Biomedical subjects

C J Kootstra

Publications and source records attributed to C J Kootstra.

6 recordsLinked to original sources

PubMed1998

Association between leukocyte infiltration and development of glomerulosclerosis in experimental lupus nephritis.

Mice with chronic graft-versus-host disease (GvHD) induced by injection of DBA/2 lymphocytes into (DBA/2 x C57BL/10) F1 hybrids (DBA/2 GvHD) develop a lupus-like glomerulonephritis with global glomerulosclerosis 12 weeks after induction of the disease. In two other strain combinations with similar H-2 incompatibilities [BALB/c into BALB/c x BL10 (BALB/c GvHD) and BALB.D2 into BALB.D2 x BL10 (BALB.D2 GvHD)], GvHD induction leads to lupus nephritis without global glomerulosclerosis. This study investigated the identity of kidney-infiltrating leukocytes and their involvement in the development of glomerulosclerosis in these three strain combinations. In mice with DBA/2 GvHD, a significant increase in glomerular CD11a-positive cells was found 4 weeks after disease induction. Mice with BALB/c or BALB.D2 GvHD did not show an increase in glomerular CD11a-positive cells at any time point. In the interstitium, CD11a-positive cells were observed 4 weeks after disease induction only in mice with DBA/2 GvHD. In mice with BALB.D2 GvHD, no increase was found in interstitial CD11a-positive cells. In mice with BALB/c GvHD, interstitial CD11a-positive cells were found from week 4 onward. Further immunohistochemical analysis of the glomerular CD11a-positive cells in mice with DBA/2 GvHD showed that these cells were neither polymorphonuclear leukocytes (PMN), nor CD3-positive (T cells), B220-positive (B cells), or F4/80-positive (macrophages). They were all CD45-positive (leukocytes) and MHC class II-positive. In conclusion, we have shown in this model of chronic lupus nephritis that glomerular influx of as yet unidentified CD11a-positive leukocytes is associated with the development of glomerulosclerosis.

Animals↗

PubMed1997

Fatal attraction: adhesion molecules and disease.

Knowledge of molecular mechanisms in cell-cell and cell-matrix adhesion has increased rapidly in the past decade. Adhesion mechanisms are of prime importance in both physiology and pathology. With respect to the kidney, expression of adhesion molecules has been studied in a variety of diseases, including various forms of glomerulonephritis. Hitherto, these descriptive studies have merely launched extensive speculation regarding the role of adhesion mechanisms in renal pathology. A logical next step is to correlate adhesion molecule expression to alterations in structures which may possibly be affected by altered adhesion, for example gap junctions. Current studies linking structural to functional adhesion expand our understanding of cell biology in health and disease.

Cell Adhesion↗

PubMed1997

Effective treatment of experimental lupus nephritis by combined administration of anti-CD11a and anti-CD54 antibodies.

Mice with chronic graft-versus-host disease (GVHD), induced by injection of DBA/2 lymphocytes in (C57BL10*DBA/2) F1 hybrids, develop a syndrome resembling systemic lupus erythematosus (SLE) with immune complex glomerulonephritis. In this model we evaluated the role of interactions between CD11a (LFA-1alpha) and CD54 (intercellular adhesion molecule-1 (ICAM-1)) molecules on leucocytes in the development of renal disease in systemic autoimmunity. Two weeks after induction of GVHD, when anti-nuclear autoantibodies were detected in the circulation and immune complexes had formed in the glomeruli, mice were injected twice per week with rat anti-CD11a and anti-CD54 MoAbs, or with their vehicle PBS, or with control rat IgG. MoAb treatment significantly lowered albuminuria and increased survival compared with control mice with GVHD. In the glomeruli of MoAb-treated mice there was markedly less binding of immunoglobulin and C3, while anti-renal tubular epithelium autoantibodies, but not anti-glomerular basement membrane autoantibodies, were significantly lowered in the circulation 4 weeks after disease induction. In addition, MoAb treatment inhibited the glomerular influx of CD11a+ cells and decreased development of histological abnormalities in the kidneys. Both rat IgG- and MoAb-treated mice developed anti-rat immunoglobulin antibodies. Furthermore, a marked splenomegaly with an increase of the T cell compartment was observed in MoAb-treated mice with GVHD. These results show that CD11a/CD54 interactions are crucial for the full-blown development of lupus nephritis in this model. Treatment aimed at blocking the activity of these molecules profoundly attenuated the development of renal disease in chronic GVHD even if started when first symptoms of SLE (i.e. anti-nuclear autoantibodies in sera and glomerular binding of immunoglobulins) were already detectable.

Albuminuria↗

PubMed1996

Cloning of the mouse fibronectin V-region and variation of its splicing pattern in experimental immune complex glomerulonephritis.

