曲尼司特对阿霉素肾硬化大鼠肾脏改变的影响
摘要
目的本实验构建阿霉素肾硬化模型,通过曲尼司特给药干预,观察曲尼司特对实验动物肾组织形态学变化以及细胞外基质金属蛋白酶诱导因子(extracellular matrix metalloproteinase inducer ,CD147)和基质金属蛋白酶2(matrix metalloproteinase 2,MMP-2)表达的影响,初步探讨曲尼司特对阿霉素肾硬化大鼠肾脏病理的影响及作用机理,为临床防治肾小球纤维化提供理论依据。
方法30只清洁级SD雄性大鼠,随机分为假手术组(S组)和手术组,手术组采用单侧左肾切除并阿霉素尾静脉注射方法建立大鼠肾小球硬化模型,造模成功后手术组大鼠随机分为模型组(M组)和曲尼司特治疗组(T组)。治疗组给予曲尼司特(400mg/kg/day),观察干预前后尿蛋白、血尿素氮(BUN)、肌酐(SCr)的变化,给药后8周处死所有大鼠,取右肾组织进行病理染色,在光镜下观察肾组织形态学变化;RT-PCR方法检测肾组织CD147和MMP-2mRNA的表达,并用免疫组化法观察肾组织CD147和MMP-2蛋白的表达,并进行图像分析。
结果(1)肾组织PAS染色显示:S组未见明显病理改变;M组见多数肾小球表现为系膜细胞轻度弥漫性增生,伴节段性加重,细胞外基质显著增多,局灶节段性硬化,少部分可见球性硬化,毛细血管腔部分节段性塌陷,肾重/体重明显增高(P<0.05),肾小球硬化指数明显增高(P<0.05);与M组相比,T组病理改变明显减轻,肾小球系膜细胞和基质轻度节段性增生,毛细血管腔轻度狭窄,偶见局灶节段硬化,肾重/体重较模型组明显降低(P<0.05),肾小球硬化指数明显降低(P<0.05)。(2)免疫组化结果显示:M组CD147和MMP-2蛋白表达降低,与S组相比有统计学意义(P<0.05); T组上述表达增加,与M组相比有统计学意义(P<0.05)。(3)RT-PCR结果显示:M组CD147和MMP-2 mRNA表达降低,与S组相比有统计学意义(P<0.05);T组上述表达增加,与M组相比有统计学意义(P<0.05)。
结论(1)在阿霉素肾硬化大鼠模型,曲尼司特能够减轻肾组织的病理损害,延缓肾小球硬化的进程;(2)曲尼司特能抑制CD147和MMP2 mRNA及其蛋白质的表达;(3)曲尼司特对肾小球硬化的防治作用可能与其提高CD147的表达从而提高MMP-2的表达有关。
Objective In this experiment, we construct a rat model of Adriamycin-induced glomerulosclerosis and observe the effect of tranilast on the pathology change of kidney and the expression of CD147 and MMP-2 . And also we discusse the mechanism of Adriamycin-induced glomerulosclerosis in rats and provide some evidence for its prospective use in treatment of glomerular fibrosis.
Methods Thirty Sprague-Dawley male rats were randomly divided into sham operation group(S group) and operation group. The operation group rats underwent unilateral nephrectomy of left kidney and intravenous injection of doxorubicin. Then the operation group rats were randomly divided into two groups: model group(M group), tranilast-treated group(T group). T group rats were fed tranilast(400mg/kg/day) and then albuminuria, creatinine, urea nitrogen, were detected. The rats were killed eight weeks later and the right renal tissues were examined by microscope. And the expression of CD147 and MMP-2 was studied by PT-PCR and immunohistochemistry. The intensity was analyaed by imagine quantitative analysis technique.
