肝细胞生长因子对高糖条件下系膜细胞基质降解酶系统及转化生长因子β1的影响

首都医科大学学报 ›› 2008, Vol. 29 ›› Issue (3): 321-326.

肝细胞生长因子对高糖条件下系膜细胞基质降解酶系统及转化生长因子β1的影响

姚兰¹, 陈海平¹, 张丽¹, 唐淑珍²

1. 首都医科大学附属北京友谊医院综合科;2. 首都医科大学附属北京友谊医院肝病中心

收稿日期:2007-12-05 修回日期:1900-01-01 出版日期:2008-06-24 发布日期:2008-06-24
通讯作者: 陈海平

Hepatocyte Growth Factor Modulate the Degradation of ECM in Mesangial Cells Under High Glucose Condition

Yao Lan¹, Chen Haiping¹, Zhang Li¹, Tang Shuzhen²

1. Department of Gerontology, Beijing Friendship Hospital, Capital Medical University;2. Department ofLiver Research Center, Beijing Friendship Hospital, Capital Medical University

Received:2007-12-05 Revised:1900-01-01 Online:2008-06-24 Published:2008-06-24

摘要/Abstract

摘要： 目的通过体外培养大鼠肾系膜细胞,研究肝细胞生长因子(hepatocyte grouth factor,HGF)对高糖条件下系膜细胞表达及分泌转化生长因子-β1(transforming growth factor-β1,TGF-β1)、基质金属蛋白酶-9(matrix metalloproteinases-9,MMP-9)及其抑制物金属蛋白酶组织抑制物-1(tissue inhibitor of metalloproteinase-1,TIMP-1)的影响,从而探讨HGF在糖尿病肾病中肾脏保护作用的机制.方法体外培养大鼠肾系膜细胞,分为正常对照组、高糖刺激组及HGF干预组,通过MTT比色测定不同时间、不同HGF浓度对大鼠肾系膜细胞增殖的影响;采用ELISA法测定细胞上清中MMP-9、TIMP-1、TGF-β1、HGF以及Ⅳ型胶原(Ⅳcol)的含量;以RT-PCR法检测系膜细胞MMP-9,TIMP-1、TGF-β1及HGF基因的表达.结果同正常对照组相比高糖刺激系膜细胞增生,HGF可以抑制高糖引起的系膜细胞增生.通过外源添加HGF可以显著抑制高糖条件下系膜细胞Ⅳcol、TIMP-1及TGF-β1的分泌,但对高糖条件下系膜细胞MMP-9的分泌则无显著影响.同高糖刺激组相比,外源HGF使系膜细胞MMP-9及HGF基因表达明显增强,而显著抑制系膜细胞TIMP-1及TGF-β1基因的表达.结论 HGF对于高糖条件下的大鼠肾系膜细胞可能具有保护性作用,这一作用可能同以下途径有关:HGF抑制高糖刺激所导致的系膜细胞增生;HGF抑制TIMP-1mRNA表达及蛋白合成,促进MMP-9mRNA表达,从而调节MMP-9与TIMP-1之间的比例促进ECM降解;HGF显著抑制TGF-β1mRNA表达及蛋白合成,并且促使内源HGFmRNA表达增高,从而恢复TGF-β1与HGF之间的平衡.

关键词: 肝细胞生长因子, 系膜细胞, 糖尿病肾病, 基质金属蛋白酶, 转化生长因子-β1

Abstract: Objective To investigate the beneficial effect of hepatocyte growth factor(HGF) on diabetic nephropathy(DN),and to observe the effect of HGF on the degradation of extra-cellular matrix(ECM) and production of TGF-β1 in cultured rat glomerular mesangial cells under high glucose condition.Methods MTT colorimetry was used to detect the proliferation of rat mesangial cells cultured under various concentrations of glucose and HGF.Then the cultured mesangial cells were divided into three groups as following:1) normal control group:the concentration of glucose in medium was 5 mmol/L;2) high glucose group:the concentration of glucose in medium was 30 mmol/L;3) HGF treatment group:the concentration of glucose in medium was 30 mmol/L and concentration of HGF is 50 μg/L.These cells were cultured for 48 hours.Then the supernatant content of TIMP-1,MMP-9,TGF-β1,HGF and Ⅳ collagen were measured by ELISA and the level of TIMP-1,MMP-9,TGF-β1,HGFmRNA were measured by RT-PCR.Results 1) HGF suppressed the proliferation induced by high glucose in cultured mesangial cells.2) High glucose concentration could stimulate the secretion of TIMP-1,TGF-β1,Ⅳcollagen and reduce the secretion of MMP-9.Compared to the high glucose group,HGF could suppress the secretion of TIMP-1,TGF-β1,and Ⅳ collagen but had little effect on MMP-9.3) Compared to high glucose group,the expression of TIMP-1mRNA and TGF-β1mRNA were significantly decreased in HGF treated group,while the expression of MMP-9mRNA and HGFmRNA were significantly upregulated.Conclusion The results suggest that HGF can protect the cultured mesangial cells from injury of high glucose concentration.This protective effect of HGF is exerted through the following mechanisms:HGF inhibit the proliferation of the mesangial cells under high glucose condition;increases ECM degradation by modulation of the balance between MMP-9 and TIMP-1;suppresses the secretion of TGF-β1 and upregulates the expression of HGF to rebuild the balance between TGF-β1 and HGF.

Key words: hepatocyte growth factor, mesangial cell, diabetic nephropathy, matrix metalloproteinases, transforming growth factor-β1

中图分类号:

R587.2

姚兰;陈海平;张丽;唐淑珍. 肝细胞生长因子对高糖条件下系膜细胞基质降解酶系统及转化生长因子β1的影响[J]. 首都医科大学学报, 2008, 29(3): 321-326.

Yao Lan;Chen Haiping;Zhang Li;Tang Shuzhen. Hepatocyte Growth Factor Modulate the Degradation of ECM in Mesangial Cells Under High Glucose Condition[J]. Journal of Capital Medical University, 2008, 29(3): 321-326.

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