三七总皂苷对腺嘌呤所致大鼠肾间质纤维化影响的实验研究
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摘要
目的:肾间质纤维化(renal interstitial fibrosis,RIF)是各种肾脏疾病进展到终末期肾病(end stage renal diseases,ESRD)的共同途径。小管间质纤维化(tubulointerstitial fibrosis,TIF)严重程度与肾功能下降程度及肾脏疾病预后密切相关,TIF越重,肾功能下降越快,肾脏疾病预后越差。因此,TIF越来越受到人们的重视。TIF的发病机制是一非常复杂的慢性病理过程,其中炎性细胞浸润,多种细胞释放大量的炎症因子,肾小管上皮细胞、间质细胞转分化为肌成纤维细胞(Myo ibroblast,Myo-FB)都起了非常重要的作用,然而至今临床上缺乏有效、可靠的抗TIF的治疗方法。三七总皂苷(panax notoginseng saponins,PNS)是从我国中草药三七中提取的主要活性成分,具有多种生物学效应,包括较强的抗组织器官纤维化作用。既往研究表明PNS具有拮抗肾小管间质炎症细胞、炎症因子,拮抗肾小管上皮细胞、间质细胞转分化为Myo-FB,改善肾脏微循环等作用。近年来对PNS干预TIF的研究取得了较多进展,但多集中在TIF形成之后的治疗上,对TIF早期的干预研究较少。本研究的主要目的是观察PNS对腺嘌呤灌胃大鼠TIF早期的防治作用并初步探讨其可能的作用机制,为PNS防治早期TIF的临床应用提供一定的理论依据。
方法:Wister雄性大鼠50只,随机分为:正常对照组(n = 6)、模型组(n = 22)、干预组(n = 22)。连续21 d给予2 %腺嘌呤(250 mg·kg~(-1)·d~(-1))混悬液灌胃,制作大鼠TIF模型;腺嘌呤灌胃7d后,干预组同时腹腔注射PNS(50 mg·kg~(-1)·d~(-1))。在实验第7d、14d、21d、28d,各组大鼠酶联免疫吸附实验(enzyme linked immunosorbent assay,ELISA)检测其血清中血小板源性生长因子(platelet-derived growth factor,PDGF)-BB水平,磺柳酸比浊法测量大鼠24 h尿蛋白含量,HE、Masson染色观察大鼠肾脏病理变化,免疫组织化学方法观察大鼠肾小管间质α–平滑肌肌动蛋白(α–smooth muscle action,α–SMA)表达并行半定量分析。
结果:在实验第7d、14 d、21 d、28 d,模型组和干预组大鼠血清PDGF-BB水平均高于正常对照组(P < 0.05),但干预组大鼠血清PDGF-BB水平低于模型组,在实验第14d、21d、28d均具有显著性差异(P < 0.05);在实验第7d、14 d、21 d、28 d,模型组和干预组大鼠24h尿蛋白量均较正常对照组增加(P < 0.05),但干预组大鼠24h尿蛋白量较模型组降低,在实验第21d、28d均具有显著性差异(P < 0.05);Masson染色结果显示,在实验第7d、14 d、21 d、28 d,模型组和干预组大鼠肾间质纤维化程度均较正常对照组加重,但干预组大鼠肾间质纤维化程度较模型组减轻,在实验第21 d、28 d均具有显著性差异(P < 0.05);免疫组织化学结果显示,在实验第7d、14 d、21 d、28 d,模型组和干预组大鼠肾小管间质α–SMA表达均较正常对照组增加,但干预组大鼠肾小管间质α–SMA表达少于模型组,在实验第21 d、28 d均具有显著性差异(P < 0.05);HE染色结果显示,干预组大鼠肾小管间质炎性细胞浸润、肾间质水肿、肾小管扩张、肾小管萎缩均轻于模型组。
结论:在腺嘌呤所致大鼠TIF早期阶段给予PNS可降低其血清PDGF-BB水平,降低24h尿蛋白含量,减少肾小管间质α–SMA表达,减少炎性细胞浸润,减轻肾间质水肿、肾小管扩张、肾小管萎缩,延缓TIF进展。
Objective:RIF is the common pathway of progressive renal disease to the end stage renal failure. A large number of studies demonstrated that the degree of TIF was correlated with the degree of decline in renal function and prognosis of renal disease, the more serious TIF was,the faster renal function declined and the worse the prognosis of kidney disease became. So, more and more people attached importance to TIF. The pathogenesis of TIF was a very complex process of chronic pathology,During which, inflammatory cell infiltration、avariety of cells releasing many inflammatory cytokines、myofibroblasts differentiated from tubular epithelial cells and mesenchymal cells had very important roles. However, so far the effective reliable treatment of anti-TIF was absent clinically. PNS was mainly active ingredient extracted from traditional herb Panax notoginseng ,which had many biological effects including the strong role of anti-fibrotic tissues and organs. Past studies showed that PNS could inhibit inflammatory cells、inflammatory factors in tubulointerstitial、myofibroblasts differentiated from tubular epithelial cells and mesenchymal cells and improve renal microcirculation etc. Much progress about the studies of PNS interfering TIF had been made in recent years,However,which focused on the treatment after TIF formation. The studies of TIF early interfered were very less. The main purpose of this study aimed to observe the role of PNS in the prevention and treatment of adenine nephropathy rat model at the early stage, explore its possible mechanism and also provide a theoretical basis for PNS clinically interfering TIF .
