迷迭香酸治疗肾间质纤维化的实验研究
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摘要
肾间质纤维化(renal interstitial fibrosis, RIF)已经成为各种肾脏疾病进展到终末期肾病(end-stage renal disease, ESRD)的共同途径和主要病理学基础。在病理状态下,肾小管上皮细胞可以发生上皮细胞-间充质转分化(epithelial- mesenchymal transition, EMT),在肾间质纤维化过程中超过1/3的肌成纤维细胞是通过肾小管上皮细胞转分化而来的,因此EMT在肾间质纤维化过程中扮演着重要的角色。
氧化应激是导致细胞损伤、衰老和死亡的重要原因之一。肾组织中需要较高的氧耗来完成水及电解质的主动转运和肾小管重吸收,所以肾小管极易受到损伤。如果氧自由基的产生不断增高或者体内的抗氧化平衡逐渐失调,过多的氧自由基将会引起肾组织细胞损伤,导致各种肾脏疾病。治疗肾脏疾病的常用药物如糖皮质激素、细胞毒药物等对慢性肾脏病有一定的治疗作用,但长期应用其副作用较大,因此迫切需要寻找一种既具有治疗效应而其副作用又较小的药物。
迷迭香酸(rosmarinic acid,RA)是一种水溶性多酚类化合物,广泛分布于唇形科中草药如迷迭香、紫苏中,因最初从迷迭香中分离提取而得名。RA具有抗氧化、抗炎、抗血栓、抗菌及免疫抑制等多种生物学活性。新近有研究发现,RA对大鼠MsPGN模型、IgA肾病模型具有保护作用,但对肾间质纤维化是否有效尚不清楚。
为进一步探讨RA的作用机制,我们开展了以下两部分研究,从细胞与整体水平证实了RA对肾间质纤维化的影响。
目的:应用醛固酮(Aldosterone, ALD)诱导人肾小管上皮细胞-间充质转分化(EMT),研究迷迭香酸(RA)对人肾小管上皮细胞转分化的影响并探讨其发生的机制。
方法:体外培养人肾小管上皮细胞(HK-2),细胞同步化后给予ALD (100nM)刺激,同时加入不同浓度的RA(5μg/ml, 25μg/ml)和rotenone (ROT, 10μM)。实验分组如下:(1)正常对照组;(2)ALD (100nM)诱导组;(3)ALD(100nM)+RA(5μg/ml)干预组;(4)ALD (100nM)+RA(25μg/ml)干预组;(5)ALD(100nM)+线粒体呼吸链酶抑制剂rotenone (ROT, 10μM)干预组。应用倒置相差显微镜观察细胞形态学的变化;RT-PCR、Western blot法检测波形蛋白(Vimentin)、平滑肌肌动蛋白(α-SMA)及钙粘蛋白(E-cadherin)的表达水平;Western blot法检测信号通路ERK1/2的磷酸化水平;荧光显微镜定性观察活性氧(ROS)表达情况;免疫荧光酶标仪定量检测活性氧(ROS)表达情况。
结果:(1)与对照组相比,醛固酮诱导肾小管上皮细胞从原有典型的上皮细胞形态转变为长梭形肌成纤维细胞样形态;Vimentin mRNA和α-SMA蛋白表达上调, E-cadherin mRNA及蛋白表达均下调;ERK1/2磷酸化水平增高;活性氧族(ROS)表达显著增高。(2)不同浓度的RA(5μg/ml, 25μg/ml)及ROT(10μM)干预组与ALD (100nM)诱导组相比,Vimentin mRNA和α-SMA蛋白表达下调,E-cadherin mRNA及蛋白表达均上调;ERK1/2磷酸化水平下降;活性氧族(ROS)表达显著下降。
结论:RA能够抑制醛固酮诱导的肾小管上皮细胞-间充质转分化,RA对EMT的负性调节作用可能是通过抑制ROS引起的ERK1/2信号转导途径实现的。
目的:探讨迷迭香酸对小鼠单侧输尿管梗阻(UUO)模型肾间质纤维化的抗氧化保护作用。
方法:将雄性C57BL/6J小鼠随机分成三大组:假手术对照组(Sham组,n=8)、UUO模型组(结扎左侧输尿管制作UUO模型,n=24)、UUO迷迭香酸干预组(UUO+RA组,n=24)。除Sham组外,其余两组根据不同的观察时间细分为3、7、14d亚组(n=8)。术后第3、7、14天分别处死各组小鼠,组织病理学方法观察肾小管间质损伤情况;Western blot方法检测肾组织中波形蛋白(Vimentin)和E-钙粘蛋白(E-cadherin)表达;比色法测定小鼠左肾皮质匀浆中脂质过氧化标志物MDA以及抗氧化酶SOD的含量。
结果:UUO模型组与假手术组比较:随着模型损伤时间的延长,肾间质损伤程度逐渐加重,Vimentin和MDA含量明显增高,E-cadherin和SOD含量明显降低。迷迭香酸干预组与UUO模型组比较:3天时肾脏病理、Vimentin、E-cadherin以及MDA、SOD含量无明显改变;7天时肾间质纤维化减轻,Vimentin、MDA含量降低,E-cadherin、SOD含量增高;14天时肾间质纤维化明显减轻,Vimentin、MDA含量明显降低,E-cadherin、SOD含量明显增高。
结论:迷迭香酸可能通过减少单侧输尿管梗阻侧肾皮质脂质过氧化物的产生、增加抗氧化酶的含量,从而改善小鼠氧化应激所致的肾间质纤维化。
Renal interstitial fibrosis (RIF) has become common basic channels and major pathology of end-stage renal disease(ESRD). In pathological conditions, tubular epithelial cells can be epithelial-mesenchymal transdifferentiation (EMT). During renal interstitial fibrosis, more than 1/3 myofibroblasts come from tubular epithelial cells, and EMT plays important role during this progress.
