Tang W W, Feng L, Loskutoff D J, Wilson C B
Department of Immunology, The Scripps Research Institute, La Jolla, CA, USA.
Nephron. 2000 Jan;84(1):40-8. doi: 10.1159/000045537.
Thickening of the glomerular basement membrane (GBM) results from excessive accumulation of extracellular matrix (ECM) proteins following glomerular injury. We studied the temporal relationship between the expression of growth factors, ECM accumulation, ECM degrading proteinases, and their inhibitors in a rat model of anti-GBM antibody (Ab) glomerulonephritis (GN) by the RNase protection assay and immunohistochemistry. There were two- or fourfold increases in the expression of transforming growth factor-beta(1) (TGF-beta(1)) and platelet-derived growth factor (PDGF) A and B chain mRNAs 4 days after anti-GBM Ab administration. These changes were temporally associated with increased accumulation of alpha1(III) and alpha2(IV) collagens, fibronectin, and heparan sulfate proteoglycan along the GBM. The increase in matrix accumulation was associated with little or no increases in the proteinases, urokinase plasminogen activator (u-PA) and transin, respectively. There was a 1.6x increase in the u-PA/28s mRNA ratio on day 4 in rats with anti-GBM Ab GN, but this was not associated with an increase in u-PA biologic activity. By comparison, the mRNAs of the proteinase inhibitors, plasminogen activator inhibitor-1 (PAI-1) and tissue inhibitor of metalloproteinase (TIMP) were 5x greater than that of control rats on day 4. PAI-1 mRNA correlate with increased biologic activity. These data demonstrate a temporal association between TGF-beta(1) and PDGF expression and matrix accumulation within the GBM in anti-GBM Ab GN. In addition, it suggest that this matrix accumulation results from an imbalance between matrix synthesis and degradation.
肾小球基底膜（GBM）增厚是肾小球损伤后细胞外基质（ECM）蛋白过度积累所致。我们通过核糖核酸酶保护试验和免疫组织化学方法，研究了抗GBM抗体（Ab）肾小球肾炎（GN）大鼠模型中生长因子表达、ECM积累、ECM降解蛋白酶及其抑制剂之间的时间关系。给予抗GBM抗体后4天，转化生长因子-β（1）（TGF-β（1））、血小板衍生生长因子（PDGF）A链和B链mRNA的表达增加了2倍或4倍。这些变化在时间上与沿GBM的α1（III）和α2（IV）胶原、纤连蛋白及硫酸乙酰肝素蛋白聚糖积累增加相关。基质积累增加分别与蛋白酶、尿激酶型纤溶酶原激活剂（u-PA）和转胶酶的增加很少或没有增加相关。抗GBM抗体GN大鼠在第4天u-PA/28s mRNA比值增加了1.6倍，但这与u-PA生物活性增加无关。相比之下，蛋白酶抑制剂纤溶酶原激活剂抑制剂-1（PAI-1）和金属蛋白酶组织抑制剂（TIMP）的mRNA在第4天比对照大鼠高5倍。PAI-1 mRNA与生物活性增加相关。这些数据表明在抗GBM抗体GN中，TGF-β（1）和PDGF表达与GBM内基质积累之间存在时间关联。此外，这表明这种基质积累是由基质合成与降解之间的失衡所致。