Results (1)PAS staining of the renal tissue revealed that S group rats had no obvious pathological changes. M group rats tissue mainly revealed that mesangial cells mild to moderate segmental hyperplasia, extracellular matrix significantly increased, focal segmental sclerosis, and that a small portion of the ball sclerosis, capillary cavity collapse of the segmental renal weight / body weight significantly increased(P<0.05), glomerulosclerosis index increased significantly(P<0.05). Compared with M group, T group pathological changes reduced significantly, a few glomerular mesangial cells and stromal mild to moderate segmental increased capillary cavity see only a few mild stenosis, and occasionally focal segmental sclerosis, kidney weight / body weight compared model group decreased(P<0.05), glomerulosclerosis index decreased significantly(P<0.05). (2) Immunohistochemistry showed that group M CD147 and MMP-2 expression decreased, compared with the S group statistically significant(P<0.05), obove expression increased in the T group(P<0.05). (3) RT-PCR showed that in the M group CD147 and MMP-2 mRNA expression, compared with the S group statistically significant(P<0.05), obove expression increased in the T group(P<0.05).
Conclusions (1) In the doxorubicin rat model of renal sclerosis, tranilast can reduce the renal pathological damage and delay the process of glomerulosclerosis. (2)Tranilast can inhibit the expression of CD147 and MMP-2 mRNA and protein. (3) Effects of tranilast on glomerular sclerosis may be related to the preventive effect of increased expression of CD147 to enhance the expression of MMP-2.
方法30只清洁级SD雄性大鼠,随机分为假手术组(S组)和手术组,手术组采用单侧左肾切除并阿霉素尾静脉注射方法建立大鼠肾小球硬化模型,造模成功后手术组大鼠随机分为模型组(M组)和曲尼司特治疗组(T组)。治疗组给予曲尼司特(400mg/kg/day),观察干预前后尿蛋白、血尿素氮(BUN)、肌酐(SCr)的变化,给药后8周处死所有大鼠,取右肾组织进行病理染色,在光镜下观察肾组织形态学变化;RT-PCR方法检测肾组织CD147和MMP-2mRNA的表达,并用免疫组化法观察肾组织CD147和MMP-2蛋白的表达,并进行图像分析。
结果(1)肾组织PAS染色显示:S组未见明显病理改变;M组见多数肾小球表现为系膜细胞轻度弥漫性增生,伴节段性加重,细胞外基质显著增多,局灶节段性硬化,少部分可见球性硬化,毛细血管腔部分节段性塌陷,肾重/体重明显增高(P<0.05),肾小球硬化指数明显增高(P<0.05);与M组相比,T组病理改变明显减轻,肾小球系膜细胞和基质轻度节段性增生,毛细血管腔轻度狭窄,偶见局灶节段硬化,肾重/体重较模型组明显降低(P<0.05),肾小球硬化指数明显降低(P<0.05)。(2)免疫组化结果显示:M组CD147和MMP-2蛋白表达降低,与S组相比有统计学意义(P<0.05); T组上述表达增加,与M组相比有统计学意义(P<0.05)。(3)RT-PCR结果显示:M组CD147和MMP-2 mRNA表达降低,与S组相比有统计学意义(P<0.05);T组上述表达增加,与M组相比有统计学意义(P<0.05)。
结论(1)在阿霉素肾硬化大鼠模型,曲尼司特能够减轻肾组织的病理损害,延缓肾小球硬化的进程;(2)曲尼司特能抑制CD147和MMP2 mRNA及其蛋白质的表达;(3)曲尼司特对肾小球硬化的防治作用可能与其提高CD147的表达从而提高MMP-2的表达有关。
Objective In this experiment, we construct a rat model of Adriamycin-induced glomerulosclerosis and observe the effect of tranilast on the pathology change of kidney and the expression of CD147 and MMP-2 . And also we discusse the mechanism of Adriamycin-induced glomerulosclerosis in rats and provide some evidence for its prospective use in treatment of glomerular fibrosis.
Methods Thirty Sprague-Dawley male rats were randomly divided into sham operation group(S group) and operation group. The operation group rats underwent unilateral nephrectomy of left kidney and intravenous injection of doxorubicin. Then the operation group rats were randomly divided into two groups: model group(M group), tranilast-treated group(T group). T group rats were fed tranilast(400mg/kg/day) and then albuminuria, creatinine, urea nitrogen, were detected. The rats were killed eight weeks later and the right renal tissues were examined by microscope. And the expression of CD147 and MMP-2 was studied by PT-PCR and immunohistochemistry. The intensity was analyaed by imagine quantitative analysis technique.
