慢性缺血性肾损伤机制的实验研究及三七总皂苷的保护作用
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摘要
目的:慢性缺血性肾病(chronic ischaemic renal disease,CIRD)是导致终末期肾病(end stage renal diseases,ESRD)最重要的原因之一,但目前对其发病机制尚缺乏深入了解,有研究表明肾素-血管紧张素系统激活,肾小管间质炎症细胞浸润,肾脏固有细胞转分化为肌成纤维细胞(myofibroblast,Myo-FB)可能都是慢性缺血性肾病进展的重要机制。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,具有改善肾脏微循环和抗肾间质纤维的作用,在肾脏疾病临床治疗中起到了重要的作用。本研究的主要目的是探讨慢性缺血性肾损伤的机制,并观察PNS对慢性缺血性肾病的防治作用,为临床上应用PNS防治慢性肾病提供一定的理论依据。
方法:48只SD雄性大鼠随机分为3组,假手术组、模型组和PNS组,每组16只。采用双侧肾动脉不全结扎术建立双侧肾动脉狭窄模型,PNS组于术后开始给予腹腔注射PNS 50mg?kg-1?d-1,其余2组给药同等容量的灭菌注射用水。于术后14d、28d、45d、60d,用酶联免疫吸附实验(enzyme linked immunosorbent assay,ELISA)检测各组大鼠血清细胞间黏附分子1(intercellular adhesion molecule-1,ICAM-1),放射免疫法测大鼠血浆血管紧张素Ⅱ(angiotensin11,AngⅡ)水平,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:在同一时间点,模型组血清ICAM-1及血浆AngⅡ水平较假手术组的水平明显升高(P < 0.01),且模型组的血清ICAM-1及血浆AngⅡ水平均随缺血时间的延长而逐渐升高(P < 0.05);HE、Masson染色结果显示,模型组大鼠可见大量萎缩和扩张的小管,肾小管上皮细胞坏死脱落,肾间质增宽,炎性细胞浸润,肾间质纤维化;免疫组织化学结果显示,模型组于术后14d在部分受损的肾小管上皮细胞即可见α-SMA表达,28d肾间质也可见少量α-SMA表达,且随着缺血时间的延长肾小管-间质细胞α-SMA表达的量逐渐增加;而假手术组各时间点肾脏病理未见明显改变,亦未见α-SMA表达。在予以PNS治疗后,可观察到PNS组大鼠各时间点血清ICAM-1及血浆AngⅡ水平较模型组明显下降(P < 0.05),肾脏病理改变及肾小管-间质细胞α-SMA表达情况与模型组相似,但同一个时间点肾脏病理改变程度及α-SMA表达的量均轻于模型组。
结论:在慢性肾缺血时,肾脏固有细胞转分化为Myo-FB表达α-SMA,肾素-血管紧张素系统过渡活化及ICMA-1表达增加可能是导致慢性缺血性肾损伤发生发展的重要环节,而三七皂苷能够通过抑制上述各环节,而延缓肾间质纤维化的进展,保护肾功能。
Objective:Chronic ischemic renal disease is one of the most important reasons leading to end-stage renal disease , but its pathogenesis is still a lack in depth .Studies have shown that the renin - angiotensin system activation, renal tubular interstitial infiltration of inflammatory cells, renal intrinsic cells transdifferentiation to myofibroblasts, may have effects on the progress of chronic ischemic nephropathy .PNS was mainly active ingredient extracted from traditional herb Panax notoginseng ,which had many biological effects including the strong role of inhibiting mesenchymal cells and improving renal microcirculation ,and may play an important role in the clinical treatment of renal disease. The main purpose of this study was to explore the mechanism of chronic ischemic renal injury, and to observe the PNS’effects on the prevention and treatment of chronic ischemic nephropathy and these may provide some theoretical basis the application of PNS for clinical prevention and treatment of chronic kidney disease.
