p38MAPK对高糖诱导肾小球系膜细胞MMP-2/TIMP-2及Ⅳ型胶原表达的影响
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摘要
目的糖尿病肾病(diabetic nephropathy, DN)是糖尿病重要的微血管并发症之一,目前20%-30%的糖尿病患者合并肾病,已成为糖尿病主要致死原因。DN的病理学特征包括肾小球系膜区增宽和肾小球基底膜弥漫性增厚,这种变化的组织学基础即是细胞外基质(ECM)积聚。正常情况下,ECM产生和降解的动态平衡处于机体的精确调控下。基质金属蛋白酶(MMPs)及其组织抑制剂(TIMPs)是ECM降解的主要调节因素。高糖通过何种途径调节肾脏中MMPs和TIMPs的表达在国内外的研究中尚不明确。丝裂原活化蛋白激酶(MAPK)信号通路作为直接调节转录因子活性和基因表达的信息传递系统与MMPs及TIMPs表达的关系值得深入探讨。MMPs主要降解底物是ECM的重要成分Ⅳ型胶原,但p38MAPK信号通路在糖尿病肾病发生中的作用与Ⅳ型胶原的关系尚无定论。本研究通过观察高糖刺激下SD大鼠肾小球系膜细胞p38MAPK、MMP-2/TIMP-2、Ⅳ型胶原mRAN及蛋白表达的变化和MMP-2/TIMP-2比值的改变,以及使用特异性抑制剂SB203580干预后它们的改变,明确糖尿病肾病时MMP-2/TIMP-2及Ⅳ型胶原的表达变化,探讨p38MAPK信号通路是否参与高糖诱导的肾小球系膜细胞MMP-2/TIMP-2及Ⅳ型胶原的表达变化的调节。
方法将培养的SD大鼠肾小球系膜细胞分为6组：(1)正常对照组：5.6mmol/L的葡萄糖；(2)高糖A组：10 mmol/L的葡萄糖；(3)高糖B组：20 mmol/L的葡萄糖；(4)高糖C组：30 mmol/L的葡萄糖；(5)SB203580组：30 mmol/L的葡萄糖+10μmol/L SB203580; (6)甘露醇组：5.6mmol/L的葡萄糖+24.4mmol/L的甘露醇。待细胞生长状况良好,细胞生长至90%左右密度后,同步化24小时,分别用以上各因素处理细胞并继续培养,于培养48小时后收集细胞,提取总mRNA,逆转录成cDNA,采用实时荧光定量PCR法检测各组肾小球系膜细胞p38MAPK、MMP-2、TIMP-2及Ⅳ型胶原mRNA表达；提取总蛋白,采用Western-blot法检测MMP-2、TIMP-2及Ⅳ型胶原的蛋白表达。
结果(1)正常条件下系膜细胞p38MAPK、MMP-2、TIMP-2及Ⅳ型胶原在mRNA水平上均有表达,MMP-2、TIMP-2及Ⅳ型胶原在蛋白水平上均有表达；(2)高糖组和甘露醇组p38MAPKmRNA的表达均高于正常组,但高糖组p38MAPKmRNA的表达增加更明显,且当葡萄糖浓度由10mmol/L增加到20mmol/L及30mmol/L时,p38MAPKmRNA的表达也逐渐增加；(3)高糖组和甘露醇组TIMP-2 mRNA和蛋白的表达较正常组增高,而MMP-2 mRNA和蛋白的表达较正常组下降,MMP-2/TIMP-2比值较正常组下降,高糖组的这些改变较相同渗透压的甘露醇组更为明显,且随着葡萄糖浓度的增加,这些变化也越来越明显；(4)高糖组和甘露醇组Ⅳ型胶原mRNA和蛋白的表达较正常组增高,高糖组的这些改变较相同渗透压的甘露醇组更为明显,Ⅳ型胶原mRNA表达随着葡萄糖浓度增加而增加,但Ⅳ型胶原的蛋白表达并无此规律；(5)与同浓度葡萄糖组相比,p38MAPK抑制剂SB203580组系膜细胞MMP-2mRNA与蛋白表达和MMP-2/TIMP-2比值增加,TIMP-2及Ⅳ型胶原mRNA与蛋白表达下降,p38MAPK mRNA表达无明显变化。
结论(1)高糖诱导SD大鼠肾小球系膜细胞p38MAPK和TIMP-2 mRNA和蛋白表达升高,而使系膜细胞MMP-2 mRNA和蛋白表达降低,MMP-2/TIMP-2比值下降,且高糖引起的这些变化呈浓度依赖性；(2)高糖诱导SD大鼠肾小球系膜细胞Ⅳ型胶原mRNA和蛋白表达升高,且Ⅳ型胶原的mRNA的表达呈葡萄糖浓度依赖性,而Ⅳ型胶原的蛋白表达并非呈葡萄糖浓度依赖性；(3)甘露醇增加系膜细胞p38MAPK和TIMP-2及Ⅳ型胶原mRNA和蛋白表达,减少MMP-2mRNA与蛋白表达。高糖诱导的系膜细胞p38MAPKmRNA表达的增多可能部分是由于高渗透压引起的；(4) p38MAPK抑制剂SB203580能逆转高糖诱导的MMP-2、TIMP-2及Ⅳ型胶原mRNA和蛋白表达,却不能改变高糖诱导的p38MAPKmRNA表达的增加；(5)在糖尿病肾病中,p38MAPK的表达水平及活性与MMP-2、TIMP-2及Ⅳ型胶原mRNA和蛋白表达有密切关系。p38MAPK信号通路与MMP-2/TIMP-2在糖尿病肾病时细胞外Ⅳ型胶原的聚集过程发挥了重要作用,对p38MAPK信号通路与MMP-2、TIMP-2的深入研究将为今后糖尿病肾病的预防和治疗及新药研发提供思路。
Objective Diabetic nephropathy (DN) is an important microvascular complication in diabetes, about 20%-30% of diabetic patients complicate with kidney disease. Diabetic nephropathy has become a major cause of death in diabetic patients. The pathological features of DN include glomerular mesangial broadening and diffuse thickening of glomerular basement membrane. The histological basis for this change is extracellular matrix (ECM) accumulation. Under normal circumstances, ECM production and degradation in body is under precise control. Matrix metalloproteinases (MMPs) and tissue inhibitor metalloproteinases (TIMPs) is the main regulator of ECM degradation. How high glucose regulating the expression of MMPs and TIMPs is not clear. The relationship between the expression of MMPs/ TIMPs and the p38MAPK should be explored. How p38MAPK signal pathway regulating the expression of collagen IV in diabetic nephropathy is inconclusive. In this study, we investigated the effect of high glucose and SB203580, inhibitor of p38MAPK, on the expression of p38MAPK and MMP-2/TIMP-2 in cultured SD rat glomerular mesangial cell and discussed the mechanism of p38MAPK signal transduction pathways in DN as well as the relation between p38MAPK and MMP-2/TIMP-2.