Oxidative stress is one of the important reasons leading to cell damage, aging and death. Renal tissues require higher oxygen consumption to complete tubular reabsorption and active transport. If the generation of oxygen free radicals increases or antioxidant capacity imbalance is destoried, excessive oxygen free radicals will cause cell damage in renal tissue, leading to a variety of kidney diseases. Several pharmacotherapeutics are used for treating kidney disease, although these treatments are effective, some occasionally cause inherent and unavoidable side effects. Moreover, these pharmacotherapeutics cannot be used for long periods of time. Hence, traditional herbal medicines may improve treatment and inhibit the progression of chronic renal disease, especially in patients with weak disease activity.
Rosmarinic acid (RA) is a widely distributed phenolic compound in various Labiatae herbs such as Rosmarinus officinalis (rosemary) and Perilla frutescens (perilla). RA is reported to exhibit pharmacological effects, including anti-oxidative, anti-inflammatory, anti-thrombotic, anti-bacterial, anti-mutagen and immunosuppressive effects. Recent studies have revealed that suppressive effects of RA on MsPGN and IgA nephropathy model in rats. But it is unclear whether RA on renal interstitial fibrosis is effective.
In the present study, we evaluated the effects of RA on ALD induced EMT in HK-2 cells and antioxidative effects on mouse kidney with unilateral ureteral obstruction. The following two-part were studied.
Objective: To explore the effects of rosmarinic acid (RA) on the tubular epithelial-mesenchymal transition and mechanisms induced by Aldosterone in vitro.
Methods: HK-2 cells were cultured with Aldosterone(100nM) in the presence of different concentration of RA (5μg/ml, 25μg/ml) and mitochondrial respiratory chain complexⅠinhibitor rotenone (ROT, 10μM). Then the cultured HK-2 cells were divided into five groups: (1)normal group; (2)HK-2 cells induced by Aldosterone(ALD); (3)RA group (5μg/ml,); (4)RA group (25μg/ml); (5)rotenone group (ROT, 10μM), collected the supernatant and the cells respectively. The morphology of transdifferentiate tubular cells was observed using phase-contrast-microscopy, E-cadherin, Vimentin,α-SMA and ERK1/2 were determined by semi-quantitative RT-PCR and Western blot; Reactive oxygen species(ROS) was detected by Fluorescence Microscopic and Fluorescence Eliasa.
Results: compared with control groups, HK-2 cells induced by ALD converted into spindle shape from typical epithelium shape, the expression of Vimentin mRNA,α-SMA, phosphor-ERK1/2 proteins and ROS significantly increased, the expression of E-cadherin significantly decreased; compared with ALD treated groups, RA (5μg/ml, 25μg/ml) and mitochondrial respiratory chain complexⅠinhibitor rotenone (ROT, 10μM) could inhibit ROS, vimentin,α-SMA and phosphor-ERK1/2 expression, E-cadherin mRNA expression and protein production increased.
Conclusion: RA treatment could inhibit ALD-induced EMT which was activated via mitochondrial-originated, ROS-dependent ERK1/2 activation.
Objective: To investigate the antioxidative effect of Rosmarinic acid on kidney of mice with unilateral ureteral obstruction (UUO).
Methods: male C57BL/6J mice were randomly divided into 3 groups: Sham-operated group (n=8), UUO model group (UUO model was established by ligating the left ureter, n=24) and UUO+RA group (UUO model mice were treated with RA, n=24). The latter 2 groups were divided into subgroups according to times (3d, 7d and 14d) after intervention (n=8). Mice underwent UUO were killed at 3, 7, 14 days. The time course of injurious process in mice with UUO were examined by histopathology; Western blot of Vimentin as well as E-cadherin were measured; Malondialdehyde (MDA), superoxide dismutase (SOD) contents in the homogenized lysate of obstructive renal cortex were determined.
Results: Compared with those in Sham-operated group, from 3 to 14 day, injury of renal interstitum exacerbated gradually in UUO model group, Vimentin and MDA increased significantly, E-cadherin and SOD decreased significantly. Compared with those in UUO model group, Vimentin, E-cadherin, SOD and MDA showed no significant difference in UUO+RA group on 3d; Vimentin and MDA decreased, E-cadherin and SOD increased, renal interstitial fibrosis attenuated in UUO+RA group on 7d, till 14d, these expression demonstrated significantly.
Conclusion: Rosmarinic acid may attenuate renal interstitial fibrosis in mice underwent UUO by reducing lipid peroxidation production and improving antioxidative enzyme contents.
氧化应激是导致细胞损伤、衰老和死亡的重要原因之一。肾组织中需要较高的氧耗来完成水及电解质的主动转运和肾小管重吸收,所以肾小管极易受到损伤。如果氧自由基的产生不断增高或者体内的抗氧化平衡逐渐失调,过多的氧自由基将会引起肾组织细胞损伤,导致各种肾脏疾病。治疗肾脏疾病的常用药物如糖皮质激素、细胞毒药物等对慢性肾脏病有一定的治疗作用,但长期应用其副作用较大,因此迫切需要寻找一种既具有治疗效应而其副作用又较小的药物。
迷迭香酸(rosmarinic acid,RA)是一种水溶性多酚类化合物,广泛分布于唇形科中草药如迷迭香、紫苏中,因最初从迷迭香中分离提取而得名。RA具有抗氧化、抗炎、抗血栓、抗菌及免疫抑制等多种生物学活性。新近有研究发现,RA对大鼠MsPGN模型、IgA肾病模型具有保护作用,但对肾间质纤维化是否有效尚不清楚。
