移植肾组织中TGF-_（β1）、MMP-2及TIMP-1的表达及其与肾纤维化的关系
摘要
目的:研究转化生长因子TGF-β1和基质金属蛋白酶MMP-2及其抑制剂TIMP-1在不同程度肾纤维化组织中的表达,探讨肾纤维化发生、进展的分子病理学机制及在治疗中的指导意义。方法:对21例肾移植后,因移植肾功能进行性减退,再次行移植肾切除手术,切除的移植肾标本及10例正常肾组织进行HE染色,根据移植肾纤维化程度和Banff病理标准进行分期和TGF-β1、MMP-2、TIMP-1蛋白免疫组化染色,对免疫组化染色结果,应用体视学技术作图像定量分析;同时检测患者血肌酐(Cr)和尿素氮(BUN)的水平;并分析TGF-β1、MMP-2、TIMP-1蛋白表达和血肌酐(Cr)和尿素氮(BUN)的水平与移植肾纤维化程度的关系。结果:在轻度肾间质纤维化(1期),肾组织中TGF-β1、MMP-2、TIMP-1免疫染色阳性强度均较正常肾组织(0期)明显增加;随着纤维化进展(2期、3期),TGF-β1、TIMP-1阳性表达强度逐渐增加,纤维化各期与正常组之间差异有统计学意义ρ＜0.01;MMP-2蛋白表达随着移植肾纤维化程度加重而逐渐降低,纤维化各期与正常组之间及纤维化1期与2、3期之间,差异有统计学意义ρ＜0.01:TGF-β1、TIMP-1二者在纤维化肾组织中的表达呈正相关性。MMP-2、TIMP-1二者在纤维化肾组织中的表达呈负相关性。随着移植肾纤维化程度的加重,血清肌酐(Cr)和尿素氮(BUN)的平均水平逐渐升高。结论:TGF-β1、MMP-2、TIMP-1参与了肾纤维化的发生、发展,提示TGF-β1表达量增高及TIMP-1的活性增加可能是促进细胞外基质积聚形成纤维化的重要条件,而MMP-2则抑制其进展。检测三者的表达与血清肌酐(Cr)和尿素氮(BUN)水平,可以做为临床判断肾纤维化程度的辅助指标。
Objective:To dectect the protein expression of TGF-β1,MMP-2 and TIMP-1 and to study the molecular pathological mechanism of renal fibrosis and its significance for treament in the Chronic allograft nephropathy(CAN) with fibrosis.Methods:21 cases kidney specimens were collected from patients with CAN and 10 normal kidney specimens of non-nephropathy patients.HE and immunohistochemical staining were performed to detect pathological stage according to Banff pathological standard for renal fibrosis and protain expression of TGF-β1,MMP-2 and TIMP-1.An image quantitative assessment was carried out by stereological to analysis expression of TGF-β1,MMP-2 and TIMP-1.At the same time serum creatinine(Cr) and urea nitrogen(BUN) were detected.. Results:In the early staging of renal fibrosis(1 stage) positive expression of TGF-β1、MMP-2、TIMP-1 were revealed stronger than normal kidney tiassues(0 stage).With renal fibrosis increasing,expression of TGF-β1 and TIMP-1 protain were revealed a increasing gradually positive staining,and there are significant difference between the fibrosis groups and normal one(p＜0.01).Positive staining of MMP-2 was gradual weak and low even negative.There are significant difference between fibrosis groups and normal one for MMP-2 expression(p＜0.01).It showed that there was positive correlation between expression of TGF-β1 and TIMP-1 and negative correlation between expression MMP-2 and TIMP-1 and no correlation between TGF-β1 and MMP-2.With renal fibrosis progressing,the level of serum creatinine(Cr) and urea nitrogen(BUN) were higher by degree.Conclusions:It suggested that TGF-β1,MMP-2 and TIMP-1 maybe participated in the genesis and development of renal fibrosis.Higher bioactivity of TGF-β1、TIMP-1 may be important factors in renal fibrosis,and function of MMP-2 was reverse to TGF-β1、TIMP-1.It is valuable o detect TGF-β1、MMP-2、TIMP-1 and the level of serum creatinine(Cr) and urea nitrogen(BUN) for judgement stage of renal fibrosis