Methods The cultured SD rat mesangial cells were divided into six groups, normal glucose group(5.6mmol/L), high glucose group(including different concentration gluclose:10 mmol/L,20mmol/L,30 mmol/L), SB203580 group(30 mmol/L glucose plus 10μmol/L SB203580) and mannitol group(5.6mmol/L glucose+24.4mmol/L mannitol). After the cells were incubated in different conditions for 48 hours, total RNA was isolated with Trizol reagent, the expression of p38MAPK, MMP-2 and TIMP-2 mRNA were examined by Real time Quantitative PCR. Total protein was isolated with RIPA, the expression of MMP-2/TIMP-2 and collagenⅣprotein were examined by western blot.
Results (1) p38MAPK, MMP-2 and TIMP-2 mRNA express in normal glucose group; (2) The expression of p38MAPK mRNA is increased in high glucose group and mannitol group than that in normal glucose group, but the expression of p38MAPK mRNA in high glucose groups is much higher than mannitol group, which is in a concentration-dependent manner; (3) Compared with normal glucose group, the expression of TIMP-2 mRNA and protein is increased, but MMP-2 mRNA and protein and MMP-2/TIMP-2 mRNA and protein ratio in high glucose groups and in mannitol group are decreased; these changes in high glucose groups are more significantly than that in mannitol group, which are dependent of glucose concentration; (4) Compared with normal glucose group, the expression of collagen IVmRNA and protein is increased, these changes in high glucose groups are more significantly than that in mannitol group, the expression of collagenⅣmRNA are dependent of glucose concentration, but the expression of collagenⅣprotein are independent of glucose concentration,(5) The mRNA and protein expression of MMP-2 and MMP-2/TIMP-2 mRNA and protein ratio are higher in SB203580 group, and TIMP-2 mRNA and protein is lower than that in high glucose group (30 mmol/L), whereas there is no significant difference between high glucose group and SB203580 group in the expression of p38MAPK mRNA
Conclusion (1) High glucose can increase significantly the mRNA and protein expression of p38MAPK and TIMP-2, and decrease the mRNA and protein expression of MMP-2, and also decrease MMP-2/TIMP-2 mRNA and protein ratio in cultured mesangial cells, and these changes are dependent of glucose concentration; (2) The expression of collagen IV mRNA are dependent of glucose concentration, but the expression of collagen IV protein are independent of glucose concentration; (3) Mannitol increase the expression of p38MAPK mRNA in mesangial cells, high osmitic pressure at least partly participates in increasing of p38MAPK mRNA induced by high glucose; (4) The inhibitor of p38MAPK can reverse the changes of MMP-2, TIMP-2 mRNA、protein and MMP-2/TIMP-2 mRNA and protein ratio induced by high glucose, but can not inhibit the increased expression of p38MAPK mRNA induced by high glucose; (5) P38MAPK is related to the mRNA and protein expression of MMP-2、TIMP-2 and collagen IV in diabetic nephropathy.