为进一步探讨RA的作用机制,我们开展了以下两部分研究,从细胞与整体水平证实了RA对肾间质纤维化的影响。
目的:应用醛固酮(Aldosterone, ALD)诱导人肾小管上皮细胞-间充质转分化(EMT),研究迷迭香酸(RA)对人肾小管上皮细胞转分化的影响并探讨其发生的机制。
方法:体外培养人肾小管上皮细胞(HK-2),细胞同步化后给予ALD (100nM)刺激,同时加入不同浓度的RA(5μg/ml, 25μg/ml)和rotenone (ROT, 10μM)。实验分组如下:(1)正常对照组;(2)ALD (100nM)诱导组;(3)ALD(100nM)+RA(5μg/ml)干预组;(4)ALD (100nM)+RA(25μg/ml)干预组;(5)ALD(100nM)+线粒体呼吸链酶抑制剂rotenone (ROT, 10μM)干预组。应用倒置相差显微镜观察细胞形态学的变化;RT-PCR、Western blot法检测波形蛋白(Vimentin)、平滑肌肌动蛋白(α-SMA)及钙粘蛋白(E-cadherin)的表达水平;Western blot法检测信号通路ERK1/2的磷酸化水平;荧光显微镜定性观察活性氧(ROS)表达情况;免疫荧光酶标仪定量检测活性氧(ROS)表达情况。
结果:(1)与对照组相比,醛固酮诱导肾小管上皮细胞从原有典型的上皮细胞形态转变为长梭形肌成纤维细胞样形态;Vimentin mRNA和α-SMA蛋白表达上调, E-cadherin mRNA及蛋白表达均下调;ERK1/2磷酸化水平增高;活性氧族(ROS)表达显著增高。(2)不同浓度的RA(5μg/ml, 25μg/ml)及ROT(10μM)干预组与ALD (100nM)诱导组相比,Vimentin mRNA和α-SMA蛋白表达下调,E-cadherin mRNA及蛋白表达均上调;ERK1/2磷酸化水平下降;活性氧族(ROS)表达显著下降。
结论:RA能够抑制醛固酮诱导的肾小管上皮细胞-间充质转分化,RA对EMT的负性调节作用可能是通过抑制ROS引起的ERK1/2信号转导途径实现的。
目的:探讨迷迭香酸对小鼠单侧输尿管梗阻(UUO)模型肾间质纤维化的抗氧化保护作用。
方法:将雄性C57BL/6J小鼠随机分成三大组:假手术对照组(Sham组,n=8)、UUO模型组(结扎左侧输尿管制作UUO模型,n=24)、UUO迷迭香酸干预组(UUO+RA组,n=24)。除Sham组外,其余两组根据不同的观察时间细分为3、7、14d亚组(n=8)。术后第3、7、14天分别处死各组小鼠,组织病理学方法观察肾小管间质损伤情况;Western blot方法检测肾组织中波形蛋白(Vimentin)和E-钙粘蛋白(E-cadherin)表达;比色法测定小鼠左肾皮质匀浆中脂质过氧化标志物MDA以及抗氧化酶SOD的含量。
结果:UUO模型组与假手术组比较:随着模型损伤时间的延长,肾间质损伤程度逐渐加重,Vimentin和MDA含量明显增高,E-cadherin和SOD含量明显降低。迷迭香酸干预组与UUO模型组比较:3天时肾脏病理、Vimentin、E-cadherin以及MDA、SOD含量无明显改变;7天时肾间质纤维化减轻,Vimentin、MDA含量降低,E-cadherin、SOD含量增高;14天时肾间质纤维化明显减轻,Vimentin、MDA含量明显降低,E-cadherin、SOD含量明显增高。
结论:迷迭香酸可能通过减少单侧输尿管梗阻侧肾皮质脂质过氧化物的产生、增加抗氧化酶的含量,从而改善小鼠氧化应激所致的肾间质纤维化。
Renal interstitial fibrosis (RIF) has become common basic channels and major pathology of end-stage renal disease(ESRD). In pathological conditions, tubular epithelial cells can be epithelial-mesenchymal transdifferentiation (EMT). During renal interstitial fibrosis, more than 1/3 myofibroblasts come from tubular epithelial cells, and EMT plays important role during this progress.
Oxidative stress is one of the important reasons leading to cell damage, aging and death. Renal tissues require higher oxygen consumption to complete tubular reabsorption and active transport. If the generation of oxygen free radicals increases or antioxidant capacity imbalance is destoried, excessive oxygen free radicals will cause cell damage in renal tissue, leading to a variety of kidney diseases. Several pharmacotherapeutics are used for treating kidney disease, although these treatments are effective, some occasionally cause inherent and unavoidable side effects. Moreover, these pharmacotherapeutics cannot be used for long periods of time. Hence, traditional herbal medicines may improve treatment and inhibit the progression of chronic renal disease, especially in patients with weak disease activity.
Rosmarinic acid (RA) is a widely distributed phenolic compound in various Labiatae herbs such as Rosmarinus officinalis (rosemary) and Perilla frutescens (perilla). RA is reported to exhibit pharmacological effects, including anti-oxidative, anti-inflammatory, anti-thrombotic, anti-bacterial, anti-mutagen and immunosuppressive effects. Recent studies have revealed that suppressive effects of RA on MsPGN and IgA nephropathy model in rats. But it is unclear whether RA on renal interstitial fibrosis is effective.
In the present study, we evaluated the effects of RA on ALD induced EMT in HK-2 cells and antioxidative effects on mouse kidney with unilateral ureteral obstruction. The following two-part were studied.
Objective: To explore the effects of rosmarinic acid (RA) on the tubular epithelial-mesenchymal transition and mechanisms induced by Aldosterone in vitro.
Methods: HK-2 cells were cultured with Aldosterone(100nM) in the presence of different concentration of RA (5μg/ml, 25μg/ml) and mitochondrial respiratory chain complexⅠinhibitor rotenone (ROT, 10μM). Then the cultured HK-2 cells were divided into five groups: (1)normal group; (2)HK-2 cells induced by Aldosterone(ALD); (3)RA group (5μg/ml,); (4)RA group (25μg/ml); (5)rotenone group (ROT, 10μM), collected the supernatant and the cells respectively. The morphology of transdifferentiate tubular cells was observed using phase-contrast-microscopy, E-cadherin, Vimentin,α-SMA and ERK1/2 were determined by semi-quantitative RT-PCR and Western blot; Reactive oxygen species(ROS) was detected by Fluorescence Microscopic and Fluorescence Eliasa.
Results: compared with control groups, HK-2 cells induced by ALD converted into spindle shape from typical epithelium shape, the expression of Vimentin mRNA,α-SMA, phosphor-ERK1/2 proteins and ROS significantly increased, the expression of E-cadherin significantly decreased; compared with ALD treated groups, RA (5μg/ml, 25μg/ml) and mitochondrial respiratory chain complexⅠinhibitor rotenone (ROT, 10μM) could inhibit ROS, vimentin,α-SMA and phosphor-ERK1/2 expression, E-cadherin mRNA expression and protein production increased.