Results (1)PAS staining of the renal tissue revealed that S group rats had no obvious pathological changes. M group rats tissue mainly revealed that mesangial cells mild to moderate segmental hyperplasia, extracellular matrix significantly increased, focal segmental sclerosis, and that a small portion of the ball sclerosis, capillary cavity collapse of the segmental renal weight / body weight significantly increased(P<0.05), glomerulosclerosis index increased significantly(P<0.05). Compared with M group, T group pathological changes reduced significantly, a few glomerular mesangial cells and stromal mild to moderate segmental increased capillary cavity see only a few mild stenosis, and occasionally focal segmental sclerosis, kidney weight / body weight compared model group decreased(P<0.05), glomerulosclerosis index decreased significantly(P<0.05). (2) Immunohistochemistry showed that group M CD147 and MMP-2 expression decreased, compared with the S group statistically significant(P<0.05), obove expression increased in the T group(P<0.05). (3) RT-PCR showed that in the M group CD147 and MMP-2 mRNA expression, compared with the S group statistically significant(P<0.05), obove expression increased in the T group(P<0.05).
Conclusions (1) In the doxorubicin rat model of renal sclerosis, tranilast can reduce the renal pathological damage and delay the process of glomerulosclerosis. (2)Tranilast can inhibit the expression of CD147 and MMP-2 mRNA and protein. (3) Effects of tranilast on glomerular sclerosis may be related to the preventive effect of increased expression of CD147 to enhance the expression of MMP-2.
引文
1 He C, Zalups RK, Henderson DA, Striker GE, Striker LJ: Molecular analysis of spontaneous glomerulosclerosis in Os/1 mice, a model with reduced nephron mass. Am J Physiol 269: F266–F273, 1995.
2孔令敏,廖成功,张思河,陈志南.CD147和AnnexinII在正常人体组织中的表达分布.现代肿瘤医学,2007,15(4):447-450.
3 oon YW, Kwon HM, Hwang KC, et al. Upstream regulation of matrix metalloproteinase by EMMPRIN; extracellular matrix metalloproteinase inducer in advanced atherosclerotic plaque. Atherosclerosis, 2005,180:37-44.
4 Biswas C, Zhang Y, DeCastro R, et al. The human tumor cell-derived collagenase stimulatory factor (renamed EMMPRIN) is a member of the immunoglobulin superfamily. Cancer Res, 1995,55:434-9.
5 Biswas Shigeki S, Murakami T, Yata N et al. Treatment of keloid and hypertrophic scars by iontophoretic transdermal delivery of tranilast. Scand J Plast Reconstr Surg Hand Surg 1997; 31: 151–158.
6 Mifsud S, Kelly, Qi W et al. Intervention with tranilast attenuates renal pathology and albuminuria in advanced experimental diabetic nephropathy. Nephron 2003; 95: 83–91.
7 Puente XS, Sanchez LM, Overall CM, Lopez-Otin C. Human and mouse proteases: a comparative genomic approach. Nat Rev Genet 2003;4: 544–558.
8 Mott JD,Werb Z. Regulation of matrix biology by matrix metalloproteinases. Curr Opin Cell Biol 2004;16:558–564.
9 Woessner JF Jr: Matrix metalloproteinases and their inhibitors in connective tissue remodeling. FASEB J 5: 2145–2154, 1991
10 Turck J, Pollock AS, Lovett DH: Gelatinase A is a glomerular mesangial cell growth and differentiation factor. Kidney Int 51: 1397–1400, 1997
11 Giannelli G, Falk-Marzillier J, Schiraldi O, Stetler-Stevenson WG, Quaranta V: Induction of cell migration by matrix metalloprotease-2 cleavage of laminin-5. Science 277: 225–228, 1997
12 Akiyama K,Shikata K,Suglmoto H,et a1. Changes in sertlln Concentrations of matrixmetalloproteinases, tissue inhibitors of metalloproteinases and typeⅣcollagen inpatients with Various types of glomerulonephrltis. Res Commun Mol Pathol Pharma 2 col, 1997, 95( 2 ):15.
13 Vincenti MP. The matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) genes. Transcriptional and posttranscriptional regulation, signal transduction and cell-type-specific expression. Methods Mol Biol, 2001, 151: 121-48.
14 Riethdorf S, Reimers N, Assmann V, et al. High incidence of EMMPRIN expression in human tumors. Int J Cancer, 2006,119:1800-10.