Methods:Fifty male clearly healthy Wister rats were randomly divided into 3 groups: normal group(n=6),adenine treated group(n=22) and PNS treated group(n=22). Tubulointerstitial fibrosis models were established by gavage with 250 mg.kg~(-1).d~(-1) adenine solved in a solution of 2 % starch for 21d. After 7d, PNS 50 mg.kg~(-1).d~(-1) was injested into the abdomens of the rats in PNS treated group. On days 7,14,21 and 28,Concentration of platelet-derived growth factor (PDGF) -BB in serum was determined by enzyme linked immunosorbent assay (ELISA) methods, 24 h Urine protein content was determined by huangliusuan methods, the rat kidneys were examed pathologically by HE,Masson staining and immunohistochemmical staining forα–smooth muscle action (α–SMA) expression,meanwhile,semiquantitative analysis was performed.
Results:On days 7d、14d、21d and 28d,the level of serum PDGF–BB in PNS treated group and adenine treated group was higher than in normal group(P < 0.05),which in PNS treated group was lower than in adenine treated group on days 14d、21d and 28d(P < 0.05); On days 7d、14d、21d and 28d,24 h Urine protein content in PNS treated group and adenine treated group was higher than in normal group(P < 0.05),which in PNS treated group was lower than in adenine treated group on days 21d and 28d(P < 0.05); Masson staining showed that on days 7d、14d、21d and 28d, semiquantitative analysis for TIF in PNS treated group and adenine treated group was higher than in normal group(P < 0.05),which in PNS treated group was lower than in adenine treated group on days 21d and 28d ( P < 0.05 ) ; Immunohistochemmical staining demonstrated that on days 7d、14d、21d and 28d, semiquantitative analysis forα–SMA expression was higher than in normal group(P < 0.05),which in PNS treated group was lower than in adenine treated group on days 21d and 28d(P < 0.05); HE staining showed that inflammatory cell infiltration、the renal interstitial edema、the renal tubular expansion and the renal tubular atrophy were reduced in PNS treated group at the same time point ,in contrast to adenine treated group.
Conclusions:PNS might inhibit tubulointerstitial fibrosis in adenine nephropathy rat model at the early stage by suppressing the level of PDGF-BB in serum、reducing 24 h Urine protein content and the expression ofα–SMA in the tubulointerstitium. PNS might reduce inflammatory cell infiltration、the renal interstitial edema、the renal tubular expansion and the renal tubular atrophy and slow down the progress of renal interstitial fibrosis.