Conclusion: RA treatment could inhibit ALD-induced EMT which was activated via mitochondrial-originated, ROS-dependent ERK1/2 activation.
Objective: To investigate the antioxidative effect of Rosmarinic acid on kidney of mice with unilateral ureteral obstruction (UUO).
Methods: male C57BL/6J mice were randomly divided into 3 groups: Sham-operated group (n=8), UUO model group (UUO model was established by ligating the left ureter, n=24) and UUO+RA group (UUO model mice were treated with RA, n=24). The latter 2 groups were divided into subgroups according to times (3d, 7d and 14d) after intervention (n=8). Mice underwent UUO were killed at 3, 7, 14 days. The time course of injurious process in mice with UUO were examined by histopathology; Western blot of Vimentin as well as E-cadherin were measured; Malondialdehyde (MDA), superoxide dismutase (SOD) contents in the homogenized lysate of obstructive renal cortex were determined.
Results: Compared with those in Sham-operated group, from 3 to 14 day, injury of renal interstitum exacerbated gradually in UUO model group, Vimentin and MDA increased significantly, E-cadherin and SOD decreased significantly. Compared with those in UUO model group, Vimentin, E-cadherin, SOD and MDA showed no significant difference in UUO+RA group on 3d; Vimentin and MDA decreased, E-cadherin and SOD increased, renal interstitial fibrosis attenuated in UUO+RA group on 7d, till 14d, these expression demonstrated significantly.
Conclusion: Rosmarinic acid may attenuate renal interstitial fibrosis in mice underwent UUO by reducing lipid peroxidation production and improving antioxidative enzyme contents.
引文
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24. Wano M, Plieth D, Danoff TM et al. Evidence that fibroblasts derive from epithelium during tissue fibrosis. JClin Invest, 2002, 110(3):341-350.
25.司徒镇强，吴军正主编，细胞培养，第一版，西安：世界图书出版公司, 1996.
26. Strutz F, Zeisberg M, Ziyadeh FN, et al. Role of basic fibroblast growth factor-2 in epithelial-mesenchymal transformation. Kidney Int, 2002,61(5): 1714-1728.
27. Ng YY, Huang TP, Yang WC, et al. Tubular epithelial-myofibroblast trans differentiation in progressive tubulointerstitial fibrosis in 5/6 nephrectomized rats. Kidney Int, 1998,54(3):864-876.
28. Xie L, Law BK, Chvtil AM, et al. Activation of the ERK pathway is required for TGF-beta l-induced EMT in vitro. Neoplasia, 2004, 6(5):603-10.
29. Ruyu DY, Yang Y, Ha H, et al. Role of reactive oxygen species in TGF-beta 1 induced mitogen-activated protein kinase activation and epithelial-mesenchymal transition in renal tubular epithelial cells. J Am Soc Nephrol, 2005, 16(3):667-675.
30. Ha H, Lee HB. Reactive oxygen species and matrix remodeling in diabetic Kidney. J Am Soc Nephrol, 2003, 14:S246-249.
31. Rhyu DY, Yang Y, Ha H, et al. Role of reactive oxygen species in TGF-betal-induced mitogen-activated protein kinase activation and epithelial-mesenchymal transition in renal tubular epithelial cells. J Am Soc Nephol, 2005,16(3):667-675.16(3):667-675.
32. Batandier C, Fontaine E, Keriel C, et al. Determination of mitochondrial reactive oxygen species: methodological aspects. J Cell Mol Med,2002,6(2):175-187.
33. St-Pierre J, Buckingham J A, Roebuck SJ, et al. Topology of superoxide production from different sites in the mitochondrial electron transport chain. J Biol Chem, 2002,277(47):44784-44790.
34. Jezek P, Hlavata L. Mitochondria in homeostasis of reactive oxygen species in cell, tissue, and organizon. Int J Biolchem Cell Biol, 2005, 37(12):2478-2503.
35. Turrens JF. Mitochondrial formation of reactive oxygen species. J Physiol, 2003, 552(2):335-344.
36. Rodriguez-Pena A, Eleno N, Duwell A, et al. Endoglin upregulation during experimental renal interstitial fibrosis in mice. Hypertension, 2002,40(5):713-720.
37. Klahr S, Morrissey J. Obstructive nephropathy and renal fibrosis: The role of bone morphogenic protein-7 and hepatocyte growth factor. Kidney Int Suppl, 2003,87(4):S105-112.
38. Kim JH, Yang JI, Jung MH et al. Heme oxygenase-l protects rat kidney from ureteral obstruction via an antiapoptotic pathway. J Am Nephrol, 2006,17(5): 1373-1381.
39. Yang J,Liu Y Blockage of tubular epithelial to myofibroblast transition by hepatocyte growth factor prevents renal interstitial fibrosis.J Am Soc Nephrol, 2002,13(l):96-107.
40. Moriyama T, Kawada N, Nagatoya K, et al. Fluvastatin suppresses oxidative stress and fibrosis in the interstitium of mouse kidneys with unilateral ureteral obstruction. Kidney Int, 2001,59(6): 2095-103.
41. Sun Y, Oberley LW, Li Y A simple method for clinical assay of superoxide dismutase. Clin chem, 1988,34(3):497-500.
42. Draper H, Hadley M. Malondialdehyde determination as index of lipid peroxidation. Methods Enzymol, 1990,186(6):421-431.
43. Tang W W, Van G Y, Qi M et al. Myofibroblast and alphale l(III)collagen expression in experimental tubulo inters ititial nephritis. Kidney Int, 1999,51(3): 926-930.
44.何玉华，冯梅，梁勇，等.肾小管上皮细胞表型转化在肾小管间质纤维化中的作用.中国中西医结合肾病杂志，2005, 5（6）:308-311.
45. Inazaki K, Kanamaru Y, Kojima Y, et al. Smad3 deficiency attenuates renal fibrosis, inflammation, and apoptosis after unilateral ureteral obstruction. Kidney Int, 2004,66(2):597-604.