15 Sun J, Hemler ME. Regulation of MMP-1 and MMP-2 production through CD147/extracellular matrix metalloproteinase inducer interactions. Cancer Res, 2001, 61:2276-81.
16 Major TC, Liang L, Lu X, et al. Extracellular matrix metalloproteinase inducer (EMMPRIN) is induced upon monocyte differentiation and is expressed in human atheroma. Arterioscler Thromb Vasc Biol, 2002,22:1200-7.
17 Lim M, Martinez T, Jablous D, et al. Tumor-derived EMMPRIN stimulates collagenase transcription through MAKP p38[J]. FEBS Lett, 1988, 441(1):88
18 Portik Dobosv, Anstadtm P, Hutchnson J, et al. Evidence for matrix metallo-proteinase induction/activation system in arteral vasculature and decreased synthesis and activity in diabetes[J]. Diabetes, 2002, 51(10): 3063-3068.
19 Tang Y, Kesavan P, Nakada M T, et al. Tumor-stroma interaction: positive feedback regulation of extracellular matrix metalloproteinase inducer(EMMPRIN) expression and matrix metalloteinase dependent generation of soluble EMMPRIN[J]. MolCancer Res, 2004,2:73.
20 Hibi H, Katok, et al. The treatment with tranilast a mast cell blocker for idiopatic diagozoospermia[J]. Arch Androl, 2001,47(2): 107-111.
21 Nogechi, Natsugo, Kawashiri, et al. Effect of fibroblast growth inhibitor on proliferation and metastasis of oral squamous cell carcinoma[J]. Oral Oncology,2003,66(7): 1263-1270.
22 Doggrell, Sheila A, Wanstal Jan, et al. Vascular hymase: pathophysiological and therapeutic potential of inhabitin[J]. Cardiovascular Research, 2004, 61(4):653-662.
23 Asachi S, Maruyama T, Kondo T, et al. The prevention of postoperative intra- peritoneal adhesions by tranilast. Surg Today, 1999,29(1):51-54.
24 Furuichi H, Yamashita K,Okada M, et al. Identification of tranilast-binding protein as 36-kDa microfibrin-associated glycoprotein by drug affinity chromatography, and its localization in human skin[J]. Biochem Biophys Res Commum, 2000, 270(3):1002-1008.
25 Tosh iyuk i M atsumura, Kiyotaka Kugiyama, Seigo Sugiyama, et al. Supp ression of atherosclerotic development in W atanabe heritable hyperlip idemic rabbits treated w ith an oral antiallergic drug, tranilast. Circulation, 1999, 99 (7) : 919
26 Hocher B, Godes M, Olivier J, et al. Inhibition of left ventricular fibrosis by tranilast in rats with renovascular hypertension. J Hypertens, 2002,20:745-51.
27 Miyajima A, Asano T, Asano T, et al. Tranilast ameliorates renal tubular damage in unilateral ureteral obstruction. J Urol, 2001,165:1714-8.
28 Chikaraishi A, Hirahashi J, Takase O, et al. Tranilast inhibits interleukin- 1beta- induced monocyte chemoattractant protein-1 expression in rat mesangial cells. Eur J Pharmacol, 2001,427:151-8.
29 Hishikawa K, Nakaki T, Hirahashi J, et al. Tranilast inhibits the effects of platelet- derived growth factor on cell proliferation and induction of nitric oxide. Eur J Pharmacol, 1995,291:435-8.
30 Ikeda M, Ikeda U, Shimada K, et al. Tranilast inhibits the growth of rat mesangial cells. Eur J Pharmacol, 1997,324:283-7.
31 Mifsud S, Kelly DJ, Qi W, et al. Intervention with tranilast attenuates renal pathology and albuminuria in advanced experimental diabetic nephropathy. Nephron Physiol, 2003,95:p83-91.
32 Jones S,Gilbert R,Kelly D.Tranilast reduces mesenteric vascular collagen deposition and chymase-positive cells in experimenal diabetes. Diabetes Complications, 2004, 18(5): 309- 315.
33 Akahori H, Ota T, Torita M, et al. Tranilast prevents the progression of experimental diabetic nephropathy through suppression of enhanced extracellular matrix gene expression J Phamacol Exp Ther, 2005, 314(2): 514-521.
