Differential expression of collagen IV isoforms in experimental glomerulosclerosis

Abstract

Expansion of the glomerular mesangial matrix (MM), thickening of the glomerular basement membrane (GBM), and eventually the development of glomerulosclerosis are often seen in immunologically mediated kidney diseases. In addition to quantitative changes in the extracellular matrix (ECM), qualitative changes in ECM molecules may contribute to alterations in the composition of the glomerular matrix. The expression of collagen IV, α1–5(IV) mRNA, and polypeptides was therefore investigated during the development of chronic graft-versus-host disease (GvHD) in mice, a model for lupus nephritis, and in chronic serum sickness (CSS) in rats, a model for membranous nephropathy. Immunohistochemical studies showed increased mesangial expression of α1 and α2 early in the disease, but only late in the GBM. In contrast, α3 and α4 increased in the GBM during disease, but not in the MM. The mRNA levels for all collagen IV chains were increased in isolated glomeruli before morphological alterations were detectable. The mRNA increase was earlier and more profound for α3, α4 and α5 than for α1 and α2. Expression of α3(IV) was greatest in GvHD, whereas expression of α4 was greatest in CSS. As determined by in situ hybridization (ISH), α1 mRNA was observed dispersed in the glomerulus, but α3, α4, and α5 mRNAs were mainly located in cells at the periphery of the glomerular tuft. The changes in the relative abundance of collagen IV mRNA in disease states may perturb the collagen IV network, altering glomerular structure and function, and may thereby play a central role in the development of glomerulonephritis and glomerulosclerosis. © 1998 John Wiley & Sons, Ltd.