Methods: All forty-eight male healty SD rats were randomly divided into sham-operation group, model group, and PNS group, every group has sixteen rats. The bilateral renal arteries were partly ligated to establish rat model with bilateral renal artery stenosis, Rats of PNS group we start to give the PNS 50mg.kg-1.d-1 by intra-abdominal injection after operation, the other groups′rats are given sterile water for injection 50mg.kg-1.d-1. On the 14th day, 28th, 45th and 60th day, we detected serum ICAM-1 by ELISA ,measuring plasma AngⅡby radioimmunoassay,observing pathological changes in rat kidneys using HE,/Masson staining and observed the change of expression of tubulointerstitialα-smooth muscle actin ,parallelly semi-quantitative analysis.
Results: At the same time point, levels of serum ICAM-1 and plasma AngⅡlevels of model group group were significantly higher compared with sham-operated group (P <0.01), and the serum ICAM-1 and plasma AngⅡgradually increased with the extension of ischemic time in model group (P <0.05); A large number of Shrinkage and expansion of tubular ,renal tubular epithelial cell necrosis, renal interstitial widened, inflammatory cell infiltration and renal interstitial fibrosis were observed by HE and Masson staining. Immunohistochemistry results showed that,α-SMA expressed in part of the damaged renal tubular epithelial cells in model group 14 days later, a small amount ofα-SMA also expressed in renal interstitia after 28 days, and the amount of expression in tubular - interstitial cells gradually increased with the extension of ischemic time;Yet we found no significant changes in renal pathology and noα-SMA expression in sham operation group at any time point.,The serum ICAM-1 and plasma AngⅡlevels decreased significantly compared with model group after treatment of PNS. (P <0.05), and the renal pathological changes and expression ofα-SMA in renal tubular - interstitial cells were similar to the model group, however the extent of renal pathological changes and the amout ofα-SMA expression were lighter than the model group at the same point.
Conclusions:In the cases of chronic renal ischemia, the expression ofα-SMA (Myo-FB the transdifferentiation from renal intrinsic cells expressα-SMA ), renin - angiotensin system activation and the increasing expression of ICMA-1 may speed up the process chronic ischemic renal injury . PNS could inhibit the related links, and postpone the development of renal interstitial fibrosis and protect the kidney.
方法:48只SD雄性大鼠随机分为3组,假手术组、模型组和PNS组,每组16只。采用双侧肾动脉不全结扎术建立双侧肾动脉狭窄模型,PNS组于术后开始给予腹腔注射PNS 50mg?kg-1?d-1,其余2组给药同等容量的灭菌注射用水。于术后14d、28d、45d、60d,用酶联免疫吸附实验(enzyme linked immunosorbent assay,ELISA)检测各组大鼠血清细胞间黏附分子1(intercellular adhesion molecule-1,ICAM-1),放射免疫法测大鼠血浆血管紧张素Ⅱ(angiotensin11,AngⅡ)水平,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:在同一时间点,模型组血清ICAM-1及血浆AngⅡ水平较假手术组的水平明显升高(P < 0.01),且模型组的血清ICAM-1及血浆AngⅡ水平均随缺血时间的延长而逐渐升高(P < 0.05);HE、Masson染色结果显示,模型组大鼠可见大量萎缩和扩张的小管,肾小管上皮细胞坏死脱落,肾间质增宽,炎性细胞浸润,肾间质纤维化;免疫组织化学结果显示,模型组于术后14d在部分受损的肾小管上皮细胞即可见α-SMA表达,28d肾间质也可见少量α-SMA表达,且随着缺血时间的延长肾小管-间质细胞α-SMA表达的量逐渐增加;而假手术组各时间点肾脏病理未见明显改变,亦未见α-SMA表达。在予以PNS治疗后,可观察到PNS组大鼠各时间点血清ICAM-1及血浆AngⅡ水平较模型组明显下降(P < 0.05),肾脏病理改变及肾小管-间质细胞α-SMA表达情况与模型组相似,但同一个时间点肾脏病理改变程度及α-SMA表达的量均轻于模型组。
结论:在慢性肾缺血时,肾脏固有细胞转分化为Myo-FB表达α-SMA,肾素-血管紧张素系统过渡活化及ICMA-1表达增加可能是导致慢性缺血性肾损伤发生发展的重要环节,而三七皂苷能够通过抑制上述各环节,而延缓肾间质纤维化的进展,保护肾功能。
Objective:Chronic ischemic renal disease is one of the most important reasons leading to end-stage renal disease , but its pathogenesis is still a lack in depth .Studies have shown that the renin - angiotensin system activation, renal tubular interstitial infiltration of inflammatory cells, renal intrinsic cells transdifferentiation to myofibroblasts, may have effects on the progress of chronic ischemic nephropathy .PNS was mainly active ingredient extracted from traditional herb Panax notoginseng ,which had many biological effects including the strong role of inhibiting mesenchymal cells and improving renal microcirculation ,and may play an important role in the clinical treatment of renal disease. The main purpose of this study was to explore the mechanism of chronic ischemic renal injury, and to observe the PNS’effects on the prevention and treatment of chronic ischemic nephropathy and these may provide some theoretical basis the application of PNS for clinical prevention and treatment of chronic kidney disease.