46. Liu Y Epithelial to mesenchymal transition in renal fibrogenesis: pathologic significance, molecular mechanism, and therapeutic intervention. J Am Nephrol, 2004,15(l):l-12.
47. Klahr S, Morrissey J. Obstructive nephropathy and renal fibrosis. Am J Physiol Renal Physiol, 2002,283(5):861-875.
48. Ito K, Chen J, El Chaar M , et al. Renal damage progresses despite improvement of renal function after relief of unilateral ureteral obstruction in adult rats. Am J Physiol Renal Physiol, 2004, 287(6):1283-1293.
1. Irani K. Oxidant signaling in vascular cell growth, death, and survival : a review of the roles of reactive oxygen species in smooth muscle and endothelial cell
mitogenic and apoptotic signaling. Circ Res , 2000,87(3):179-183.
2. Balaban RS, Nemoto S, Finkel T. Mitochondria, oxidants, and aging. Cell, 2005,120(4):483-495.
3. Himmelfarb J, Stenvinkel P, Ikizler TA,et al. The elephant in uremia: oxidant stress as a unifying concept of cardiovascular disease in uremia. Kidney lnt, 2002, 62(5): 1524-1538.
4. Agarwal R. Proinflammatory effects of oxidative stress in chronic kidney disease: role of additional angiotensin II blockade. Am J Physiol Renal Physiol, 2003, 284(4):F863-869.
5. Lombard DB, Chua KF, Mostoslavsky R, et al. DNA repair, genome stability, and aging. Cell, 2005,120(4):497-512.
6. Hsieh CC, Yen MH, Yen CH, et al. Oxidized low density lipoprotein induces apoptosis via generation of reactive oxygen species in vascular smooth muscle cells. Cardiovasc Res, 2001,49(l):135-145.
7. Hamdheydari L, Christov A, Ottman T, et al. Oxidized LDLs affect nitric oxide and radical generation in brain endothelial cells. Biochem Biophys Res Commun, 2003, 311(2):486-490.
8. Tarng DC, Huang TP, Wei YH, et al. 8-hydroxy-2'-deoxyguanosine of leukocyte DNA as a marker of oxidative stress in chronic hemodialysis patients. Am J Kidney Dis, 2000,36(5):934-944.
9. Tarng DC, Wen Chen T, Huang TP, et al. Increased oxidative damage to peripheral blood leukocyte DNA in chronic peritoneal dialysis patients. J Am Soc Nephrol, 2002,13(5):1321-1330.
10.Tomida C, Aoyagi K, Nagase S, et al. Creatol, an oxidative product of creatinine inhemodialysis patients. Free Radic Res, 2000,32(l):85-92.
11.Ogawa S, Mori T, Nako K, et al. Angiotensin II type 1 receptor blockers reduceurinary oxidative stress markers in hypertensive diabetic nephropathy. Hypertension, 2006,47(4):699-705.
12.Castro L, Freeman BA. Reactive oxygen species in human health and disease. Nutrition, 2001,17(2):161, 3-5.
13. Young IS, Woodside JV. Antioxidants in health and disease. J Clin Pathol, 2001, 54(3):176-186.
14. Grignard E, Morin J, Vernet P, et al. GPX5 orthologs of the mouse epididymis-restricted and sperm-bound selenium-independent glutathione peroxidase are not expressed with the same quantitative and spatial characteristics in large domestic animals. Theriogenology, 2005,64(4):1016-1033.
15. Vaziri ND. Oxidative stress in uremia: nature, mechanisms, and potential consequences. Semin Nephrol, 2004,24(5):469-473.
16. Babior BM. The respiratory burst oxidase. Adv Enzymol Relat Areas Mol Biol, 1992,65:49-95.
17. Himmelfarb J, Hakim RM. Oxidative stress in uremia. Curr Opin Nephrol Hypertens, 2003,12(6):593-598.
18. Ichikawa I, Kiyama S, Yoshioka T. Renal antioxidant enzymes: their regulation and function. Kidney Int, 1994,45(l):l-9.
19. Fortuno A, Beloqui O, San Jose G, et al. Increased phagocytic nicotinamide adenine dinucleotide phosphate oxidase-dependent superoxide production in patients with early chronic kidney disease. Kidney Int Suppl, 2005,99:S71-75.
20. Galli F, Varga Z, Balla J, et al. Vitamin E, lipid profile, and peroxidation in hemodialysis patients. Kidney Int Suppl, 2001,78:S148-154.
21. Sardenberg C, Suassuna P, Watanabe R, et al. Balance between cytokine production by peripheral blood mononuclear cells and reactive oxygen species production by monocytes in patients with chronic kidney disease. Ren Fail,2004,26(6):673-681.
22. Fortuno A, San Jose G, Moreno MU,et al. Phagocytic NADPH oxidase overactivity underlies oxidative stress in metabolic syndrome. Diabetes, 2006, 55(l):209-215.
23. Witko-Sarsat V, Gausson V, Nguyen AT, et al. AOPP-induced activation of human neutrophil and monocyte oxidative metabolism: a potential target for N-acetylcysteine treatment in dialysis patients. Kidney Int, 2003,64(l):82-91.
24. Witko-Sarsat V, Friedlander M, Nguyen Khoa T, et al. Advanced oxidation protein products as novel mediators of inflammation and monocyte activation in chronic renal failure. J Immunol, 1998,161(5):2524-2532.
25. Sarnak MJ, Levey AS, Schoolwerth AC, et al. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Hypertension, 2003,42(5): 1050-1065.
26. Vanholder R, Massy Z, Argiles A, et al. Chronic kidney disease as cause of cardiovascular morbidity and mortality. Nephrol Dial Transplant, 2005,20(6): 1048-1056.
27. Redon J, Cea-Calvo L, Lozano JV, et al. Kidney function and cardiovascular disease in the hypertensive population: the ERIC-HTA study. J Hypertens, 2006, 24(4):663-669.
28. Locatelli F, Canaud B, Eckardt KU, et al. Oxidative stress in end-stage renal disease: an emerging threat to patient outcome. Nephrol Dial Transplant, 2003, 18(7): 1272-1280.