Objective:To dectect the protein expression of TGF-β1,MMP-2 and TIMP-1 and to study the molecular pathological mechanism of renal fibrosis and its significance for treament in the Chronic allograft nephropathy(CAN) with fibrosis.Methods:21 cases kidney specimens were collected from patients with CAN and 10 normal kidney specimens of non-nephropathy patients.HE and immunohistochemical staining were performed to detect pathological stage according to Banff pathological standard for renal fibrosis and protain expression of TGF-β1,MMP-2 and TIMP-1.An image quantitative assessment was carried out by stereological to analysis expression of TGF-β1,MMP-2 and TIMP-1.At the same time serum creatinine(Cr) and urea nitrogen(BUN) were detected.. Results:In the early staging of renal fibrosis(1 stage) positive expression of TGF-β1、MMP-2、TIMP-1 were revealed stronger than normal kidney tiassues(0 stage).With renal fibrosis increasing,expression of TGF-β1 and TIMP-1 protain were revealed a increasing gradually positive staining,and there are significant difference between the fibrosis groups and normal one(p＜0.01).Positive staining of MMP-2 was gradual weak and low even negative.There are significant difference between fibrosis groups and normal one for MMP-2 expression(p＜0.01).It showed that there was positive correlation between expression of TGF-β1 and TIMP-1 and negative correlation between expression MMP-2 and TIMP-1 and no correlation between TGF-β1 and MMP-2.With renal fibrosis progressing,the level of serum creatinine(Cr) and urea nitrogen(BUN) were higher by degree.Conclusions:It suggested that TGF-β1,MMP-2 and TIMP-1 maybe participated in the genesis and development of renal fibrosis.Higher bioactivity of TGF-β1、TIMP-1 may be important factors in renal fibrosis,and function of MMP-2 was reverse to TGF-β1、TIMP-1.It is valuable o detect TGF-β1、MMP-2、TIMP-1 and the level of serum creatinine(Cr) and urea nitrogen(BUN) for judgement stage of renal fibrosis
引文
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[1]Paul LC.Chronic allograft nephropathy-amodel of impaired repair from injury[J].Nephrol Dial Transplant,2000,15:149.
[2]Womer KL,Vella JP,Sayegh MH.Chronic allograft dysfunction;mechanisms and new approaches to therapy[J].semin Nephrol,2000,20:126.
[3]Racusen LC,Solez K,Colvin RB,et al.The Banff97 working classification of renal allograft pathology[J].Kidney int,1999,55(2):713-723.
[4]王平贤,肖亚,张昆甫,等.减少神经钙蛋白阻滞剂对CAN影响的临床研究[J].医学临床研究,2004,21(7):709-711.
[5]姚丽娜,李红,刘章锁.结缔组织生长因子与肾纤维化的研究进展[J].国外医学移植与血液净化分册,2005,3(1):16-19.
[6]Liu Youhua.Renal fibrosis:New insights into the pathogenesis and therapiutics[J].Kidney International,2006,69:213-217.
[7]许良中主编.实用肿瘤病理方法学[M].上海:上海医科大学出版社,1997:562-566.
[8]Cubaci B,Kumar MS,Bloom RD,et al.Transforming growth factor betalevels in human allograft chronic fibrosis correlate with rate of decline in renal function[J].Transplantation,1999,68(6):785.
[9]Nabas AM,Muchaneta Kubara EC,Essawy M,et al.Renal fibrosis:insights into pathogenesis and treatment[J].Int J Biochem Cell BioL,1997,29(1):55-62.