34 Kelly DJ, Zhang Y, Gow R et al. Tranilast attenuates structural and functional aspects of renal injury in the remnant kidney model. J Am Soc Nephrol 2004; 15: 2619–2629.
5 Hibi H, Katok, et al. The treatment with tranilast a mast cell blocker for idiopatic diagozoospermia[J]. Arch Androl, 2001,47(2): 107-111.
6 Nogechi, Natsugo, Kawashiri, et al. Effect of fibroblast growth inhibitor on proliferation and metastasis of oral squamous cell carcinoma[J]. Oral Oncology, 2003, 66(7): 1263-1270.
5 Doggrell, Sheila A, Wanstal Jan, et al. Vascular hymase: pathophysiological and therapeutic potential of inhabitin[J]. Cardiovascular Research, 2004, 61(4):653-662.
4 Asachi S, Maruyama T, Kondo T, et al. The prevention of postoperative intra-peritoneal adhesions by tranilast. Surg Today, 1999,29(1):51-54.
5 Miyajima A, Asano T, Asano T, et al. Tranilast ameliorates renal tubular damage in unilateral ureteral obstruction. J Urol, 2001,165:1714-8.
6 Ward, M. R. Sasahara, T, Agrotis, A. et al: Inhibitory effects of tranilast on expression of transforming growth factor-βisoforms and receptors in injured arteries. Atheroserosis, 1998, 137: 267
7 Chikaraishi A, Hirahashi J, Takase O, et al. Tranilast inhibits interleukin-1beta-induced monocyte chemoattractant protein-1 expression in rat mesangial cells. Eur J Pharmacol, 2001,427:151-8.
8 Hishikawa K, Nakaki T, Hirahashi J, et al. Tranilast inhibits the effects of platelet-derived growth factor on cell proliferation and induction of nitric oxide. Eur J Pharmacol, 1995,291:435-8.
9 Ikeda M, Ikeda U, Shimada K, et al. Tranilast inhibits the growth of rat mesangial cells. Eur J Pharmacol, 1997,324:283-7.
10 Mifsud S, Kelly DJ, Qi W, et al. Intervention with tranilast attenuates renal pathology and albuminuria in advanced experimental diabetic nephropathy. Nephron Physiol, 2003,95:p83-91.
11 Jones S,Gilbert R,Kelly D.Tranilast reduces mesenteric vascular collagen deposition and chymase-positive cells in experimenal diabetes. Diabetes Complications, 2004, 18(5): 309- 315.
12 Akahori H, Ota T, Torita M, et al. Tranilast prevents the progression of experimental diabetic nephropathy through suppression of enhanced extracellular matrix gene expression J Phamacol Exp Ther, 2005, 314(2): 514-521.
13 Jun Soma, Kozo Sato, Harutaka Saito, et al. Effect of tranilast in early-stage diabetic nephropathy. Nephrol Dial Transplant, 2006,21:2795-2799.
14 Qi W, Chen X, Twigg S,et al. Tranilast attenuates connective tissue growth factor- induced extracellular matrix accumulation in renal cells. Kidney Int. 2006, 69(6): 989- 995.
15 Kelly DJ, Zhang Y, Gow R, Gilbert RE.Tranilast attenuates structural and functional aspects of renal injury in the remnant kidney model. J Am Soc Nephrol. 2004,15 (10): 2619-2629.
16 Caiying G, Haisong J, Debbie L, et al. A novel vascular smooth muscle chymase is upregulated in hypertensive rats J. J Clin Incest, 2001,107:703-715.
17 Ju H, Gros R, You X, et al. Conditional and targeted overexpression of vascular chymase causes hypertention in trasgenic mice[J]. Proc Natl Acad Sci USA, 2001, 98(18): 7469.
18 Best P.J.M./Berger P.B./Davis B.R.et al. Impact of mild or moderate chronic kidney disease on the frequency of restenosis: Results from the PRESTO trial. AM. COLL. CARDIOL. 2004, 44(9): 1786-1791.
19 Min-Ji Chang, Chieh-His Wu. Transcriptional activation of p21 by Tranilast is mediated via transforming growth factor beta signal pathway. 2006,147:117-124
20陈世金,冯胜刚.周期素激酶抑制剂p21和糖尿病肾病. 2007,19(1): 133-135.