29. Danielski M, Ikizler TA, McMonagle E, et al. Linkage of hypoalbuminemia, inflammation, and oxidative stress in patients receiving maintenance hemodialysistherapy. Am J Kidney Dis, 2003,42(2):286-294.
30. Stenvinkel P, Heimburger O, Paultre F, et al. Strong association between malnutrition, inflammation, and atherosclerosis in chronic renal failure. Kidney Int, 1999,55(5):1899-1911.
31. Sindhu RK, Ehdaie A, Farmand F, et al. Expression of catalase and glutathione peroxidase in renal insufficiency. Biochim Biophys Acta, 2005,1743(l-2):86-92.
32. Shimizu MH, Coimbra TM, de Araujo M,et al. N-acetylcysteine attenuates the progression of chronic renal failure. Kidney Int, 2005,68(5):2208-2217.
33. Ivanovski O, Szumilak D, Nguyen-Khoa T, et al. The antioxidant N-acetylcysteine prevents accelerated atherosclerosis in uremic apolipoprotein E knockout mice. Kidney Int, 2005,67(6):2288-2294.
34. Pawlak K, Pawlak D, Mysliwiec M. Cu/Zn superoxide dismutase plasma levels as a new useful clinical biomarker of oxidative stress in patients with end-stage renal disease. CLin Biochem, 2005,38(8):700-705.
35. Zachwieja J, Zaniew M, Bobkowski W, et al. Beneficial in vitro effect of N-acetyl-cysteine on oxidative stress and apoptosis. Pediatr Nephrol, 2005,20(6):725-731.
36. Galle J, Seibold S. Has the time come to use antioxidant therapy in uraemic patients? Nephrol Dial Transplant, 2003,18(8):1452-1455.
37. Massy ZA, Nguyen-Khoa T. Oxidative stress and chronic renal failure: markers and management. J Nephrol, 2002;15(4):336-341.
2. Zeisberg M, Kalluri R. The role of epithelial-to-mesenchymal transition in renal fibrosis. J Mol Med, 2004,82(3):175-81.
3. Yang J, Liu Y Dissection of key events in tubular epithelial to myofibroblast transition and its implications in renal interstitial fibrosis. Am J Pathol, 2001, 159(4): 1465-75.
4. Li JH, Zhu HJ, Huang XR et al.Smad 7 inhibits fibrotic effect of TGF-βon renal tubular epithelial cells by blocking Smad2 activation. J Am Soc Nephrol. 2002, 13(6):1464-1472.
5. Okada H, Kalluri R. Cellular and molecular pathways that lead to progression and regression of renal fbrogenesis. Curr Mol Med, 2005,5(5):467-474.
6. Zhang A, Jia Z, Guo X,et al. Aldosterone induces epithelial-mesenchymal transition via ROS of mitochondrial origin. Am J Physiol Renal Physiol, 2007, 293(3):723-731.
7. Funder JW. Non-genomic action of aldosterone: role in hypertension. Curr Opin Nephrol Hypertens, 2001,10(2):227-230.
8. Hostetter TH, Rosenberg ME, Ibrahim HN, et al. Aldosterone in renal disease. Curr Opin Nephrol Hypertens, 2001, 10(1): 105-110.
9. Feria I, Pichardo I, Juarez P, et al. Therapeutic benefit of spironolactone in experimental chronic cyclosporine A nephrotoxicity. Kidney Int, 2003, 63(1): 43-52.
10. Blasi ER, Rocha R, Rudolph AE, et al. Aldosterone/Salt induces renal
inflammation and fbrosis in hypertensive rats. Kidney iInt, 2003, 63(5): 1791-1800.
11. Manucha W. Biochemical-molecular markers in unilateral ureteral obstruction. Biocell, 2007, 31(1):1-12.
12. Petersen M, Simmonds MS. Rosmarinic acid. Phytochemistry, 2003, 62(2): 121-125.
13. Al-Sereiti MR, Abu-Amer KM, Sen P. Pharmacology of rosemary (Rosmarinus officinalis Linn) and its therapeutic potentials. Indian J Exp Biol, 1999, 37(2): 124-130.
14.尚雁君，黄才国，蒋三好，等，迷迭香酸对黄嘌呤氧化酶的抑制作用，第二军医大学学报，2006, 27(2):189-191.
15. Huang SS, Zheng RL. Rosmarinic acid inhibits angiogenesis and its mechanism of action in vitro. Cancer Lett, 2006, 239(2):271-280.
16. Qiao S, Li W, Tsubouchi R, et al. Rosmarinic acid inhibits the formation of reactive oxygen and nitrogen species in RAW264.7 macrophages. Free Radic Res, 2005,39(9):995-1003.
17. Englberger W, Hadding U, Etschenberg E, et al. Rosmarinic acid: a new inhibitor of complement C3-convertase with anti-inflammatory activity. Int J Immunopharmacol, 1988,10(6):729-737.
18. Peake PW, Pussell BA, Martyn P, et al. The inhibitory effect of rosmarinic acid on complement involves the C5 convertase. Int J Immunopharmacol, 1991,13(7): 853-857.
19. Kang MA, Yun SY, Won J. Rosmarinic acid inhibits Ca2+-dependent pathways of T-cell antigen receptor-mediated signaling by inhibiting the PLC-gamma 1 and Itk activity. Blood, 2003,101(9):3534-3542.
20. Makino T, Ono T, Muso E, et al. Inhibitory effects of rosmarinic acid on theproliferation of cultured murine mesangial cells. Nephrol Dial Transplant, 2000, 15(8):1140-1145.
21. Makino T, Ono T, Liu N, et al. Suppressive effects of rosmarinic acid on mesangioprolifrative glomerulonephritis in rats. Nephron, 2002,92(4):898-904.
22. Makino T, Ono T, Matsuyama K, et al. Suppressive effects of Perilla frutescens on IgAnephropathy in HIGAmice. Nephrol Dial Transplant, 2003,18(3):484-490.
23.赵三龙，黄松明，冯泉城，等，迷失香酸对大系膜增生性肾小球肾炎肾内TGF-1表达的影响。南京医科大学学报。2006, 26(12):1168-1172.