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[13]Ishimura T,Fujisawa M,Isotani S,et al.Transforming growth factor betal expression in early biopsy specimen predicts long-term graft function following pediatric renal transplantation[J].Clin Transplant,2001,15(3):185.
[14]Schnaper HW,Hayashida J,Hubchak SC,et al.TGF-beta signal transduct and mesangial cell fibrosis[J].Am J Physiol Renal Physiol 2003,284:F243-F252.
[15]Liu Y.Epithelial to mesenecrymal transition renal fibrogenesis:Pathologic significance of molecular mechanism and therapeutic intervention[J].J Am Soc Nephrol 2004,15:1-12.
[16]Okada H,Kikata T,Kobayashi T,et al.Connective tissue growth factor ecpressed in tubula epithelium play pivotal role in renal fibrogenesis[J].Jam Soc NEPHROL,2002,16:133-143.
[17]Boratynska M.Urine excretion of transforming growth factor betal in chronic allograft nephropathy[J].Ann Transplant,1999,4(2):23.
[18]Baboolal K,Jones GA,Janezic A,et al.Molecular and structural consequences of early renal allograft injury[J].Kidney Int,2002,61(2):686.
[19]Eikmans M,Sijpke YW,Baelde HJ,et al.High transforming growth factor-β and extracellular matrix mRNA response in renal allograft during early acute rejection is associated with absence of chronic rejection[J].Transplantation,2002,73(4):573.
[20]王俊,郭继华,孟伟,等.慢性移植肾病TGF-β1、MMP-2表达及Ⅳ型胶原沉积与慢性移植肾肾病的关系[J].中华器官移植杂志,2006,27(8):478-480.
[21]郭继华,王俊,孟伟,等.慢性肾移植肾病纤维化发展临床病理观察[J].临床肾脏病杂志,2007,7(3):110-111.
[22]Huang,HC LZ JZ,Wang HY.connective tissue growth factor induces Transformation of renal fibroblact into myofibroblact[J].Sci Bulletin,2002,47:38-40.
[23]Nagase H,Woessner JF.Matrix metalloproteinases[J].J Biol Chem,1999,21:491.
[24]Ye S,Humphries S,Henney A.Matrix metalloproteinases:implication in vascular matrix remodeling during atherogenesis[J].Clin Sci,1998,94:103.
[25]Sato H,Takino T,Okado Y,et al.A matrix metalloproteinase expressed on the surface of invasive tumor cells[J].Nature,1994,370:61.
[26]Peters CA,Freeman MR,Fernandez CA,et al.Dysregulated proteolytic balance as the basis of excess extracellular matrix in fibrotic disease[J].Am J Physiol,1997,272(6pt2):R1960-1965.
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[31]Bode W,Fernandez-Catalan C.Tschesche H.Structural properties of matrix metalloproteinases[J].cell Mol life Sci,1999,55:639-652.
[32]Mach F,Schonbeck U,Fabunmi RP,et al.Tlymphocyten induce endothelial cell matrix metalloproteinase expression by a CD40L-dependent mechanism,implication for rubule formation[J].Am J Pathol,1999,154(1):229-38.
[33]Collen A,Hanemanijer R,Lupu F,et al.Membrane-type matrix metalloproteinase mediated angiogenesis in a fibin-callagen matrix[J].Blood,2003,101(5):1810-1817.
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[35]Backer AH,Zaltsman AB,George SJ,et al.Divergent effects of tissue inhibitor of metalloproteinase-1,-2,or-3 overexpression on rat vascular smooth muscle cell invasion,proliferation and death in vitro[J].J Clin invest,1998,101(6):1478-1487.
[36]Greene J,Wang M,Lin YE,et al.Molecular cloning and characterization of human tissue inhibitor of metalloproteinases 4[J].J Biol Chem,1996,271(48):30375-30380.
[37]Bicknell GR,Williams ST,Shaw JA,et al.Differential effects of cyclosporin and tacrolimus on the expression of fibrosis associated genes in isolated glomeruli from renal transplants[J].Br J Surg,2000,87(11):1569.