21 Tufro A, Teichman J, Banu N, et al. Crosstalk between VEGF-A/VEGFR2 and GDNF/RET signaling pathways Biochem Biophys Res Commun,2007,358(2): 410-416.
22 Isaji M,Miyata H, Ajisawa Y, et al. Inhibition by tranilast of vascular endothelial growth factor(VEGF)/ vascular permeability factor(VPF)-induced increase in vascular permeability in rats. 1998, 63(4): 71-74.
23代红,袁发焕.肥大细胞与肾纤维化[J].重庆医学,2004,33(1): 130
24 Jones SE, Kelly DJ, Cox AJ, et al. Mast cell infiltration and chemokine expression in progressive renal diease[J]. Kidney Int,2003,64(3):906
2孔令敏,廖成功,张思河,陈志南.CD147和AnnexinII在正常人体组织中的表达分布.现代肿瘤医学,2007,15(4):447-450.
3 oon YW, Kwon HM, Hwang KC, et al. Upstream regulation of matrix metalloproteinase by EMMPRIN; extracellular matrix metalloproteinase inducer in advanced atherosclerotic plaque. Atherosclerosis, 2005,180:37-44.
4 Biswas C, Zhang Y, DeCastro R, et al. The human tumor cell-derived collagenase stimulatory factor (renamed EMMPRIN) is a member of the immunoglobulin superfamily. Cancer Res, 1995,55:434-9.
5 Biswas Shigeki S, Murakami T, Yata N et al. Treatment of keloid and hypertrophic scars by iontophoretic transdermal delivery of tranilast. Scand J Plast Reconstr Surg Hand Surg 1997; 31: 151–158.
6 Mifsud S, Kelly, Qi W et al. Intervention with tranilast attenuates renal pathology and albuminuria in advanced experimental diabetic nephropathy. Nephron 2003; 95: 83–91.
7 Puente XS, Sanchez LM, Overall CM, Lopez-Otin C. Human and mouse proteases: a comparative genomic approach. Nat Rev Genet 2003;4: 544–558.
8 Mott JD,Werb Z. Regulation of matrix biology by matrix metalloproteinases. Curr Opin Cell Biol 2004;16:558–564.
9 Woessner JF Jr: Matrix metalloproteinases and their inhibitors in connective tissue remodeling. FASEB J 5: 2145–2154, 1991
10 Turck J, Pollock AS, Lovett DH: Gelatinase A is a glomerular mesangial cell growth and differentiation factor. Kidney Int 51: 1397–1400, 1997
11 Giannelli G, Falk-Marzillier J, Schiraldi O, Stetler-Stevenson WG, Quaranta V: Induction of cell migration by matrix metalloprotease-2 cleavage of laminin-5. Science 277: 225–228, 1997
12 Akiyama K,Shikata K,Suglmoto H,et a1. Changes in sertlln Concentrations of matrixmetalloproteinases, tissue inhibitors of metalloproteinases and typeⅣcollagen inpatients with Various types of glomerulonephrltis. Res Commun Mol Pathol Pharma 2 col, 1997, 95( 2 ):15.
13 Vincenti MP. The matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) genes. Transcriptional and posttranscriptional regulation, signal transduction and cell-type-specific expression. Methods Mol Biol, 2001, 151: 121-48.
14 Riethdorf S, Reimers N, Assmann V, et al. High incidence of EMMPRIN expression in human tumors. Int J Cancer, 2006,119:1800-10.
15 Sun J, Hemler ME. Regulation of MMP-1 and MMP-2 production through CD147/extracellular matrix metalloproteinase inducer interactions. Cancer Res, 2001, 61:2276-81.
16 Major TC, Liang L, Lu X, et al. Extracellular matrix metalloproteinase inducer (EMMPRIN) is induced upon monocyte differentiation and is expressed in human atheroma. Arterioscler Thromb Vasc Biol, 2002,22:1200-7.
17 Lim M, Martinez T, Jablous D, et al. Tumor-derived EMMPRIN stimulates collagenase transcription through MAKP p38[J]. FEBS Lett, 1988, 441(1):88
18 Portik Dobosv, Anstadtm P, Hutchnson J, et al. Evidence for matrix metallo-proteinase induction/activation system in arteral vasculature and decreased synthesis and activity in diabetes[J]. Diabetes, 2002, 51(10): 3063-3068.