24. Wano M, Plieth D, Danoff TM et al. Evidence that fibroblasts derive from epithelium during tissue fibrosis. JClin Invest, 2002, 110(3):341-350.
25.司徒镇强，吴军正主编，细胞培养，第一版，西安：世界图书出版公司, 1996.
26. Strutz F, Zeisberg M, Ziyadeh FN, et al. Role of basic fibroblast growth factor-2 in epithelial-mesenchymal transformation. Kidney Int, 2002,61(5): 1714-1728.
27. Ng YY, Huang TP, Yang WC, et al. Tubular epithelial-myofibroblast trans differentiation in progressive tubulointerstitial fibrosis in 5/6 nephrectomized rats. Kidney Int, 1998,54(3):864-876.
28. Xie L, Law BK, Chvtil AM, et al. Activation of the ERK pathway is required for TGF-beta l-induced EMT in vitro. Neoplasia, 2004, 6(5):603-10.
29. Ruyu DY, Yang Y, Ha H, et al. Role of reactive oxygen species in TGF-beta 1 induced mitogen-activated protein kinase activation and epithelial-mesenchymal transition in renal tubular epithelial cells. J Am Soc Nephrol, 2005, 16(3):667-675.
30. Ha H, Lee HB. Reactive oxygen species and matrix remodeling in diabetic Kidney. J Am Soc Nephrol, 2003, 14:S246-249.
31. Rhyu DY, Yang Y, Ha H, et al. Role of reactive oxygen species in TGF-betal-induced mitogen-activated protein kinase activation and epithelial-mesenchymal transition in renal tubular epithelial cells. J Am Soc Nephol, 2005,16(3):667-675.16(3):667-675.
32. Batandier C, Fontaine E, Keriel C, et al. Determination of mitochondrial reactive oxygen species: methodological aspects. J Cell Mol Med,2002,6(2):175-187.
33. St-Pierre J, Buckingham J A, Roebuck SJ, et al. Topology of superoxide production from different sites in the mitochondrial electron transport chain. J Biol Chem, 2002,277(47):44784-44790.
34. Jezek P, Hlavata L. Mitochondria in homeostasis of reactive oxygen species in cell, tissue, and organizon. Int J Biolchem Cell Biol, 2005, 37(12):2478-2503.
35. Turrens JF. Mitochondrial formation of reactive oxygen species. J Physiol, 2003, 552(2):335-344.
36. Rodriguez-Pena A, Eleno N, Duwell A, et al. Endoglin upregulation during experimental renal interstitial fibrosis in mice. Hypertension, 2002,40(5):713-720.
37. Klahr S, Morrissey J. Obstructive nephropathy and renal fibrosis: The role of bone morphogenic protein-7 and hepatocyte growth factor. Kidney Int Suppl, 2003,87(4):S105-112.
38. Kim JH, Yang JI, Jung MH et al. Heme oxygenase-l protects rat kidney from ureteral obstruction via an antiapoptotic pathway. J Am Nephrol, 2006,17(5): 1373-1381.
39. Yang J,Liu Y Blockage of tubular epithelial to myofibroblast transition by hepatocyte growth factor prevents renal interstitial fibrosis.J Am Soc Nephrol, 2002,13(l):96-107.
40. Moriyama T, Kawada N, Nagatoya K, et al. Fluvastatin suppresses oxidative stress and fibrosis in the interstitium of mouse kidneys with unilateral ureteral obstruction. Kidney Int, 2001,59(6): 2095-103.
41. Sun Y, Oberley LW, Li Y A simple method for clinical assay of superoxide dismutase. Clin chem, 1988,34(3):497-500.
42. Draper H, Hadley M. Malondialdehyde determination as index of lipid peroxidation. Methods Enzymol, 1990,186(6):421-431.
43. Tang W W, Van G Y, Qi M et al. Myofibroblast and alphale l(III)collagen expression in experimental tubulo inters ititial nephritis. Kidney Int, 1999,51(3): 926-930.
44.何玉华，冯梅，梁勇，等.肾小管上皮细胞表型转化在肾小管间质纤维化中的作用.中国中西医结合肾病杂志，2005, 5（6）:308-311.
45. Inazaki K, Kanamaru Y, Kojima Y, et al. Smad3 deficiency attenuates renal fibrosis, inflammation, and apoptosis after unilateral ureteral obstruction. Kidney Int, 2004,66(2):597-604.
46. Liu Y Epithelial to mesenchymal transition in renal fibrogenesis: pathologic significance, molecular mechanism, and therapeutic intervention. J Am Nephrol, 2004,15(l):l-12.
47. Klahr S, Morrissey J. Obstructive nephropathy and renal fibrosis. Am J Physiol Renal Physiol, 2002,283(5):861-875.
48. Ito K, Chen J, El Chaar M , et al. Renal damage progresses despite improvement of renal function after relief of unilateral ureteral obstruction in adult rats. Am J Physiol Renal Physiol, 2004, 287(6):1283-1293.
1. Irani K. Oxidant signaling in vascular cell growth, death, and survival : a review of the roles of reactive oxygen species in smooth muscle and endothelial cell
mitogenic and apoptotic signaling. Circ Res , 2000,87(3):179-183.
2. Balaban RS, Nemoto S, Finkel T. Mitochondria, oxidants, and aging. Cell, 2005,120(4):483-495.
3. Himmelfarb J, Stenvinkel P, Ikizler TA,et al. The elephant in uremia: oxidant stress as a unifying concept of cardiovascular disease in uremia. Kidney lnt, 2002, 62(5): 1524-1538.
4. Agarwal R. Proinflammatory effects of oxidative stress in chronic kidney disease: role of additional angiotensin II blockade. Am J Physiol Renal Physiol, 2003, 284(4):F863-869.
5. Lombard DB, Chua KF, Mostoslavsky R, et al. DNA repair, genome stability, and aging. Cell, 2005,120(4):497-512.
6. Hsieh CC, Yen MH, Yen CH, et al. Oxidized low density lipoprotein induces apoptosis via generation of reactive oxygen species in vascular smooth muscle cells. Cardiovasc Res, 2001,49(l):135-145.