[38]Gomez DE,Alonso DF,Yoshiji H.Tissue inhibitors of metalloproteinases:structure,regulation and biological functions[J].Eur J Cell Biol,1997,74:111-122.
[39]Bigg HF,Morrison CJ,Butler CS,et al.Tissue inhibitor of metalloproteinases-4 inhibits but does not support the activation of gelatinase A via efficient inhibition of membrane type 1-matrix metalloproteinase[J].Cancer Res,2001,61(9):3610.
[40]RIES C,PETRIDES PE.Cytokine regulation of matrix metalloproteinase activity and its regulatory dysfunction in disease[J].Biol Chem Hoppe Seyler,1995,376(6):345-355.
[41]汤询,袁发焕.金属蛋白酶组织抑制因子-1、基质金属蛋白酶-9的表达与肾纤维化的关系[J].中国现代医学杂志,2002,12(2):13-15.
[42]Lewis MP,Norman JT.Differential response of activated versus non- activated renal fibroblasts to tubular epithelial cells:a model of initiation and progeression of fibrosis [J].Exp Nepbrol,1998,6(2):132-143.
[43]Lewis MP,Fine LG,Norman JT,et al.Pexicrine effects of basement membrane components on paracrine signaling by renal tubular cells[J].Kidney Int,1996,49(1): 48-58.
[44] Anderson SS,Wu K,Nagase H,et al.Effect of matrix glycation on expression of type IV collagen,MMP-2,MMP-9 and TIMP-1 by human mesangtal cell[J].Cell Adhes Commun,1996,4(2):89-101.
[45] Morales JM ,And res A,Rengel M ,et al . Influence of cyclosporin,tacrolimus and rapamycin on renal function and arterial hypertension after renal transplantation[J].Nephrol Dial Transplant,2001,16(1):121-124.
[46]Abdel WN,Weston BS,Roberts T,et al. Connective tissue growth factor and regulation of the mesangial cell cycle role in cellular hypertrophy[J]. J Am Soc Nephrol, 2003(10):2437-2445.
[2]Womer KL,Vella JP,Sayegh MH.Chronic allograft dysfunction;mechanisms and new approaches to therapy[J].semin Nephrol,2000,20:126.
[3]Racusen LC,Solez K,Colvin RB,et al.The Banff97 working classification of renal allograft pathology[J].Kidney int,1999,55(2):713-723.
[4]姚丽娜,李红,刘章锁.结缔组织生长因子与肾纤维化的研究进展[J].国外医学移植与血液净化分册,2005,3(1):16-19.
[5]Liu Youhua.Renal fibrosis:New insights into the pathogenesis and therapiutics[J].Kidney International,2006,69:213-217.
[6]许良中主编.实用肿瘤病理方法学[M].上海:上海医科大学出版社,1997:562-566.
[7]Cubaci B,Kumar MS,Bloom RD,et al.Transforming growth factor beta levels in human allograft chronic fibrosis correlate with rate of decline in renal function[J].Transplantation,1999,68(6):785.
[8]陈琛,叶冬梅.转化生长因子-β/Smad信号通路的研究进展[J].医学分子生物学杂志,2006,3(2):126-128.
[9]Eddy AA.Molecular basis of renal fibrosis[J].Pediat Nephrol,2001,15:290-301.
[10]Ishimura T,Fujisawa M,Isotani S,et al.Transforming growth factor betal expression in early biopsy specimen predicts long-term graft function following pediatric renal transplantation[J].Clin Transplant,2001,15(3):185.
[11]Schnaper HW,Hayashida J,Hubchak SC,et al.TGF-beta signal transduct and mesangial cell fibrosis[J].Am J Physiol Renal Physiol,2003,284:F243-F252.
[12]Liu Y.Epithelial to mesenecrymal transition renal fibrogenesis:Pathologic significance of molecular mechanism and therapeutic intervention[J].J Am Soc Nephrol,2004,15:1-12.
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