19 Tang Y, Kesavan P, Nakada M T, et al. Tumor-stroma interaction: positive feedback regulation of extracellular matrix metalloproteinase inducer(EMMPRIN) expression and matrix metalloteinase dependent generation of soluble EMMPRIN[J]. MolCancer Res, 2004,2:73.
20 Hibi H, Katok, et al. The treatment with tranilast a mast cell blocker for idiopatic diagozoospermia[J]. Arch Androl, 2001,47(2): 107-111.
21 Nogechi, Natsugo, Kawashiri, et al. Effect of fibroblast growth inhibitor on proliferation and metastasis of oral squamous cell carcinoma[J]. Oral Oncology,2003,66(7): 1263-1270.
22 Doggrell, Sheila A, Wanstal Jan, et al. Vascular hymase: pathophysiological and therapeutic potential of inhabitin[J]. Cardiovascular Research, 2004, 61(4):653-662.
23 Asachi S, Maruyama T, Kondo T, et al. The prevention of postoperative intra- peritoneal adhesions by tranilast. Surg Today, 1999,29(1):51-54.
24 Furuichi H, Yamashita K,Okada M, et al. Identification of tranilast-binding protein as 36-kDa microfibrin-associated glycoprotein by drug affinity chromatography, and its localization in human skin[J]. Biochem Biophys Res Commum, 2000, 270(3):1002-1008.
25 Tosh iyuk i M atsumura, Kiyotaka Kugiyama, Seigo Sugiyama, et al. Supp ression of atherosclerotic development in W atanabe heritable hyperlip idemic rabbits treated w ith an oral antiallergic drug, tranilast. Circulation, 1999, 99 (7) : 919
26 Hocher B, Godes M, Olivier J, et al. Inhibition of left ventricular fibrosis by tranilast in rats with renovascular hypertension. J Hypertens, 2002,20:745-51.
27 Miyajima A, Asano T, Asano T, et al. Tranilast ameliorates renal tubular damage in unilateral ureteral obstruction. J Urol, 2001,165:1714-8.
28 Chikaraishi A, Hirahashi J, Takase O, et al. Tranilast inhibits interleukin- 1beta- induced monocyte chemoattractant protein-1 expression in rat mesangial cells. Eur J Pharmacol, 2001,427:151-8.
29 Hishikawa K, Nakaki T, Hirahashi J, et al. Tranilast inhibits the effects of platelet- derived growth factor on cell proliferation and induction of nitric oxide. Eur J Pharmacol, 1995,291:435-8.
30 Ikeda M, Ikeda U, Shimada K, et al. Tranilast inhibits the growth of rat mesangial cells. Eur J Pharmacol, 1997,324:283-7.
31 Mifsud S, Kelly DJ, Qi W, et al. Intervention with tranilast attenuates renal pathology and albuminuria in advanced experimental diabetic nephropathy. Nephron Physiol, 2003,95:p83-91.
32 Jones S,Gilbert R,Kelly D.Tranilast reduces mesenteric vascular collagen deposition and chymase-positive cells in experimenal diabetes. Diabetes Complications, 2004, 18(5): 309- 315.
33 Akahori H, Ota T, Torita M, et al. Tranilast prevents the progression of experimental diabetic nephropathy through suppression of enhanced extracellular matrix gene expression J Phamacol Exp Ther, 2005, 314(2): 514-521.
34 Kelly DJ, Zhang Y, Gow R et al. Tranilast attenuates structural and functional aspects of renal injury in the remnant kidney model. J Am Soc Nephrol 2004; 15: 2619–2629.
5 Hibi H, Katok, et al. The treatment with tranilast a mast cell blocker for idiopatic diagozoospermia[J]. Arch Androl, 2001,47(2): 107-111.
6 Nogechi, Natsugo, Kawashiri, et al. Effect of fibroblast growth inhibitor on proliferation and metastasis of oral squamous cell carcinoma[J]. Oral Oncology, 2003, 66(7): 1263-1270.
5 Doggrell, Sheila A, Wanstal Jan, et al. Vascular hymase: pathophysiological and therapeutic potential of inhabitin[J]. Cardiovascular Research, 2004, 61(4):653-662.