7. Hamdheydari L, Christov A, Ottman T, et al. Oxidized LDLs affect nitric oxide and radical generation in brain endothelial cells. Biochem Biophys Res Commun, 2003, 311(2):486-490.
8. Tarng DC, Huang TP, Wei YH, et al. 8-hydroxy-2'-deoxyguanosine of leukocyte DNA as a marker of oxidative stress in chronic hemodialysis patients. Am J Kidney Dis, 2000,36(5):934-944.
9. Tarng DC, Wen Chen T, Huang TP, et al. Increased oxidative damage to peripheral blood leukocyte DNA in chronic peritoneal dialysis patients. J Am Soc Nephrol, 2002,13(5):1321-1330.
10.Tomida C, Aoyagi K, Nagase S, et al. Creatol, an oxidative product of creatinine inhemodialysis patients. Free Radic Res, 2000,32(l):85-92.
11.Ogawa S, Mori T, Nako K, et al. Angiotensin II type 1 receptor blockers reduceurinary oxidative stress markers in hypertensive diabetic nephropathy. Hypertension, 2006,47(4):699-705.
12.Castro L, Freeman BA. Reactive oxygen species in human health and disease. Nutrition, 2001,17(2):161, 3-5.
13. Young IS, Woodside JV. Antioxidants in health and disease. J Clin Pathol, 2001, 54(3):176-186.
14. Grignard E, Morin J, Vernet P, et al. GPX5 orthologs of the mouse epididymis-restricted and sperm-bound selenium-independent glutathione peroxidase are not expressed with the same quantitative and spatial characteristics in large domestic animals. Theriogenology, 2005,64(4):1016-1033.
15. Vaziri ND. Oxidative stress in uremia: nature, mechanisms, and potential consequences. Semin Nephrol, 2004,24(5):469-473.
16. Babior BM. The respiratory burst oxidase. Adv Enzymol Relat Areas Mol Biol, 1992,65:49-95.
17. Himmelfarb J, Hakim RM. Oxidative stress in uremia. Curr Opin Nephrol Hypertens, 2003,12(6):593-598.
18. Ichikawa I, Kiyama S, Yoshioka T. Renal antioxidant enzymes: their regulation and function. Kidney Int, 1994,45(l):l-9.
19. Fortuno A, Beloqui O, San Jose G, et al. Increased phagocytic nicotinamide adenine dinucleotide phosphate oxidase-dependent superoxide production in patients with early chronic kidney disease. Kidney Int Suppl, 2005,99:S71-75.
20. Galli F, Varga Z, Balla J, et al. Vitamin E, lipid profile, and peroxidation in hemodialysis patients. Kidney Int Suppl, 2001,78:S148-154.
21. Sardenberg C, Suassuna P, Watanabe R, et al. Balance between cytokine production by peripheral blood mononuclear cells and reactive oxygen species production by monocytes in patients with chronic kidney disease. Ren Fail,2004,26(6):673-681.
22. Fortuno A, San Jose G, Moreno MU,et al. Phagocytic NADPH oxidase overactivity underlies oxidative stress in metabolic syndrome. Diabetes, 2006, 55(l):209-215.
23. Witko-Sarsat V, Gausson V, Nguyen AT, et al. AOPP-induced activation of human neutrophil and monocyte oxidative metabolism: a potential target for N-acetylcysteine treatment in dialysis patients. Kidney Int, 2003,64(l):82-91.
24. Witko-Sarsat V, Friedlander M, Nguyen Khoa T, et al. Advanced oxidation protein products as novel mediators of inflammation and monocyte activation in chronic renal failure. J Immunol, 1998,161(5):2524-2532.
25. Sarnak MJ, Levey AS, Schoolwerth AC, et al. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Hypertension, 2003,42(5): 1050-1065.
26. Vanholder R, Massy Z, Argiles A, et al. Chronic kidney disease as cause of cardiovascular morbidity and mortality. Nephrol Dial Transplant, 2005,20(6): 1048-1056.
27. Redon J, Cea-Calvo L, Lozano JV, et al. Kidney function and cardiovascular disease in the hypertensive population: the ERIC-HTA study. J Hypertens, 2006, 24(4):663-669.
28. Locatelli F, Canaud B, Eckardt KU, et al. Oxidative stress in end-stage renal disease: an emerging threat to patient outcome. Nephrol Dial Transplant, 2003, 18(7): 1272-1280.
29. Danielski M, Ikizler TA, McMonagle E, et al. Linkage of hypoalbuminemia, inflammation, and oxidative stress in patients receiving maintenance hemodialysistherapy. Am J Kidney Dis, 2003,42(2):286-294.
30. Stenvinkel P, Heimburger O, Paultre F, et al. Strong association between malnutrition, inflammation, and atherosclerosis in chronic renal failure. Kidney Int, 1999,55(5):1899-1911.
31. Sindhu RK, Ehdaie A, Farmand F, et al. Expression of catalase and glutathione peroxidase in renal insufficiency. Biochim Biophys Acta, 2005,1743(l-2):86-92.
32. Shimizu MH, Coimbra TM, de Araujo M,et al. N-acetylcysteine attenuates the progression of chronic renal failure. Kidney Int, 2005,68(5):2208-2217.
33. Ivanovski O, Szumilak D, Nguyen-Khoa T, et al. The antioxidant N-acetylcysteine prevents accelerated atherosclerosis in uremic apolipoprotein E knockout mice. Kidney Int, 2005,67(6):2288-2294.
34. Pawlak K, Pawlak D, Mysliwiec M. Cu/Zn superoxide dismutase plasma levels as a new useful clinical biomarker of oxidative stress in patients with end-stage renal disease. CLin Biochem, 2005,38(8):700-705.
35. Zachwieja J, Zaniew M, Bobkowski W, et al. Beneficial in vitro effect of N-acetyl-cysteine on oxidative stress and apoptosis. Pediatr Nephrol, 2005,20(6):725-731.
36. Galle J, Seibold S. Has the time come to use antioxidant therapy in uraemic patients? Nephrol Dial Transplant, 2003,18(8):1452-1455.
37. Massy ZA, Nguyen-Khoa T. Oxidative stress and chronic renal failure: markers and management. J Nephrol, 2002;15(4):336-341.