN(阿霉素肾病)大鼠的干预作用及与NF-ΚB(核因子)、TXA2(血栓素A2)和PGI2(前列环素)等的关系，旨在阐明NS的发病机理及中药干预治疗的可能机制。
方法：用ADR(阿霉素)5.5mg／kg诱导大鼠类似于人类MCD(微小病变)型肾病模型，用强的松+肾康灵(D组)、强的松+知柏地黄汤(E组)及强的松+桃红四物汤(F组)治疗，并设正常(A组)、病理(B组)和强的松(C组)为对照组，采用简单随机法分组，每组各10只。检测各组治疗前后NF-ΚB，血尿液TXB2(血栓素B2)和6-keto-PGF_(1α)(6-酮-前列腺素F_(1α))，24小时尿蛋白定量，血清Alb(白蛋白)、Ch(胆固醇)、TG(甘油三酯)和肾脏病理形态学改变。结果用SPSS 11.0软件系统进行统计学分析。
结果：与A组相比，B组一般状况明显较差，尿蛋白显著增多，Alb显著下降，Ch和TG、血尿TXB_2和TXB_2／6-keto-PGF1α比值显著升高，NF-ΚB活性显著增强，P＜0.01；肾脏病理损害明显加重。治疗后，与B组相比，各治疗组大鼠一般状况有不同程度恢复；除了TXB_2和6-keto-PGF_(1α)(P＞0.05)，C组能显著改善上述指标(P＜0.05)，D、E、F三组都能极显著改善上述指标(P＜0.01)，D组和F组皆能明显减轻肾脏病理损害，而C组和E组则不明显；与C组相比，D组在上述指标中都表现出显著性差异(P＜0.01或0.05)，E组在降低Ch上有显著性差异(P＜0.05)，F组则在升高血浆6-keto-PGF_(1α)上有显著性差异(P＜0.05)；D组和E、F两组相比，在提高Alb上，D组与E组间有显著性差异(P＜0.05)，与F组间有极显著性差异(P＜0.01)，在提高血浆6-keto-PGF_(1α)上，D组与E组间有显著性差异(P＜0.05)，其余各指标改善程度略强，但无统计学意义(P＞0.05)。
结论：
1、按5.5mg／kg大鼠体重一次性尾静脉注射ADR的方法，可以成功造成人类肾病病理
福建中医学院2003届中医儿科学硕l刀于究生学位论文
模型，其临床表现和实验指标改变类似于中医的“肾虚血癖”病变。
2、AN鼠的表现及病情进展，与其NF一B活性异常升高，TXAZ/PGIZ失衡，神经内分
泌免疫(NEI)网络功能失调，导致炎症/硬化介质作用及血液高凝有关;也与其尿蛋白
进行性增多，Alb进行性下降、Ch和TG进行性升高，肾脏局部病理进行性损害(包括
肾小管一间质损害)有关。其中NF一B活性的异常升高起着关键作用。
3、祖国医学的肾虚血癖证与现代医学的NEI网络功能紊乱有其相似之处。益肾活血
中药肾康灵能显著改善AN鼠的肾虚血疲证的临床表现和实验指标，这一可能与中药肾
康灵能调理AN鼠机体的NEI网络功能稳态，降低异常升高的NF一B活性，抑制免
疫炎症/硬化介质环节，纠正失衡的TXAZ/PGIZ，改善AN鼠血液高凝状态，提高AN鼠
的血清Alb，降低ch和TG，减轻AN鼠的肾脏组织病理学变化，保护肾小管一间质功
能，阻止MCD向FSGS转化;显著减轻AN鼠的尿蛋白水平以及减轻激素副作用有关。
4、NF一KB、TxBZ和6一keto一PGFI。以及肾脏病理形态学改变等，都可作为中医肾虚
血癖证诊断和益肾活血法应用的客观指标。
5、I一护西医结合干预AN鼠疗效优于单纯激素治疗;强的松配合益肾活血中药肾康灵组
的综合疗效显著优于单纯强的松组。
6、知柏地黄汤组在降低尿蛋白、提高血清Alb、降低Cll和TG疗效上优于桃红四物
汤组:桃红四物汤组在纠正失衡的TXAZ/PG工2和减轻肾脏病理损害方面优于知柏地黄
汤组。
7、激素配合益肾活血法干预AN鼠在一定程度上优于激素配合益肾法或活血法。
Objective: To observe the curative effects of Decoction Shenkangling, having the function of "Benefiting the kidney and Promoting blood ciuculation", on the adriamycin-induced nephrotic (AN) rats, and meanwhile to research the relationship among nuclear factor-Kappa B(NF- K B), thromboxane A2 (TXA2) , prostacyclin (PGI2) and other factors in AN rats, then to explain the pathogenesis of nephrotic syndrome (NS) and the mechanisms of Chinese medication.
