摘要
目的:通过实验研究观察补脾肾活血升阳除湿法组方加味升阳益胃汤对阿霉素肾病大鼠肾小管间质α-平滑肌肌动蛋白(α-SMA)、血管内皮细胞生长因子(VEGF)、结缔组织生长因子(CTGF)及CTGFmRNA的影响,探讨此方对肾小管间质损害的保护性作用及其作用机理。
方法:本实验采用尾静脉二次注射阿霉素建立模型。实验动物分为空白组、模型组、苯那普利组、中药低剂量组及中药高剂量组。观察实验大鼠治疗前后一般状态及肾功能情况;将肾组织病理切片进行HE、Masson染色,观察动物模型治疗前后的病理改变及肾间质病变情况;采用免疫组化半定量分析法检测肾小管间质中的α-SMA、VEGF及CTGF表达水平;采用原位杂交法检测肾小管间质CTGFmRNA表达水平。
结果:1、实验10周末,与模型组比较,中药低、高剂量组、苯那普利组大鼠尿蛋白明显下降且差异显著(P<0.05),而中药组与苯那普利组比较差异不显著(P>0.05);2、实验10周末,与模型组比较,中药低、高剂量组及苯那普利组大鼠血肌酐、血尿素氮水平均有所降低且差异显著(P<0.05),中药组与苯那普利组比较差异不显著( P>0.05); 3、肾小管间质损害程度病理评分显示,与模型组比较,中药高剂量组的肾小管间质损害评分下降明显(P<0.05),而中药低剂量组及苯那普利组肾小管间质损害评分下降不明显(P>0.05);4、与模型组比较,中药低、高剂量组及苯那普利组肾间质中α-SMA和CTGF的过度表达均减少,肾间质中VEGF表达均增加,且差异显著(P<0.05),而中药组与苯那普利组比较差异不显著(P>0.05);5、与模型组比较,中药低、高剂量组及苯那普利组肾小管间质CTGFmRNA的表达均下调,且差异显著(P<0.05),而中药组与苯那普利组比较差异不显著(P>0.05);6、肾小管间质α-SMA、VEGF、CTGF的表达水平与肾小管间质损害程度及肾功能有明显相关性(P<0.05)。结论:1、补脾肾活血升阳除湿法组方加味升阳益胃汤能减少阿霉素肾病大鼠尿蛋白排泄量;2、加味升阳益胃汤能下调肾小管间质α-SMA表达,从而抑制肾小管上皮细胞向肌成纤维细胞(间充质细胞)转分化来减轻肾小管间质损害;3、加味升阳益胃汤能下调肾小管间质组织CTGF及CTGFmRNA表达水平,并上调肾小管间质VEGF表达水平,从而减轻肾小管间质损害,延缓肾小管间质纤维化进展;4、补脾肾活血升阳除湿法组方加味升阳益胃汤通过多靶点、多部位干预对阿霉素肾病大鼠肾小管间质损害起到保护性作用。
Objective:To investigate the effect of the modified decoction of elevating the spleen yang reinforcing stomach which induced from the method of supplementing spleen and kidney activating the blood circulation raise yang and release dampness(SAR) onα-smooth muscle actin(α-SMA)、Vascular endothelial growth factor( VEGF)、Connective tissue growth factor( CTGF)、CTGFmRNA of kidney tissue of adriamycin-induced nephrotic rats, and to illustrate the mechanism of the modified decoction of elevating the spleen yang reinforcing stomach on protecting renal tubular interstial lesion.
Methods:In the experiment,the rats by tail vein injection of adriamycin were adopted.The rats were randomly divided into the normal control group (n=10),the model control group (n=10),the low dosage chinese medicine group(n=15),the high dosage chinese medicine group (n=15)and the lotensin group(n=15).It is observed for the change of the common physical order,24h urinary Protein level,blood urea nitrogen(Bun) and serum creatinine(Scr) of experimental rats.HE and Masson staining method for pathologic slice are used to observe the pathologic change of the experimental rats, kidney tissue after treated and the phase of renal fibroblast.The expression ofα-SMA、VEGF、CTGF of renal tissue were determined by immunohistochemistry methods.The expression of CTGFmRNA of renal tissue was determined by in situ hybridization.
Results:1.Compared with the model control group,24h urinary Protein levels in the Chinese medicine group and lotensin group were markedly intervented at the end of ten weeks(P<0.05).2.Compared with the model control group,the level of blood urea nitrogen and serum creatinine in the Chinese medicine group and lotensin group were obviously decreased (P<0.05).3.Compared with other groups, the renal tubulointerstitial lesion degree in high dosage Chinese medicine group was ameliorated significantly (P<0.05).4.The expression ofα-SMA、CTGF in kidney tissue were decreased and the expression of VEGF was increased in the Chinese medicine group and the lotensin group which were significantly different with the control and model group (P<0.05).4.The expression of CTGFmRNA was also reduced which was significantly different with the control and model group (P<0.05).5.The renal tubulointerstitial lesion degree and the level of blood urea nitrogen and serum creatinine were closely related withα-SMA、VEGF and CTGF.
Conclusions:1.Modified decoction of elevating the spleen yang reinforcing stomach could effectively reduced the 24h urinary protein of adriamycin-induced nephrotic rats.2.Modified decoction of elevating the spleen yang reinforcing stomach could inhibit the transdifferentiation of renal tubular epithelial and reduce the impairment of tubular interstial.3.Modified decoction of elevating the spleen yang reinforcing stomach can alleviate the renal interstitial lesion in adriamycin-induced nephrotic rats through decreasingα-SMA、CTGF and increasing the VEGF expression to reduce the impairment of tubulointerstitium.4.Modified decoction of elevating the spleen yang reinforcing stomach plays a remarkable role in preventing the development of tubular interstial lesion of adriamycin-induced nephrotic rats.
引文
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