方法:Wister雄性大鼠50只,随机分为:正常对照组(n = 6)、模型组(n = 22)、干预组(n = 22)。连续21 d给予2 %腺嘌呤(250 mg·kg~(-1)·d~(-1))混悬液灌胃,制作大鼠TIF模型;腺嘌呤灌胃7d后,干预组同时腹腔注射PNS(50 mg·kg~(-1)·d~(-1))。在实验第7d、14d、21d、28d,各组大鼠酶联免疫吸附实验(enzyme linked immunosorbent assay,ELISA)检测其血清中血小板源性生长因子(platelet-derived growth factor,PDGF)-BB水平,磺柳酸比浊法测量大鼠24 h尿蛋白含量,HE、Masson染色观察大鼠肾脏病理变化,免疫组织化学方法观察大鼠肾小管间质α–平滑肌肌动蛋白(α–smooth muscle action,α–SMA)表达并行半定量分析。
结果:在实验第7d、14 d、21 d、28 d,模型组和干预组大鼠血清PDGF-BB水平均高于正常对照组(P < 0.05),但干预组大鼠血清PDGF-BB水平低于模型组,在实验第14d、21d、28d均具有显著性差异(P < 0.05);在实验第7d、14 d、21 d、28 d,模型组和干预组大鼠24h尿蛋白量均较正常对照组增加(P < 0.05),但干预组大鼠24h尿蛋白量较模型组降低,在实验第21d、28d均具有显著性差异(P < 0.05);Masson染色结果显示,在实验第7d、14 d、21 d、28 d,模型组和干预组大鼠肾间质纤维化程度均较正常对照组加重,但干预组大鼠肾间质纤维化程度较模型组减轻,在实验第21 d、28 d均具有显著性差异(P < 0.05);免疫组织化学结果显示,在实验第7d、14 d、21 d、28 d,模型组和干预组大鼠肾小管间质α–SMA表达均较正常对照组增加,但干预组大鼠肾小管间质α–SMA表达少于模型组,在实验第21 d、28 d均具有显著性差异(P < 0.05);HE染色结果显示,干预组大鼠肾小管间质炎性细胞浸润、肾间质水肿、肾小管扩张、肾小管萎缩均轻于模型组。
结论:在腺嘌呤所致大鼠TIF早期阶段给予PNS可降低其血清PDGF-BB水平,降低24h尿蛋白含量,减少肾小管间质α–SMA表达,减少炎性细胞浸润,减轻肾间质水肿、肾小管扩张、肾小管萎缩,延缓TIF进展。
Objective:RIF is the common pathway of progressive renal disease to the end stage renal failure. A large number of studies demonstrated that the degree of TIF was correlated with the degree of decline in renal function and prognosis of renal disease, the more serious TIF was,the faster renal function declined and the worse the prognosis of kidney disease became. So, more and more people attached importance to TIF. The pathogenesis of TIF was a very complex process of chronic pathology,During which, inflammatory cell infiltration、avariety of cells releasing many inflammatory cytokines、myofibroblasts differentiated from tubular epithelial cells and mesenchymal cells had very important roles. However, so far the effective reliable treatment of anti-TIF was absent clinically. PNS was mainly active ingredient extracted from traditional herb Panax notoginseng ,which had many biological effects including the strong role of anti-fibrotic tissues and organs. Past studies showed that PNS could inhibit inflammatory cells、inflammatory factors in tubulointerstitial、myofibroblasts differentiated from tubular epithelial cells and mesenchymal cells and improve renal microcirculation etc. Much progress about the studies of PNS interfering TIF had been made in recent years,However,which focused on the treatment after TIF formation. The studies of TIF early interfered were very less. The main purpose of this study aimed to observe the role of PNS in the prevention and treatment of adenine nephropathy rat model at the early stage, explore its possible mechanism and also provide a theoretical basis for PNS clinically interfering TIF .
Methods:Fifty male clearly healthy Wister rats were randomly divided into 3 groups: normal group(n=6),adenine treated group(n=22) and PNS treated group(n=22). Tubulointerstitial fibrosis models were established by gavage with 250 mg.kg~(-1).d~(-1) adenine solved in a solution of 2 % starch for 21d. After 7d, PNS 50 mg.kg~(-1).d~(-1) was injested into the abdomens of the rats in PNS treated group. On days 7,14,21 and 28,Concentration of platelet-derived growth factor (PDGF) -BB in serum was determined by enzyme linked immunosorbent assay (ELISA) methods, 24 h Urine protein content was determined by huangliusuan methods, the rat kidneys were examed pathologically by HE,Masson staining and immunohistochemmical staining forα–smooth muscle action (α–SMA) expression,meanwhile,semiquantitative analysis was performed.