Methods: Using adriamycin with the dosage of 5.5mg/kg to inject the caudal vein of 50 rats to produce the animal models similar to mankind minimal change nephropathy (MCD). Then these rats were averagely divided randomly into 4 groups, namely Group B (Pathologic Contrast Group) and the other three Treated Groups including Group C (Prednisone), Group D (Prednisone plus Decoction Shenkangling), Group E (Prednisone plus Decoction Zhibodihuang) and Group F (Prednisone plus Decoction Taohongsiwu). Synchronously, Normal Contrast Group (Group A) with 10 rats was established. Before the treatment and after 3-week's treatment, NF-K B, TXB2 and 6-keto-PGF1 a of plasm and urine, urine protein of 24 hours, as well as serum albumin, cholesterol and triglyceride of all rats were tested. And their renal pathomorphology was also observed by light microscope and electron microscope. Statistical analysis was performed by SPSS 11.0 system software.
Results: Compared with Group A, in Group B, its general status was significantly worse; its urine protein increased clearly, albumin decreased markedly, cholesterol, triglyceride, TXB2 of plasm and urine and the ratio of TXB2/6-keto-PGF1 a increased distinctly; simultaneously, the activity of NF-K.B enhanced evidently, p<0.01 all; Moreover, its renal pathomorphology aggravated. After treatment, compared with Group B, the general status of all
treated rats recovered in different level. In Group C, all the above-mentioned indexes ameliorated obviously (p<0.05) other than TXB2 and 6-keto-PGF] a (p>0.05). However, in Group D, Group E and Group F, all the above-mentioned indexes ameliorated much more obviously (p<0.01). In Group D and Group F, the renal lesion markedly lessened; while in Group C and Group E, it didn't present. Compared with Group C, in Group D, all the above-mentioned indexes improved distinctly (p<0.01 or p<0.05); in Group E, its cholesterol reduced observably (p<0.05); and in Group F, its plasm 6-keto-PGF| a gained markedly (p<0.05). The difference in increasing albumin between Group D and Group E was significant (p<0.05), but it was much more obviously between Group D and Group F (p<0.01). Besides, the significance in elevating plasm 6-keto-PGF1 a between Group D and Group E was great (p<0.05). Last, there was no statistical significance of other indexes among Group D, Group E and Group F (p>0.05).
Conclusions:
1. Animal model similar to mankind nephrotic syndrome can be achieved by injecting adriamycin into the caudal vein of rat once with the dosage of 5.5mg/kg, and its clinical situation resembles the Symptom of "Kidney Deficiency and Blood Stasis" in TCM.
2.The clinical situation and progression of AN rats may be related to their further increase of the activity of NF- K B, the disequilibrium of the ratio of TXA2/PGI2 and Neuro-endocrine-immune (NEI) Network, which led to the action of inflammatory-sclerotic media and the hypercoagulable state. Besides, the further increase of urine protein, cholesterol, triglyceride and further decrease of albumin and the processing lesion of kidney (including the damage of renal tubule and stroma) may also be concerned with their episode. Among the above-mentioned, the increase of the activity of NF- K. B was the key point.