方法将培养的SD大鼠肾小球系膜细胞分为6组：(1)正常对照组：5.6mmol/L的葡萄糖；(2)高糖A组：10 mmol/L的葡萄糖；(3)高糖B组：20 mmol/L的葡萄糖；(4)高糖C组：30 mmol/L的葡萄糖；(5)SB203580组：30 mmol/L的葡萄糖+10μmol/L SB203580; (6)甘露醇组：5.6mmol/L的葡萄糖+24.4mmol/L的甘露醇。待细胞生长状况良好,细胞生长至90%左右密度后,同步化24小时,分别用以上各因素处理细胞并继续培养,于培养48小时后收集细胞,提取总mRNA,逆转录成cDNA,采用实时荧光定量PCR法检测各组肾小球系膜细胞p38MAPK、MMP-2、TIMP-2及Ⅳ型胶原mRNA表达；提取总蛋白,采用Western-blot法检测MMP-2、TIMP-2及Ⅳ型胶原的蛋白表达。
结果(1)正常条件下系膜细胞p38MAPK、MMP-2、TIMP-2及Ⅳ型胶原在mRNA水平上均有表达,MMP-2、TIMP-2及Ⅳ型胶原在蛋白水平上均有表达；(2)高糖组和甘露醇组p38MAPKmRNA的表达均高于正常组,但高糖组p38MAPKmRNA的表达增加更明显,且当葡萄糖浓度由10mmol/L增加到20mmol/L及30mmol/L时,p38MAPKmRNA的表达也逐渐增加；(3)高糖组和甘露醇组TIMP-2 mRNA和蛋白的表达较正常组增高,而MMP-2 mRNA和蛋白的表达较正常组下降,MMP-2/TIMP-2比值较正常组下降,高糖组的这些改变较相同渗透压的甘露醇组更为明显,且随着葡萄糖浓度的增加,这些变化也越来越明显；(4)高糖组和甘露醇组Ⅳ型胶原mRNA和蛋白的表达较正常组增高,高糖组的这些改变较相同渗透压的甘露醇组更为明显,Ⅳ型胶原mRNA表达随着葡萄糖浓度增加而增加,但Ⅳ型胶原的蛋白表达并无此规律；(5)与同浓度葡萄糖组相比,p38MAPK抑制剂SB203580组系膜细胞MMP-2mRNA与蛋白表达和MMP-2/TIMP-2比值增加,TIMP-2及Ⅳ型胶原mRNA与蛋白表达下降,p38MAPK mRNA表达无明显变化。
结论(1)高糖诱导SD大鼠肾小球系膜细胞p38MAPK和TIMP-2 mRNA和蛋白表达升高,而使系膜细胞MMP-2 mRNA和蛋白表达降低,MMP-2/TIMP-2比值下降,且高糖引起的这些变化呈浓度依赖性；(2)高糖诱导SD大鼠肾小球系膜细胞Ⅳ型胶原mRNA和蛋白表达升高,且Ⅳ型胶原的mRNA的表达呈葡萄糖浓度依赖性,而Ⅳ型胶原的蛋白表达并非呈葡萄糖浓度依赖性；(3)甘露醇增加系膜细胞p38MAPK和TIMP-2及Ⅳ型胶原mRNA和蛋白表达,减少MMP-2mRNA与蛋白表达。高糖诱导的系膜细胞p38MAPKmRNA表达的增多可能部分是由于高渗透压引起的；(4) p38MAPK抑制剂SB203580能逆转高糖诱导的MMP-2、TIMP-2及Ⅳ型胶原mRNA和蛋白表达,却不能改变高糖诱导的p38MAPKmRNA表达的增加；(5)在糖尿病肾病中,p38MAPK的表达水平及活性与MMP-2、TIMP-2及Ⅳ型胶原mRNA和蛋白表达有密切关系。p38MAPK信号通路与MMP-2/TIMP-2在糖尿病肾病时细胞外Ⅳ型胶原的聚集过程发挥了重要作用,对p38MAPK信号通路与MMP-2、TIMP-2的深入研究将为今后糖尿病肾病的预防和治疗及新药研发提供思路。
Objective Diabetic nephropathy (DN) is an important microvascular complication in diabetes, about 20%-30% of diabetic patients complicate with kidney disease. Diabetic nephropathy has become a major cause of death in diabetic patients. The pathological features of DN include glomerular mesangial broadening and diffuse thickening of glomerular basement membrane. The histological basis for this change is extracellular matrix (ECM) accumulation. Under normal circumstances, ECM production and degradation in body is under precise control. Matrix metalloproteinases (MMPs) and tissue inhibitor metalloproteinases (TIMPs) is the main regulator of ECM degradation. How high glucose regulating the expression of MMPs and TIMPs is not clear. The relationship between the expression of MMPs/ TIMPs and the p38MAPK should be explored. How p38MAPK signal pathway regulating the expression of collagen IV in diabetic nephropathy is inconclusive. In this study, we investigated the effect of high glucose and SB203580, inhibitor of p38MAPK, on the expression of p38MAPK and MMP-2/TIMP-2 in cultured SD rat glomerular mesangial cell and discussed the mechanism of p38MAPK signal transduction pathways in DN as well as the relation between p38MAPK and MMP-2/TIMP-2.
