Glomerular extracellular matrix accumulation in experimental anti-GEM Ab glomerulonephritis

Thickening of the glomerular basement membrane (GBM) results from excessive accumulation of extracellular matrix (ECM) proteins following glomerular i njury. We studied the temporal relationship between the expression of growt h factors, ECM accumulation, ECM degrading proteinases, and their inhibitor s in a rat model of anti-GEM antibody (Ab) glomerulonephritis (GN) by the R Nase protection assay and immunohistochemistry. There were two- or fourfold increases in the expression of transforming growth factor-beta(1) (TGF-bet a(1))and platelet-derived growth factor (PDGF) a and B chain mRMAs 4 days a fter anti-GEM Ab administration, These changes were temporally associated w ith increased accumulation of alpha 1(III) and alpha 2(IV) collagens, fibro nectin, and heparan sulfate proteoglycan along the GEM. The increase in mat rix accumulation was associated with little or no increases in the proteina ses, urokinase plasminogen activator (u-PA) and transin, respectively There was a 1.6 x increase in the u-PA/28s mRNA ratio on day 4 in rats with anti -GEM Ab GN, but this was not associated with an increase in u-PA biologic a ctivity. By comparison, the mRNAs of the proteinase inhibitors, plasminogen activator inhibitor-1 (PAI-1) and tissue inhibitor of metalloproteinase (T IMP) were 5 x greater than that of control rats on day 4, PAI-1 mRNA correl ate with increased biologic activity, These data demonstrate a temporal ass ociation between TGF-beta(1) and PDGF expression and matrix accumulation wi thin the GEM in anti-GEM Ab GN. In addition, it suggest that this matrix ac cumulation results from an imbalance between matrix synthesis and degradati on. Copyright (C) 2000 S. Karger AG, Basel.