3.The clinical situation of the disequilibrium of NEI Network is similar to the Symptom of "Kidney Deficiency and Blood Stasis" in TCM. Decoction Shenkangling with the function of "Benefiting the kidney and Promoting blood circulation" can remarkably ameliorate the clinical situation and experimental indexes of the Symptom of "Kidney Deficiency and B
方法：用ADR(阿霉素)5.5mg／kg诱导大鼠类似于人类MCD(微小病变)型肾病模型，用强的松+肾康灵(D组)、强的松+知柏地黄汤(E组)及强的松+桃红四物汤(F组)治疗，并设正常(A组)、病理(B组)和强的松(C组)为对照组，采用简单随机法分组，每组各10只。检测各组治疗前后NF-ΚB，血尿液TXB2(血栓素B2)和6-keto-PGF_(1α)(6-酮-前列腺素F_(1α))，24小时尿蛋白定量，血清Alb(白蛋白)、Ch(胆固醇)、TG(甘油三酯)和肾脏病理形态学改变。结果用SPSS 11.0软件系统进行统计学分析。
结果：与A组相比，B组一般状况明显较差，尿蛋白显著增多，Alb显著下降，Ch和TG、血尿TXB_2和TXB_2／6-keto-PGF1α比值显著升高，NF-ΚB活性显著增强，P＜0.01；肾脏病理损害明显加重。治疗后，与B组相比，各治疗组大鼠一般状况有不同程度恢复；除了TXB_2和6-keto-PGF_(1α)(P＞0.05)，C组能显著改善上述指标(P＜0.05)，D、E、F三组都能极显著改善上述指标(P＜0.01)，D组和F组皆能明显减轻肾脏病理损害，而C组和E组则不明显；与C组相比，D组在上述指标中都表现出显著性差异(P＜0.01或0.05)，E组在降低Ch上有显著性差异(P＜0.05)，F组则在升高血浆6-keto-PGF_(1α)上有显著性差异(P＜0.05)；D组和E、F两组相比，在提高Alb上，D组与E组间有显著性差异(P＜0.05)，与F组间有极显著性差异(P＜0.01)，在提高血浆6-keto-PGF_(1α)上，D组与E组间有显著性差异(P＜0.05)，其余各指标改善程度略强，但无统计学意义(P＞0.05)。
结论：
1、按5.5mg／kg大鼠体重一次性尾静脉注射ADR的方法，可以成功造成人类肾病病理
福建中医学院2003届中医儿科学硕l刀于究生学位论文
模型，其临床表现和实验指标改变类似于中医的“肾虚血癖”病变。
2、AN鼠的表现及病情进展，与其NF一B活性异常升高，TXAZ/PGIZ失衡，神经内分
泌免疫(NEI)网络功能失调，导致炎症/硬化介质作用及血液高凝有关;也与其尿蛋白
进行性增多，Alb进行性下降、Ch和TG进行性升高，肾脏局部病理进行性损害(包括
肾小管一间质损害)有关。其中NF一B活性的异常升高起着关键作用。
3、祖国医学的肾虚血癖证与现代医学的NEI网络功能紊乱有其相似之处。益肾活血
中药肾康灵能显著改善AN鼠的肾虚血疲证的临床表现和实验指标，这一可能与中药肾
康灵能调理AN鼠机体的NEI网络功能稳态，降低异常升高的NF一B活性，抑制免
疫炎症/硬化介质环节，纠正失衡的TXAZ/PGIZ，改善AN鼠血液高凝状态，提高AN鼠
的血清Alb，降低ch和TG，减轻AN鼠的肾脏组织病理学变化，保护肾小管一间质功
能，阻止MCD向FSGS转化;显著减轻AN鼠的尿蛋白水平以及减轻激素副作用有关。
4、NF一KB、TxBZ和6一keto一PGFI。以及肾脏病理形态学改变等，都可作为中医肾虚
血癖证诊断和益肾活血法应用的客观指标。
5、I一护西医结合干预AN鼠疗效优于单纯激素治疗;强的松配合益肾活血中药肾康灵组
的综合疗效显著优于单纯强的松组。
6、知柏地黄汤组在降低尿蛋白、提高血清Alb、降低Cll和TG疗效上优于桃红四物
汤组:桃红四物汤组在纠正失衡的TXAZ/PG工2和减轻肾脏病理损害方面优于知柏地黄
汤组。
7、激素配合益肾活血法干预AN鼠在一定程度上优于激素配合益肾法或活血法。
Objective: To observe the curative effects of Decoction Shenkangling, having the function of "Benefiting the kidney and Promoting blood ciuculation", on the adriamycin-induced nephrotic (AN) rats, and meanwhile to research the relationship among nuclear factor-Kappa B(NF- K B), thromboxane A2 (TXA2) , prostacyclin (PGI2) and other factors in AN rats, then to explain the pathogenesis of nephrotic syndrome (NS) and the mechanisms of Chinese medication.