Methods The cultured SD rat mesangial cells were divided into six groups, normal glucose group(5.6mmol/L), high glucose group(including different concentration gluclose:10 mmol/L,20mmol/L,30 mmol/L), SB203580 group(30 mmol/L glucose plus 10μmol/L SB203580) and mannitol group(5.6mmol/L glucose+24.4mmol/L mannitol). After the cells were incubated in different conditions for 48 hours, total RNA was isolated with Trizol reagent, the expression of p38MAPK, MMP-2 and TIMP-2 mRNA were examined by Real time Quantitative PCR. Total protein was isolated with RIPA, the expression of MMP-2/TIMP-2 and collagenⅣprotein were examined by western blot.
Results (1) p38MAPK, MMP-2 and TIMP-2 mRNA express in normal glucose group; (2) The expression of p38MAPK mRNA is increased in high glucose group and mannitol group than that in normal glucose group, but the expression of p38MAPK mRNA in high glucose groups is much higher than mannitol group, which is in a concentration-dependent manner; (3) Compared with normal glucose group, the expression of TIMP-2 mRNA and protein is increased, but MMP-2 mRNA and protein and MMP-2/TIMP-2 mRNA and protein ratio in high glucose groups and in mannitol group are decreased; these changes in high glucose groups are more significantly than that in mannitol group, which are dependent of glucose concentration; (4) Compared with normal glucose group, the expression of collagen IVmRNA and protein is increased, these changes in high glucose groups are more significantly than that in mannitol group, the expression of collagenⅣmRNA are dependent of glucose concentration, but the expression of collagenⅣprotein are independent of glucose concentration,(5) The mRNA and protein expression of MMP-2 and MMP-2/TIMP-2 mRNA and protein ratio are higher in SB203580 group, and TIMP-2 mRNA and protein is lower than that in high glucose group (30 mmol/L), whereas there is no significant difference between high glucose group and SB203580 group in the expression of p38MAPK mRNA
Conclusion (1) High glucose can increase significantly the mRNA and protein expression of p38MAPK and TIMP-2, and decrease the mRNA and protein expression of MMP-2, and also decrease MMP-2/TIMP-2 mRNA and protein ratio in cultured mesangial cells, and these changes are dependent of glucose concentration; (2) The expression of collagen IV mRNA are dependent of glucose concentration, but the expression of collagen IV protein are independent of glucose concentration; (3) Mannitol increase the expression of p38MAPK mRNA in mesangial cells, high osmitic pressure at least partly participates in increasing of p38MAPK mRNA induced by high glucose; (4) The inhibitor of p38MAPK can reverse the changes of MMP-2, TIMP-2 mRNA、protein and MMP-2/TIMP-2 mRNA and protein ratio induced by high glucose, but can not inhibit the increased expression of p38MAPK mRNA induced by high glucose; (5) P38MAPK is related to the mRNA and protein expression of MMP-2、TIMP-2 and collagen IV in diabetic nephropathy.
引文
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[36]Li X, Liu W, Wang Q, et al. Emodin suppresses cell proliferation and fibronectin expression via p38MAPK pathway in rat mesangial cells cultured under high glucose. Mol Cell Endocrinol[J],2009,307(1-2):157-62.
[37]Tang X, Zhang J, Cai DH, et al. Effect of high glucose exposure on connective tissue growth factor expression in cultured human renal tubular epithelial cells and the role of p38MAPK pathway[J]. Nan Fang Yi Ke Da Xue Xue Bao,2009,29(1):50-3.
[38]Park JK, Ronkina N, Hoft A, et al. Deletion of MK2 signalling in vivo inhibits small Hsp phosphorylation but not diabetic nephropathy[J]. Nephrol Dial Transplant, 2008,23(6):1844-53.
[39]Sakai N, Wada T, Furuichi K, et al. Involvement of extracellular signal-regulated kinase and p38 in human diabetic nephropathy[J]. Am J Kidney Dis, 2005,45(1):54-65.
[40]Tossidou I, Starker G, Kruger J, et al. PKC-alpha modulates TGF-beta signaling and impairs podocyte survival[J]. Cell Physiol Biochem,2009,24(5-6):627-34.
[41]Liu W, Tang F, Deng Y, Berberine reduces fibronectin and collagen accumulation in rat glomerular mesangial cells cultured under high glucose condition[J].Mol Cell Biochem,2009,325(1-2):99-105.
[42]Gharagozlian S, Svennevig K, Bangstad HJ, et al. Matrix metalloproteinases in subjects with type 1 diabetes[J]. BMC Clin Pathol,2009,16(9):7.
[43]Yang J, Zhou Q, Wang Y,et al. Effect of high glucose on PKC and MMPs/TIMPs in human mesangial cells[J].2009,34(5):425-31.
[44]Kowluru RA, Kanwar M. Oxidative stress and the development of diabetic retinopathy:contributory role of matrix metalloproteinase-2[J]. Free Radic Biol Med, 2009,46(12):1677-85.
[45]Sodha NR, Clements RT, Boodhwani M, et al. Endostatin and angiostatin are increased in diabetic patients with coronary artery disease and associated with impaired coronary collateral formation[J]. Am J Physiol Heart Circ Physiol,2009, 296(2):H428-34.
