Differential expression of collagen type IV alpha-chains in the tubulointerstitial compartment in experimental chronic serum sickness nephritis.

The expression of collagen type IV chains in the renal tubulointerstitium was investigated during the development of chronic serum sickness (CSS) in rats, a model for immune complex-mediated renal disease. Immunohistochemical studies showed increased expression of alpha4(IV) collagen early during disease development, followed by an increase in alpha1(IV) through alpha3(IV) collagen subchain expression, especially in the tubular basement membrane. Dot-blot and in situ hybridization analysis showed a transient increase in steady-state mRNA levels for all collagen IV subchains during the development of CSS, which was most abundant for alpha1(IV), alpha2(IV), and alpha4(IV). Statistical correlations were found between the mRNA levels of alpha1(IV) and alpha2(IV) collagen and between alpha3(IV) and alpha4(IV), in line with the results of others which showed that these chains are co-distributed as heterotrimer collagen type IV molecules. However, additional correlations were found between the mRNA levels coding for alpha1(IV) and alpha3(IV) collagen, and between alpha1(IV) and alpha4(IV) mRNAs in the course of CSS. These abnormal correlations support the hypothesis that changes occur in the co-expression of the collagen IV subchains during the development of CSS. In addition, a strong correlation was found between the presence in the tubulointerstitium of alpha1(IV) and alpha2(IV) collagen chains, on the one hand, and the tubulointerstitial influx of R73+ and ED1+ cells, on the other, suggesting the involvement of inflammatory cells in the observed alterations in matrix production. Changes in the relative abundance of collagen IV chains in disease states may perturb the collagen IV network in the tubulointerstitial compartment and thereby play a role in the development of renal failure.

Differential expression of collagen IV isoforms in experimental glomerulosclerosis.

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, alpha 1-5(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 alpha 1 and alpha 2 early in the disease, but only late in the GBM. In contrast, alpha 3 and alpha 4 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 alpha 3, alpha 4 and alpha 5 than for alpha 1 and alpha 2. Expression of alpha 3(IV) was greatest in GvHD, whereas expression of alpha 4 was greatest in CSS. As determined by in situ hybridization (ISH), alpha 1 mRNA was observed dispersed in the glomerulus, but alpha 3, alpha 4, and alpha 5 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.

T cell subsets in immunologically-mediated glomerulonephritis.

Until recently, research on the pathogenesis of glomerulonephritis has been mainly focused on the characterization of humoral immune responses in the initiation of glomerular injury. However, there is a growing recognition that both cellular and humoral immune responses, in varying proportions, are involved in the pathogenesis of immunologically-mediated glomerulonephritis. T lymphocytes are essential cellular elements of cell-mediated immunity. Both in experimental models of immune-mediated renal disease and in histopathological analyses of human nephropathies, the involvement of T cells has been demonstrated in the immunoregulation of nephritogenic immune responses and in the immune injury in the kidney. T cell activation resulting in either delayed-type hypersensitivity, cytolytic reactions, abnormal expression of major histocompatibility complex (MHC) molecules, or B cell activation can result in glomerulonephritis. These different types of responses are exerted by distinct T cell subsets defined by cell surface markers and cytokine profiles. CD4+ T cells in vivo are functionally heterogeneous with respect to cytokine production and the CD45 isoforms that are found on their surface. Like CD4+ T cells, CD8+ T cells may also be heterogeneous at the level of cytokine production. The roles of CD4+ and CD8+ cells and their cytokine profiles in glomerulonephritis have not been extensively investigated yet, but such studies might improve the understanding of the pathogenesis and possibly lead to new therapeutic approaches of human glomerulonephritis. In this review the role of distinct T lymphocyte subsets in experimental and human glomerulonephritis will be discussed.