Methods: Using adriamycin with the dosage of 5.5mg/kg to inject the caudal vein of 50 rats to produce the animal models similar to mankind minimal change nephropathy (MCD). Then these rats were averagely divided randomly into 4 groups, namely Group B (Pathologic Contrast Group) and the other three Treated Groups including Group C (Prednisone), Group D (Prednisone plus Decoction Shenkangling), Group E (Prednisone plus Decoction Zhibodihuang) and Group F (Prednisone plus Decoction Taohongsiwu). Synchronously, Normal Contrast Group (Group A) with 10 rats was established. Before the treatment and after 3-week's treatment, NF-K B, TXB2 and 6-keto-PGF1 a of plasm and urine, urine protein of 24 hours, as well as serum albumin, cholesterol and triglyceride of all rats were tested. And their renal pathomorphology was also observed by light microscope and electron microscope. Statistical analysis was performed by SPSS 11.0 system software.
Results: Compared with Group A, in Group B, its general status was significantly worse; its urine protein increased clearly, albumin decreased markedly, cholesterol, triglyceride, TXB2 of plasm and urine and the ratio of TXB2/6-keto-PGF1 a increased distinctly; simultaneously, the activity of NF-K.B enhanced evidently, p<0.01 all; Moreover, its renal pathomorphology aggravated. After treatment, compared with Group B, the general status of all
treated rats recovered in different level. In Group C, all the above-mentioned indexes ameliorated obviously (p<0.05) other than TXB2 and 6-keto-PGF] a (p>0.05). However, in Group D, Group E and Group F, all the above-mentioned indexes ameliorated much more obviously (p<0.01). In Group D and Group F, the renal lesion markedly lessened; while in Group C and Group E, it didn't present. Compared with Group C, in Group D, all the above-mentioned indexes improved distinctly (p<0.01 or p<0.05); in Group E, its cholesterol reduced observably (p<0.05); and in Group F, its plasm 6-keto-PGF| a gained markedly (p<0.05). The difference in increasing albumin between Group D and Group E was significant (p<0.05), but it was much more obviously between Group D and Group F (p<0.01). Besides, the significance in elevating plasm 6-keto-PGF1 a between Group D and Group E was great (p<0.05). Last, there was no statistical significance of other indexes among Group D, Group E and Group F (p>0.05).
Conclusions:
1. Animal model similar to mankind nephrotic syndrome can be achieved by injecting adriamycin into the caudal vein of rat once with the dosage of 5.5mg/kg, and its clinical situation resembles the Symptom of "Kidney Deficiency and Blood Stasis" in TCM.
2.The clinical situation and progression of AN rats may be related to their further increase of the activity of NF- K B, the disequilibrium of the ratio of TXA2/PGI2 and Neuro-endocrine-immune (NEI) Network, which led to the action of inflammatory-sclerotic media and the hypercoagulable state. Besides, the further increase of urine protein, cholesterol, triglyceride and further decrease of albumin and the processing lesion of kidney (including the damage of renal tubule and stroma) may also be concerned with their episode. Among the above-mentioned, the increase of the activity of NF- K. B was the key point.
3.The clinical situation of the disequilibrium of NEI Network is similar to the Symptom of "Kidney Deficiency and Blood Stasis" in TCM. Decoction Shenkangling with the function of "Benefiting the kidney and Promoting blood circulation" can remarkably ameliorate the clinical situation and experimental indexes of the Symptom of "Kidney Deficiency and B
引文
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