[46]Martinez ML, Rizzi E, Castro MM, et al. Lercanidipine decreases vascular matrix metalloproteinase-2 activity and protects against vascular dysfunction in diabetic rats[J]. Eur J Pharmacol,2008,599(1-3):110-6.
[47]Lan CC, Liu IH, Fang AH, et al. Hyperglycaemic conditions decrease cultured keratinocyte mobility:implications for impaired wound healing in patients with diabetes[J].Br J Dermatol,2008,159(5):1103-15.
[48]Ohtomo S, Nangaku M, Izuhara Y, et al. The role of megsin, a serine protease inhibitor, in diabetic mesangial matrix accumulation. Kidney Int,2008,74(6):768-74.
[49]Van Linthout S, Seeland U, Riad A,et al. Reduced MMP-2 activity contributes to cardiac fibrosis in experimental diabetic cardiomyopathy[J]. Basic Res Cardiol, 2008,103(4):319-27.
[50]Rysz J, Banach M, Stolarek RA,, et al. Serum matrix metalloproteinases MMP-2 and MMP-9 and metalloproteinase tissue inhibitors TIMP-1 and TIMP-2 in diabetic nephropathy[J]. J Nephrol,2007,20(4):444-52.
[51]李晓玲,葛秀兰,苏胜偶.2型糖尿病肾病患者血清金属蛋白酶9及其组织抑制因子1水平变化的临床意义[J].中华内分泌代谢杂志,2003.19(1)：52-53
[52]Singh R, Song RH, Alavi N, et al. High glucose decrease matrix metalloproteinase-2 activity in rat mesangial cells via transforming growth factor-betal[J]. Exp nephrol,2001,9(4):249-257
[53]Boden G, Song W, Pashko L, et al. In vivo effects of insulin and free fatty acids on matrix metalloproteinases in Rat Aorta[J]. Diabetes,2007;19
[54]Grabellus F, Worm K, Schmid KW. Induction of the matrix metalloproteinase-2 activation system in arteries by tensile stress. Involvement of the p38 MAP-kinase pathway[J]. Pathol Res Pract,2007;203(3):135-43.
[55]Lupia E, Elliot J, Lenz O, et al. IGF-1 decreases collagen degradation in diabetic NOD mesangial cell:implication for diabetic nephropathy[J]. Diabetes,1999, 48:1638-1644.
[56]Mclennan S, Fisher E, Martell Y, et al. Effect of glucose on matrix metalloproteinase and plasmin activities in mesangial cells:possible role in diabetic nephropathy[J]. Kideny Int,2000,58(Suppl 77):S81-87.
[57]Doronzo G, Russo I, Del Mese P, et al. Role of NMDA receptor in homocysteine-induced activation of mitogen-activated protein kinase and phosphatidyl inositol 3-kinase pathways in cultured human vascular smooth muscle cells[J]. Thromb Res,2010,125(2):e23-32.
[58]Jin EJ, Choi YA, Kyun Park E, et al. MMP-2 functions as a negative regulator of chondrogenic cell condensation via down-regulation of the FAK-integrin betal interaction[J]. Dev Biol,2007,308(2):474-84.
[59]Tan ZH, Shen YJ, Zhao JN, et al. Effects of rhein on the function of human mesangial cells in high glucose environment[J]. Yao Xue Xue Bao,2004,39(11): 881-6.
[60]Denkert C, Siegert A, Leclere A, et al. An inhibitor of stress-activated MAP-kinases reduces invasion and MMP-2 expression of malignant melanoma cells. Clin Exp Metastasis[J],2002,19(1):79-85.
[61]Adhikary A, Mohanty S, Lahiry L, et al. Theaflavins retard human breast cancer cell migration by inhibiting NF-kappaB via p53-ROS cross-talk[J]. FEBS Lett,2010, 584(1):7-14.
[1]Femandez C, Bode W, Huber R, et al. Crystal structure of complex formed by the membrane[J]. EMBO J,2008,17(17):5238-5248.
[2]Singh R, Song RH, Alavi N, et al. High glucose decrease matrix metalloprorteinase-2 activity in rat mesangial cells rat via transforming growth factor-beta 1[J]. Exp Nephrol,2010,9(4):249-257.
[3]Lietta LA, KIeinerman J, Catanzaro P. Degradation of basement membrane by murine tumor cells[J]. Natl Cancer Inst,2007,58(5):1427-1431.
[4]Collier IE, Bruns GA, Goldberg GI. On the structure and chromosome location of the 72-and 92-kDa human type IV collagenase genes[J]. Genomics,2010,9(3): 429-434.
[5]傅思莹,陶瑜.MMP-2与肾脏疾病[J].国外医学泌尿系统分册,2009,23(4)：466-469.
[6]朱清义,蒋玉红,谷照敏.基质金属蛋白酶-2与肾疾病关系研究进展[J].实用医学杂志,2006,22(6)：722-723.