Methods: All forty-eight male healty SD rats were randomly divided into sham-operation group, model group, and PNS group, every group has sixteen rats. The bilateral renal arteries were partly ligated to establish rat model with bilateral renal artery stenosis, Rats of PNS group we start to give the PNS 50mg.kg-1.d-1 by intra-abdominal injection after operation, the other groups′rats are given sterile water for injection 50mg.kg-1.d-1. On the 14th day, 28th, 45th and 60th day, we detected serum ICAM-1 by ELISA ,measuring plasma AngⅡby radioimmunoassay,observing pathological changes in rat kidneys using HE,/Masson staining and observed the change of expression of tubulointerstitialα-smooth muscle actin ,parallelly semi-quantitative analysis.
Results: At the same time point, levels of serum ICAM-1 and plasma AngⅡlevels of model group group were significantly higher compared with sham-operated group (P <0.01), and the serum ICAM-1 and plasma AngⅡgradually increased with the extension of ischemic time in model group (P <0.05); A large number of Shrinkage and expansion of tubular ,renal tubular epithelial cell necrosis, renal interstitial widened, inflammatory cell infiltration and renal interstitial fibrosis were observed by HE and Masson staining. Immunohistochemistry results showed that,α-SMA expressed in part of the damaged renal tubular epithelial cells in model group 14 days later, a small amount ofα-SMA also expressed in renal interstitia after 28 days, and the amount of expression in tubular - interstitial cells gradually increased with the extension of ischemic time;Yet we found no significant changes in renal pathology and noα-SMA expression in sham operation group at any time point.,The serum ICAM-1 and plasma AngⅡlevels decreased significantly compared with model group after treatment of PNS. (P <0.05), and the renal pathological changes and expression ofα-SMA in renal tubular - interstitial cells were similar to the model group, however the extent of renal pathological changes and the amout ofα-SMA expression were lighter than the model group at the same point.
Conclusions:In the cases of chronic renal ischemia, the expression ofα-SMA (Myo-FB the transdifferentiation from renal intrinsic cells expressα-SMA ), renin - angiotensin system activation and the increasing expression of ICMA-1 may speed up the process chronic ischemic renal injury . PNS could inhibit the related links, and postpone the development of renal interstitial fibrosis and protect the kidney.
引文
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[16]池泉,黄文政,等.肾素-血管紧张素系统与肾脏固有细胞表型转化的关系.长春中医药大学学报, 2007,23(4):98-99.
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[1]Peter Boor, Katarína Sebeková, et al . Treatment targets in renal fibrosis . Nephrol. Dial. Transplant., Dec 2007; 22: 3391 - 3407.
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[10]Perlman A , Lawsin LM , Kolachana P , et al . AngiotensinⅡregulation of TGF-beta in murine mesangial cells involves both PI3 kinase and MAP kinase. Ann Clin Lab Sci , 2004 , 34(3) :277-286.