Results:On days 7d、14d、21d and 28d,the level of serum PDGF–BB in PNS treated group and adenine treated group was higher than in normal group(P < 0.05),which in PNS treated group was lower than in adenine treated group on days 14d、21d and 28d(P < 0.05); On days 7d、14d、21d and 28d,24 h Urine protein content in PNS treated group and adenine treated group was higher than in normal group(P < 0.05),which in PNS treated group was lower than in adenine treated group on days 21d and 28d(P < 0.05); Masson staining showed that on days 7d、14d、21d and 28d, semiquantitative analysis for TIF in PNS treated group and adenine treated group was higher than in normal group(P < 0.05),which in PNS treated group was lower than in adenine treated group on days 21d and 28d ( P < 0.05 ) ; Immunohistochemmical staining demonstrated that on days 7d、14d、21d and 28d, semiquantitative analysis forα–SMA expression was higher than in normal group(P < 0.05),which in PNS treated group was lower than in adenine treated group on days 21d and 28d(P < 0.05); HE staining showed that inflammatory cell infiltration、the renal interstitial edema、the renal tubular expansion and the renal tubular atrophy were reduced in PNS treated group at the same time point ,in contrast to adenine treated group.
Conclusions:PNS might inhibit tubulointerstitial fibrosis in adenine nephropathy rat model at the early stage by suppressing the level of PDGF-BB in serum、reducing 24 h Urine protein content and the expression ofα–SMA in the tubulointerstitium. PNS might reduce inflammatory cell infiltration、the renal interstitial edema、the renal tubular expansion and the renal tubular atrophy and slow down the progress of renal interstitial fibrosis.
引文
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[1] Dong TT、Gui XM, et al. Chemical assessment of roots PNS in china regional and seasonal variation in active constituents [J] . Agrinc Food chem, 2003,51(16):4617-23.
[2] Brenner BM.The Kidney .6# end .pheladelphia [J].Saunders company,1999,22:19-52.
[3] Karl TW.Fibrosis:a common pathway organ failure:angiotensionII and tissure repair[J].Sem.Neph,1997, 17(5):467.
[4] Eddy AA.Molecular insights into renal interstitial fibrosis[J].AM S oc Nephrol,1996,7(17):2495-2508.
[5] Bohel A,Mackensen-Haen S,Vou Gise,et al.the consequences of tubuloinsterstitial changes for renal function in glomerulopathies[J] .A morphometric and eytologial analysis .Pathol Res Pract,1990,18(1):135-44.
[6] Feng Sheng-gang、Li Guang-ming et al.THE effect of PNS on the renal tubulointerstitial damage and inflammatory cell soakage[J] .Modern Preventive Medicine,2007,34(18):3449-3452.
[7]刘海燕,陈孝文,等.三七总甙对尿毒血清诱导的肾小管上皮细胞TGF-β、CTGS基因表达和蛋白分泌的影响[J].中国药理学通报,2005,21(11):1366-1370.
[8] FENG Sheng-gang、XIE Xi-sheng、DENG Yao et al .Panax Notoginsenosides attenuates UUO-induced renalinterstitial fibrosis effect on TGF-β/Smads signal pathwayn[J].Med J West China ,2007,19(4):526-529.
[9] WEI Ying、FAN Jun-ming、PAN Li-Ping.Effect of Panax notoginoside Sapoins on human kidney fibroblast . Chin J Integr west Med,2002,22(5),47-49.
[10]刘海燕,陈孝文,等.三七总甙对尿毒血清诱导的肾小管上皮细胞外基质分泌及降解的影响[J].中草药,2006,37(2):245-48.
[11]刘海燕,陈浩文,刘海峰,等.三七总皂甙对尿毒血清诱导的HK-2细胞增殖及总胶原的影响[J].中国中西医结合肾病杂志,2004,5(3) :143-5.
[12]张毅,陈孝文,刘海燕等.三七总皂甙对TGF-β1诱导的HK-2细胞表型转化的影响[J].中国中西医结合肾病杂志,2005,6(6) :317-20.
[13] Su BH、Fan JM、Li Z et al.Effect of panax notoginseng saponins on the process of renal interstitial fibrosis after unilateral ureteral obstruction in rats [J].Sichuan Da Xue Bao Yi Xue Ban ,2005,36(3):368-71.
[14]王宓,樊均明等.三七皂甙对IL-1a诱导的大鼠肾小管细胞转分化的影响.中国中西医结合杂志,2004,24(8) :722-725.
[15]屠庆年,陆附耳.三七总甙对糖尿病大鼠血栓素β2及6-酮-前列腺素F1a的影响.中国中西医结合消化杂志,2006,13(4):253-255.
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[18]贺五珍等.肝素钠与血塞通治疗糖尿病肾病并发高粘滞血症的临床比较.天津中医,1998,15(6):253-254.
[19]张丽华,贾钰华等.三七总甙增强人内源皮源性一氧化氮合酶基因启动子活性[J] .第一军医大学学报,2004,24(10) :1113-1116.
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