[7]侯元婕,薛克修.基质金属蛋白酶及其抑制因子与组织纤维化的研究进展[J].新乡医学院学报,2006,23(2)：204-206.
[8]Rapti M, Knallper V, Murphy G, et al. Characterization of the AB Loop Region of TIMP-2:involvement in Pro-MMP-2 Activation[J]. J Biol Chem,2006,281(33): 23386-23394.
[9]McLENNANS V, MARTELL S K Y, YUE D K. High glucose concentration inhibits the expression of membrane type metalloproteinase by mesangial cells: possible role in mesangium accumulation[J]. Diabetologia,2009,43:642-648.
[10]LuPIA E, ELLIOT S J, LENZ O, et al. IGF-1 decreases collagen degradation in diabetic NOD mesangial cell:implication for diabetic nephropathy[J]. Diabetes,2008, 48:1638-1644.
[11]McLENNAN s, FIsHER E, MARTELL S Y, et al. Effect of glucose on matrix metalloproteinase and plasmin activities in mesangial cells:possible role in diabetic nephropathy[J]. Kideny Int,2000,58(Suppl 77):S81-87.
[12]McLENNAN S V, MARTELL S K Y, YUE D K. Effect of mesangium glycation on matrix metalloproteinase activities:possible role in diabetic nephropathy[J]. Diabetes,2002,51:2612-2618.
[13]于晓燕,李才,何泽,等.糖基化终末产物对大鼠肾皮质基质金属蛋白酶2活性和表达的影响[J].中华内分泌代谢杂志,2008,19：402-405.
[14]Baricos H, Cortez L, Deboisblanc M, et al. Transforming growth factor-beta is a potent inhibitor of extracellular matrix degradation cultured human mesangual cells[J]. Am Soc Nephrol,2010,10:795.
[15]McLENNAN S V, WANGX Y, MORENO V, et al. Connective tissue growth factor mediates high glucose effects on matrix degradation through tissue inhibitor of matrix metalloproteinase type 1:implications for diabetic nephropathy[J]. Endocrinology,2007,145(12):5646-5655.
[16]钱莉玲,常立文,容志惠,等.维A酸治疗新生大鼠高氧肺发育受抑对肺组织基质金属蛋白酶及其组织抑制剂表达的影响[J].实用儿科临床杂志,2002,17(6)：602-604.
[17]Song Y, Li C, Cai L. Fluvastatin prevents nephropathy likely through suppression of connective tissue growth factor-mediated extracellular matrix accumulation[J]. Exp Mol Pathol,2009,76(1):66-75.
[18]Tashiro K, Koyanagi I, Ohara I. Levels of urinary matrix metalloproteinase-9(MMP-9) and renal injuries inpatients with type2 diabetic nephropathy[J]. J Clin Lab Anal,2004,18(3):206-210.
[19]Ebihara I, Nakamura T, Ushiyama C, et al. Effect of oral adsorbent AST-120 On plasma metalloproteinase-9 and serum tissue inhibitor of metalloproteinase-1 Concentration in chronic renal failure[J]. Nephronology,2009,83(2):169.
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[4]朱清义,蒋玉红,谷照敏.基质金属蛋白酶-2与肾疾病关系研究进展[J].实用医学杂志,2006,22(6)：722-723.
[5]侯元婕,薛克修.基质金属蛋白酶及其抑制因子与组织纤维化的研究进展[J].新乡医学院学报,2006,23(2)：204-206.
[6]Rapti M, Knallper V, Murphy G, et al. Characterization of the AB Loop Region of TIMP-2:involvement in Pro-MMP-2 Activation[J]. J Biol Chem,2006,281(33): 23386-23394.
[7]Mclennans V, Martell Y, Yue K. High glucose concentration inhibits the expression of membrane type metalloproteinase by mesangial cells:possible role in mesangium accumulation[J]. Diabetologia,2000,43:642-648.
[8]Singh R, Song RH, Alavi N, et al. High glucose decrease matrix metalloproteinase-2 activity in rat mesangial cells via transforming growth factor-betal[J]. Exp nephrol,2001,9(4):249-257
[9]李晓玲,葛秀兰,苏胜偶.2型糖尿病肾病患者血清金属蛋白酶9及其组织抑制因子1水平变化的临床意义[J].中华内分泌代谢杂志,2003.19(1)：52-53
[10]Rysz J, Banach M, Stolarek RA,et al. Serum matrix metalloproteinases MMP-2 and MMP-9 and metalloproteinase tissue inhibitors TIMP-1 and TIMP-2 in diabetic nephropathy[J]. J Nephr.2007,20(4):444-452
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[33]Ohtomo S, Nangaku M, Izuhara Y, et al. The role of megsin, a serine protease inhibitor, in diabetic mesangial matrix accumulation. Kidney Int,2008,74(6):768-74.
[34]Rysz J, Banach M, Stolarek RA, et al. Serum matrix metalloproteinases MMP-2 and MMP-9 and metalloproteinase tissue inhibitors TIMP-1 and TIMP-2 in diabetic nephropathy[J]. J Nephrol,2007,20(4):444-52.
