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基质金属蛋白酶/组织金属蛋白酶抑制物表达失衡在衰老大鼠肾小管间质损害中的意义
引用本文:Chen RQ,Chen XM,Cui SW,Cai GY,Shi SZ,Xie YS,Lu Y,Peng LX. 基质金属蛋白酶/组织金属蛋白酶抑制物表达失衡在衰老大鼠肾小管间质损害中的意义[J]. 中华医学杂志, 2004, 84(11): 937-942
作者姓名:Chen RQ  Chen XM  Cui SW  Cai GY  Shi SZ  Xie YS  Lu Y  Peng LX
作者单位:100853,北京,解放军总医院肾病科,解放军肾病中心暨重点实验室
基金项目:国家“九七三”重点基础研究发展规划基金资助项目 (G2 0 0 0 0 5 70 0 3 ),国家自然科学基金“创新研究群体”基金资助项目 ( 3 0 12 10 0 5 )
摘    要:目的研究基质金属蛋白酶(MMP)及组织金属蛋白酶抑制物(TIMP)在不同鼠龄的单侧输尿管梗阻(UUO)大鼠肾小管间质中的表达变化,探讨其可能的作用.方法选用3月、26月龄大鼠制备UUO模型,采用组织病理及逆转录-聚合酶链反应(RT-PCR)、Western印迹等方法观察UUO术后3、7、14 d不同鼠龄大鼠的肾脏组织学改变和MMP-2、MMP-9、TIMP-1、TIMP-2等在梗阻肾小管间质中的表达情况;用明胶酶谱法检测UUO术后不同时间点MMP-2、MMP-9的蛋白水解活性.结果在对照组,TIMP-1、TIMP-2仅微弱表达于3月龄肾脏中,而在26月龄大鼠肾脏中其表达显著增加(P<0.01);老年鼠肾组织中MMP-2、MMP-9的蛋白水解活性显著低于3月龄大鼠(P<0.01).与对照组相比,3月龄、26月龄大鼠梗阻侧肾脏的肾小管间质纤维化面积随UUO术后时间的延长而增加,TIMP-1、TIMP-2及MMP-2、MMP-9的mRNA及蛋白质的表达在术后各时间点均显著增高(P<0.01), MMP-2和MMP-9的蛋白水解活性随UUO术后时间的延长而逐渐下降.其活性的下降与TIMP-2及TIMP-1蛋白质表达的增加呈明显的负相关.与3月龄鼠比较,26月龄鼠肾小管间质纤维化面积在UUO术后各时间点也明显增加(P<0.01),TIMP-1、TIMP-2在肾组织中各时间点的mRNA及蛋白质表达均显著增高(P<0.01),MMP-2、MMP-9的蛋白水解活性在各时间点均显著下降(P<0.01).结论衰老引起的TIMP的高表达及MMP蛋白水解活性下降可能是使衰老大鼠肾小管间质损害加重的重要因素之一.

关 键 词:基质金属蛋白酶 MMP 金属蛋白酶抑制物 TIMP 表达失衡 大鼠 衰老现象 肾小管间质损害 输尿管梗阻

Significance of imbalance between matrix metalloproteinases and tissue type inhibitor of metalloproteinases in renal tubulointerstitial lesions of aging rats
Chen Rong-Quan,Chen Xiang-Mei,Cui Shi-Wei,Cai Guang-Yan,Shi Suo-Zhu,Xie Yuan-Sheng,Lu Yang,Peng Li-Xia. Significance of imbalance between matrix metalloproteinases and tissue type inhibitor of metalloproteinases in renal tubulointerstitial lesions of aging rats[J]. Zhonghua yi xue za zhi, 2004, 84(11): 937-942
Authors:Chen Rong-Quan  Chen Xiang-Mei  Cui Shi-Wei  Cai Guang-Yan  Shi Suo-Zhu  Xie Yuan-Sheng  Lu Yang  Peng Li-Xia
Affiliation:Department of Nephrology, General Hospital of PLA, Kidney Center and Key Laboratory of PLA, Beijing 100853, China.