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[13]Marta Ruiz-Ortega, Mónica Rupérez, Vanesa Esteban, et al . Angiotensin II: a key factor in the inflammatory and fibrotic response in kidney diseases. Nephrol. Dial. Transplant., Jan 2006; 21: 16 - 20.
[14]高山林,王希柱,等.霉酚酸酯及血管紧张素Ⅱ对人近端肾小管上皮细胞增殖的影响.中国药房,2008,19 (10):754-755.
[15]韦洮王,俭勤.血管紧张素及其受体拮抗剂与肾成纤维细胞关系的研究.中国实用内科杂志,2004 ,24 (5):291-292.
[16]池泉,黄文政,等.肾素-血管紧张素系统与肾脏固有细胞表型转化的关系.长春中医药大学学报, 2007,23(4):98-99.
[17]王锁刚,张翥.肌成纤维细胞与肾小管间质纤维化.医学综述,2008, 14(7):982-984.
[18]衣利,舒贵扬,等.转化生长因子β1在肾间质纤维化大鼠模型中的表达及意义.福建医药杂志,2007 ,29 (4):67-69.
[19]袁军,鲁艳芳,等.丹参对血管紧张素Ⅱ诱导的肾小球系膜细胞表达TGF-β1,ROS和PAI-1的影响.中国中药杂志, 2007, 32(22):2400-2403.
[20]宋彩霞,何正宏,等.纤溶酶原激活物抑制物1与肾脏疾病.国际泌尿系统杂志,2006,26(1):88-91.
[21]N Liu, S Shimizu, T Ito-Ihara, et al. Angiotensin II receptor blockade ameliorates mesangioproliferative glomerulonephritis in rats through suppression of CTGF and PAI-1, independently of the coagulation system. Nephron Exp Nephrol, Jan 2007; 105(3): e65-74.
[22]Brigitte Bauvois, Nadya Mothu, Juliette Nguyen, et al. Specific changes in plasma concentrations of matrix metalloproteinase-2 and -9, TIMP-1 and TGF-?1 in patients with distinct types of primary glomerulonephritis. Nephrol. Dial. Transplant., Apr 2007; 22: 1115 - 1122.
[23]Raghu V. Durvasula, Stuart J. Shankland. Activation of a local renin angiotensin system in podocytes by glucose, Am J Physiol Renal Physiol, Apr 2008; 294: F830 - F839.
[24]梁伟,丁国华,等.血管紧张素Ⅱ灌注大鼠模型肾小球足细胞损伤观察.实用医学杂志,2006,22,(5): 497-500.
[25]Benigni A, Gagliardini E, Remuzzi G. Changes in glomerular perm-selectivityinduced by angiotensinⅡimply podocyte dysfunction and slit diaphragm protein rearrangement. Semin Nephrol, 2004, 24:131-140.
[26]Wolf G, Chen S, Ziyadeh FN. From the periphery of the glomerular capillary wall toward the center of disease: Podocyte injury comes of age in diabetic nephropathy. Diabetes, 2005, 54: 1626-1634.
[27]贾俊亚,朱吉莉,等.血管紧张素Ⅱ灌注诱导nephrin表达改变与足细胞凋亡.中华肾脏病杂志,2007,23 (1):33-38.
[28]顾华,李艳辉,等.血浆醛固酮、血管紧张素-Ⅱ含量与肾间质纤维化相关性研究.中国实验诊断学, 2006, 7(10): 810-811.
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[30]S Mizuno, K Matsumoto, and T Nakamura. HGF as a renotrophic and anti-fibrotic regulator in chronic renal disease. Front Biosci, Jan 2008; 13: 7072-7086.
[31]Zhongyi Zhang, Yan Zhang, Gang Ning, et al. Combination therapy with AT1 blocker and vitamin D analog markedly ameliorates diabetic nephropathy: Blockade of compensatory renin increase. PNAS, Oct 2008; 105: 15896 - 15901.