[35]Liu Y, Wang Z, Yin W, et al. Severe insulin resistance and moderate glomerulosclerosis in a minipig model induced by high-fat/high-sucrose/ high-cholesterol diet[J]. Exp Anim,2007,56(1):11-20.
[36]Li X, Liu W, Wang Q, et al. Emodin suppresses cell proliferation and fibronectin expression via p38MAPK pathway in rat mesangial cells cultured under high glucose. Mol Cell Endocrinol[J],2009,307(1-2):157-62.
[37]Tang X, Zhang J, Cai DH, et al. Effect of high glucose exposure on connective tissue growth factor expression in cultured human renal tubular epithelial cells and the role of p38MAPK pathway[J]. Nan Fang Yi Ke Da Xue Xue Bao,2009,29(1):50-3.
[38]Park JK, Ronkina N, Hoft A, et al. Deletion of MK2 signalling in vivo inhibits small Hsp phosphorylation but not diabetic nephropathy[J]. Nephrol Dial Transplant, 2008,23(6):1844-53.
[39]Sakai N, Wada T, Furuichi K, et al. Involvement of extracellular signal-regulated kinase and p38 in human diabetic nephropathy[J]. Am J Kidney Dis, 2005,45(1):54-65.
[40]Tossidou I, Starker G, Kruger J, et al. PKC-alpha modulates TGF-beta signaling and impairs podocyte survival[J]. Cell Physiol Biochem,2009,24(5-6):627-34.
[41]Liu W, Tang F, Deng Y, Berberine reduces fibronectin and collagen accumulation in rat glomerular mesangial cells cultured under high glucose condition[J].Mol Cell Biochem,2009,325(1-2):99-105.
[42]Gharagozlian S, Svennevig K, Bangstad HJ, et al. Matrix metalloproteinases in subjects with type 1 diabetes[J]. BMC Clin Pathol,2009,16(9):7.
[43]Yang J, Zhou Q, Wang Y,et al. Effect of high glucose on PKC and MMPs/TIMPs in human mesangial cells[J].2009,34(5):425-31.
[44]Kowluru RA, Kanwar M. Oxidative stress and the development of diabetic retinopathy:contributory role of matrix metalloproteinase-2[J]. Free Radic Biol Med, 2009,46(12):1677-85.
[45]Sodha NR, Clements RT, Boodhwani M, et al. Endostatin and angiostatin are increased in diabetic patients with coronary artery disease and associated with impaired coronary collateral formation[J]. Am J Physiol Heart Circ Physiol,2009, 296(2):H428-34.
[46]Martinez ML, Rizzi E, Castro MM, et al. Lercanidipine decreases vascular matrix metalloproteinase-2 activity and protects against vascular dysfunction in diabetic rats[J]. Eur J Pharmacol,2008,599(1-3):110-6.
[47]Lan CC, Liu IH, Fang AH, et al. Hyperglycaemic conditions decrease cultured keratinocyte mobility:implications for impaired wound healing in patients with diabetes[J].Br J Dermatol,2008,159(5):1103-15.
[48]Ohtomo S, Nangaku M, Izuhara Y, et al. The role of megsin, a serine protease inhibitor, in diabetic mesangial matrix accumulation. Kidney Int,2008,74(6):768-74.
[49]Van Linthout S, Seeland U, Riad A,et al. Reduced MMP-2 activity contributes to cardiac fibrosis in experimental diabetic cardiomyopathy[J]. Basic Res Cardiol, 2008,103(4):319-27.
[50]Rysz J, Banach M, Stolarek RA,, et al. Serum matrix metalloproteinases MMP-2 and MMP-9 and metalloproteinase tissue inhibitors TIMP-1 and TIMP-2 in diabetic nephropathy[J]. J Nephrol,2007,20(4):444-52.
[51]李晓玲,葛秀兰,苏胜偶.2型糖尿病肾病患者血清金属蛋白酶9及其组织抑制因子1水平变化的临床意义[J].中华内分泌代谢杂志,2003.19(1)：52-53
[52]Singh R, Song RH, Alavi N, et al. High glucose decrease matrix metalloproteinase-2 activity in rat mesangial cells via transforming growth factor-betal[J]. Exp nephrol,2001,9(4):249-257
[53]Boden G, Song W, Pashko L, et al. In vivo effects of insulin and free fatty acids on matrix metalloproteinases in Rat Aorta[J]. Diabetes,2007;19
[54]Grabellus F, Worm K, Schmid KW. Induction of the matrix metalloproteinase-2 activation system in arteries by tensile stress. Involvement of the p38 MAP-kinase pathway[J]. Pathol Res Pract,2007;203(3):135-43.
[55]Lupia E, Elliot J, Lenz O, et al. IGF-1 decreases collagen degradation in diabetic NOD mesangial cell:implication for diabetic nephropathy[J]. Diabetes,1999, 48:1638-1644.
[56]Mclennan S, Fisher E, Martell Y, et al. Effect of glucose on matrix metalloproteinase and plasmin activities in mesangial cells:possible role in diabetic nephropathy[J]. Kideny Int,2000,58(Suppl 77):S81-87.