4 Asachi S, Maruyama T, Kondo T, et al. The prevention of postoperative intra-peritoneal adhesions by tranilast. Surg Today, 1999,29(1):51-54.
5 Miyajima A, Asano T, Asano T, et al. Tranilast ameliorates renal tubular damage in unilateral ureteral obstruction. J Urol, 2001,165:1714-8.
6 Ward, M. R. Sasahara, T, Agrotis, A. et al: Inhibitory effects of tranilast on expression of transforming growth factor-βisoforms and receptors in injured arteries. Atheroserosis, 1998, 137: 267
7 Chikaraishi A, Hirahashi J, Takase O, et al. Tranilast inhibits interleukin-1beta-induced monocyte chemoattractant protein-1 expression in rat mesangial cells. Eur J Pharmacol, 2001,427:151-8.
8 Hishikawa K, Nakaki T, Hirahashi J, et al. Tranilast inhibits the effects of platelet-derived growth factor on cell proliferation and induction of nitric oxide. Eur J Pharmacol, 1995,291:435-8.
9 Ikeda M, Ikeda U, Shimada K, et al. Tranilast inhibits the growth of rat mesangial cells. Eur J Pharmacol, 1997,324:283-7.
10 Mifsud S, Kelly DJ, Qi W, et al. Intervention with tranilast attenuates renal pathology and albuminuria in advanced experimental diabetic nephropathy. Nephron Physiol, 2003,95:p83-91.
11 Jones S,Gilbert R,Kelly D.Tranilast reduces mesenteric vascular collagen deposition and chymase-positive cells in experimenal diabetes. Diabetes Complications, 2004, 18(5): 309- 315.
12 Akahori H, Ota T, Torita M, et al. Tranilast prevents the progression of experimental diabetic nephropathy through suppression of enhanced extracellular matrix gene expression J Phamacol Exp Ther, 2005, 314(2): 514-521.
13 Jun Soma, Kozo Sato, Harutaka Saito, et al. Effect of tranilast in early-stage diabetic nephropathy. Nephrol Dial Transplant, 2006,21:2795-2799.
14 Qi W, Chen X, Twigg S,et al. Tranilast attenuates connective tissue growth factor- induced extracellular matrix accumulation in renal cells. Kidney Int. 2006, 69(6): 989- 995.
15 Kelly DJ, Zhang Y, Gow R, Gilbert RE.Tranilast attenuates structural and functional aspects of renal injury in the remnant kidney model. J Am Soc Nephrol. 2004,15 (10): 2619-2629.
16 Caiying G, Haisong J, Debbie L, et al. A novel vascular smooth muscle chymase is upregulated in hypertensive rats J. J Clin Incest, 2001,107:703-715.
17 Ju H, Gros R, You X, et al. Conditional and targeted overexpression of vascular chymase causes hypertention in trasgenic mice[J]. Proc Natl Acad Sci USA, 2001, 98(18): 7469.
18 Best P.J.M./Berger P.B./Davis B.R.et al. Impact of mild or moderate chronic kidney disease on the frequency of restenosis: Results from the PRESTO trial. AM. COLL. CARDIOL. 2004, 44(9): 1786-1791.
19 Min-Ji Chang, Chieh-His Wu. Transcriptional activation of p21 by Tranilast is mediated via transforming growth factor beta signal pathway. 2006,147:117-124
20陈世金,冯胜刚.周期素激酶抑制剂p21和糖尿病肾病. 2007,19(1): 133-135.
21 Tufro A, Teichman J, Banu N, et al. Crosstalk between VEGF-A/VEGFR2 and GDNF/RET signaling pathways Biochem Biophys Res Commun,2007,358(2): 410-416.
22 Isaji M,Miyata H, Ajisawa Y, et al. Inhibition by tranilast of vascular endothelial growth factor(VEGF)/ vascular permeability factor(VPF)-induced increase in vascular permeability in rats. 1998, 63(4): 71-74.
23代红,袁发焕.肥大细胞与肾纤维化[J].重庆医学,2004,33(1): 130
24 Jones SE, Kelly DJ, Cox AJ, et al. Mast cell infiltration and chemokine expression in progressive renal diease[J]. Kidney Int,2003,64(3):906