Expression profile of extracellular matrix and its regulatory proteins during the process of interstitial fibrosis after antiglomerular basement membrane antibody-induced glomerular sclerosis in Sprague-Dawley rats

Anti-glomerular basement membrane (GBM) nephritis in Sprague-Dawley (SD) ra ts was characterized by development of marked glomerular sclerosis and tubu lointerstitial fibrosis. To elucidate sequential change of the glomerular s clerosis and tubulointerstitial fibrosis, accumulation and mRNA expression of extracellular matrix (ECM) components and transforming growth factor (TG F)-beta were examined in the glomerulus and cortex during the disease cours e by histology, immunostaining and ribonuclease protection assay. Mild prol iferative and degenerative lesions appeared in the glomeruli by day 15 afte r anti-GEM antibody binding to GEM and progressed to glomerular sclerotic l esion thereafter. Conversely, interstitial change was first recognized by i nfiltration of mononuclear cells after day 20, followed by marked accumulat ion of ECM and tubular degeneration. The interstitial fibrosis was induced without apparent binding of anti-GEM antibody to tubular basement membrane. Accumulation of fibronectin, collagen type I and type IV was noted in the interstitium by immunofluorescence microscopy in association with enhanced expression of mRNA for these ECM components and their regulatory molecules such as matrix metalloproteinase (MMP2), tissue inhibitor of metalloprotein ase (TIMP)-1 and TGF-beta 1 both in glomeruli and cortex. The glomerular ex pression of these mRNA increased apparently by day 15 and reached a plateau or a peak at day 20. The expression of the same mRNA increased gradually f rom day 15 to day 29 in the cortex. These observations show that interstiti al fibrosis follows glomerular sclerosis after anti-GEM antibody injection in SD rats, suggesting that at least a part of the mechanism for ECM accumu lation in the glomerulus and interstitium is essentially the same in terms of composition of ECM and expression of its regulatory molecules.