[57]Doronzo G, Russo I, Del Mese P, et al. Role of NMDA receptor in homocysteine-induced activation of mitogen-activated protein kinase and phosphatidyl inositol 3-kinase pathways in cultured human vascular smooth muscle cells[J]. Thromb Res,2010,125(2):e23-32.
[58]Jin EJ, Choi YA, Kyun Park E, et al. MMP-2 functions as a negative regulator of chondrogenic cell condensation via down-regulation of the FAK-integrin betal interaction[J]. Dev Biol,2007,308(2):474-84.
[59]Tan ZH, Shen YJ, Zhao JN, et al. Effects of rhein on the function of human mesangial cells in high glucose environment[J]. Yao Xue Xue Bao,2004,39(11): 881-6.
[60]Denkert C, Siegert A, Leclere A, et al. An inhibitor of stress-activated MAP-kinases reduces invasion and MMP-2 expression of malignant melanoma cells. Clin Exp Metastasis[J],2002,19(1):79-85.
[61]Adhikary A, Mohanty S, Lahiry L, et al. Theaflavins retard human breast cancer cell migration by inhibiting NF-kappaB via p53-ROS cross-talk[J]. FEBS Lett,2010, 584(1):7-14.
[1]Femandez C, Bode W, Huber R, et al. Crystal structure of complex formed by the membrane[J]. EMBO J,2008,17(17):5238-5248.
[2]Singh R, Song RH, Alavi N, et al. High glucose decrease matrix metalloprorteinase-2 activity in rat mesangial cells rat via transforming growth factor-beta 1[J]. Exp Nephrol,2010,9(4):249-257.
[3]Lietta LA, KIeinerman J, Catanzaro P. Degradation of basement membrane by murine tumor cells[J]. Natl Cancer Inst,2007,58(5):1427-1431.
[4]Collier IE, Bruns GA, Goldberg GI. On the structure and chromosome location of the 72-and 92-kDa human type IV collagenase genes[J]. Genomics,2010,9(3): 429-434.
[5]傅思莹,陶瑜.MMP-2与肾脏疾病[J].国外医学泌尿系统分册,2009,23(4)：466-469.
[6]朱清义,蒋玉红,谷照敏.基质金属蛋白酶-2与肾疾病关系研究进展[J].实用医学杂志,2006,22(6)：722-723.
[7]侯元婕,薛克修.基质金属蛋白酶及其抑制因子与组织纤维化的研究进展[J].新乡医学院学报,2006,23(2)：204-206.
[8]Rapti M, Knallper V, Murphy G, et al. Characterization of the AB Loop Region of TIMP-2:involvement in Pro-MMP-2 Activation[J]. J Biol Chem,2006,281(33): 23386-23394.
[9]McLENNANS V, MARTELL S K Y, YUE D K. High glucose concentration inhibits the expression of membrane type metalloproteinase by mesangial cells: possible role in mesangium accumulation[J]. Diabetologia,2009,43:642-648.
[10]LuPIA E, ELLIOT S J, LENZ O, et al. IGF-1 decreases collagen degradation in diabetic NOD mesangial cell:implication for diabetic nephropathy[J]. Diabetes,2008, 48:1638-1644.
[11]McLENNAN s, FIsHER E, MARTELL S Y, et al. Effect of glucose on matrix metalloproteinase and plasmin activities in mesangial cells:possible role in diabetic nephropathy[J]. Kideny Int,2000,58(Suppl 77):S81-87.
[12]McLENNAN S V, MARTELL S K Y, YUE D K. Effect of mesangium glycation on matrix metalloproteinase activities:possible role in diabetic nephropathy[J]. Diabetes,2002,51:2612-2618.
[13]于晓燕,李才,何泽,等.糖基化终末产物对大鼠肾皮质基质金属蛋白酶2活性和表达的影响[J].中华内分泌代谢杂志,2008,19：402-405.
[14]Baricos H, Cortez L, Deboisblanc M, et al. Transforming growth factor-beta is a potent inhibitor of extracellular matrix degradation cultured human mesangual cells[J]. Am Soc Nephrol,2010,10:795.
[15]McLENNAN S V, WANGX Y, MORENO V, et al. Connective tissue growth factor mediates high glucose effects on matrix degradation through tissue inhibitor of matrix metalloproteinase type 1:implications for diabetic nephropathy[J]. Endocrinology,2007,145(12):5646-5655.
[16]钱莉玲,常立文,容志惠,等.维A酸治疗新生大鼠高氧肺发育受抑对肺组织基质金属蛋白酶及其组织抑制剂表达的影响[J].实用儿科临床杂志,2002,17(6)：602-604.
[17]Song Y, Li C, Cai L. Fluvastatin prevents nephropathy likely through suppression of connective tissue growth factor-mediated extracellular matrix accumulation[J]. Exp Mol Pathol,2009,76(1):66-75.
[18]Tashiro K, Koyanagi I, Ohara I. Levels of urinary matrix metalloproteinase-9(MMP-9) and renal injuries inpatients with type2 diabetic nephropathy[J]. J Clin Lab Anal,2004,18(3):206-210.
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