Abstract:OBJECTIVE: To explore the imbalance between the expression of metalloproteinases (MMPs) and that of tissue type inhibitors of metalloproteinase (TIMPs) in the renal tubulointerstitial lesions of aging rats and the potential role of this imbalance. METHODS: Forty-eight male 26-month-old Wistar rats were randomly divided into 2 groups of 24 rats: unilateral ureteral obstruction (UUO) group with the left ureter ligated and excised and false operation group used as control group. Forty-eight male 3-month-old Wistar rats were randomly divided into 2 groups of 24 rats: UUO group and false operation group just as in the 26-month-old rats. Every group was randomly divided into 3 subgroups of 8 rats: 3-day group, 7-day group, and 14-day group to be killed 2, 7, and 14 days after the operation respectively. The 2 kidneys of each rat were taken out. Routine pathological examination and immunofluorescence (IF) examination were made to calculate the area of renal tubulointerstitial fibrosis and the expression of IV type collagen. RT-PCR and Western blotting were used to detect the expressions of mRNA and protein of TIMP-1, TIMP-2, MMP-2, and MMP-9 in the kidney at different time points. Gelatin zymography was used to detect the proteolytic activity of MMP-2 and MMP-9. RESULTS: The renal interstitial lesion was more significantly in the 26-month-old UUO rats than in the 3-month-old UUO rats since the 3rd day after operation. Both the expression of MMP-2 mRNA and the expression of MMP-9 mRNA were not different between the 2 control groups. In the control groups, TIMP-1 and TIMP-2 Both MMP-2 mRNA and MMP-9 mRNA were expressed in both control groups, without significant differences between these 2 control groups. TIMP-1 mRNA and TIMP-2 mRNA were only weakly expressed in the renal tissues of the 3-month-old control group, however, the expressions of both TIMP-1 and TIMP-2 were significantly stronger in the 16-month-old control group than in the 3-month-old control group. The expressions of TIMP-1 mRNA and TIMP-2 mRNA at different time points were significantly stronger in the obstructed side than in the healthy side in the UUO groups, and significantly stronger in the 26-month-old rats than in the 3-month-old rats. MMP-2 protein and MMP-9 protein were expressed in the 3-month-old and 26-month-old controls without difference between them. The expressions of MMP-2 protein and MMP-9 protein at different time points were significantly stronger in the obstructed side than in the healthy side in the UUO groups, without significant difference between the 26-month-old UUO rats and the 3-month-old UUO rats. The expressions of TIMP-1 protein and TIMP-2 protein were very weak at different time points in the renal tissues of the 3-month-old controls and were significantly stronger in the 26-month-old control rats. In the UUO rats the expressions of TIMP-1 protein and TIMP-2 protein in the renal tissues of the obstructed side at different time points were all significantly stronger for both age groups in comparison with the control groups of the same age and were significantly stronger in the 26-month-old UUO rats than in the 3-month-old UUO rats without significant difference between the 26-month-old UUO rats and the 3-month-old UUO rats. The MMP-2 activity and MMP-9 activity of the 26-month-old rats were both significantly lower than those of the 3-month-old control rats. The MMP-2 activity and MMP-9 activity at different time points of the 2 UUO groups were all significantly lower than those of the control groups of the same age, and those of the 26-month-old were significantly lower than those of the 3-month-old rats The MMP-2 activity and MMP-9 activity were negatively correlated with the expressions of TIMP-2 and TIMP-1. CONCLUSION: The abnormal expression of MMPs/TIMPs including higher expression of TIMPs and decreased proteolytic activity of MMPs induced by aging may be one of the factors aggravating the renal tubulointerstitial lesions of aging rats.
Keywords:Aging  Ureteral obstruction  Matrix metalloproteinases  Tissue inhibitor of metalloproteinases
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