Increased mRNA and protein expression of extracellular matrix (ECM) components, including fibronectin, occurs during the development of glomerulonephritis and glomerulosclerosis in immunologically mediated kidney diseases. However, in addition to these quantitative changes in ECM expression, qualitative changes in these molecules may contribute to malformations in the composition of the glomerular matrix. These qualitative changes may include alterations in the splicing pattern of the V-region of fibronectin, since this region plays a role in its accumulation. The splicing patterns of this region have been studied in chronic graft-versus-host disease (GvHD) in mice, a model of lupus nephritis, and in chronic serum sickness (CSS) in rats, a model of immune complex nephritis. Cloning of the mouse fibronectin V-region from kidney tissue revealed 96.1 per cent homology with the corresponding domain in rat fibronectin. PCR (polymerase chain reaction) analysis of RNA from isolated glomeruli revealed three isoforms of this region in both mouse and rat fibronectin, namely inclusion or exclusion of the whole region, or exclusion of only the CS1 domain. In both models, increased exclusion of the V-region was observed early in the disease. However, in GvHD the splicing pattern returned to normal, whereas in CSS the shift persisted during the course of the experiment. Differentiated expression of fibronectin isoforms may exert an important effect on the structure and biological function of the glomerulus and may thus play a role in the development of glomerulonephritis and glomerulosclerosis.

Alternative Splicing↗

PubMed1995

Qualitative alterations in laminin expression in experimental lupus nephritis.

Previous studies have revealed quantitative alterations in laminin-1 expression at the mRNA and protein levels during the development of glomerulonephritis and glomerulosclerosis in chronic graft-versus-host disease in mice, a model for lupus nephritis. We have now studied the qualitative alterations in laminin expression with two monoclonal antibodies that recognize epitopes on either the E8 or the P1 fragment of laminin-1. Both of these fragments are involved in cell-matrix and matrix-matrix interactions. In normal glomeruli these laminin epitopes are present only in the mesangial matrix; during embryogenesis, however, they are also present in the glomerular basement membrane. The distribution of laminin epitopes was first studied by using immunofluorescence in kidneys of mice with graft-versus-host disease at different points in time after disease induction. Reflection contrast and immunoelectron microscopy were performed after in vivo injection of the horseradish peroxidase-coupled monoclonal antibodies. In glomeruli of mice 8 weeks after disease induction, both injected antibodies bound specifically in electron-dense immune deposits in the mesangium and subepithelially along the glomerular basement membrane as well as in the expanded mesangial matrix. At 11 and 12 weeks after disease induction, when focal and segmental glomerulosclerosis had developed, the antibodies additionally bound in the matrix subendothelially along the glomerular basement membrane and at the periphery of end-stage sclerotic lesions. To study changes in the distribution of laminin epitopes over time, mice were injected with either monoclonal antibody before induction of graft-versus-host disease. The antibodies were detected 8 and 12 weeks later in the mesangial matrix of mice with lupus nephritis. Once segmental glomerulosclerosis had developed, the antibodies were additionally detected within the thickened glomerular capillary wall. The specific binding of anti-laminin monoclonal antibodies in electron-dense immune deposits further substantiates the hypothesis that anti-laminin autoantibodies participate in glomerular immune complex formation in this model, as suggested by earlier studies. Furthermore, our results show that the distribution of glomerular laminin epitopes in the matrix is altered during the development of glomerular disease. These changes in the structure of the glomerular basement membrane may contribute to the abnormal cell-matrix and matrix-matrix interactions during the development of glomerular disease in this model for lupus nephritis.

Animals↗

PubMed1995

A novel rat mesangial matrix protein, MMP-50/100, involved in mesangial glomerulopathies.

BACKGROUND: Within the glomerular extracellular matrix, the glomerular basement membrane and the mesangial matrix have different compositions, presumably related to their different functions. In this study, a novel mesangial matrix protein is recognized by mAb ED5 and KiM4R, which were originally selected for reactivity with follicular dendritic cells of rat lymphoid organs. EXPERIMENTAL DESIGN: Distribution of this mesangial matrix protein (MMP-50/100) was studied in normal Wistar rat kidneys by indirect immunofluorescence and immunoelectron microscopy. For partial immunobiochemical characterization, ED5-affinity-purified glomerular matrices were subjected to SDS-PAGE analysis. Expression of MMP-50/100 was additionally studied in kidneys of rats depleted for complement and in kidneys of rats depleted for resident macrophages. Functional significance of MMP-50/100 was studied in kidneys of rats with mesangial glomerulopathies. RESULTS: Immunoelectron microscopy showed that MMP-50/100 is located in the extracellular matrix of the rat renal mesangium between mesangial cells and the basement membrane and on the mesangial cell membrane. SDS-PAGE analysis of affinity-purified glomerular matrices indicated that MMP-50/100 is a polypeptide glycoprotein with chains of apparent molecular weights of 50 and 100 kDa. Both in vivo and in vitro results indicate that MMP-50/100 does not appear to be a complement factor, or an Fc or complement receptor. In rats partially depleted for resident macrophages, the expression of MMP-50/100 was similar to that in control rats. In rats with BSA-induced chronic serum sickness nephritis, in rats with anti-Thy-1 nephritis, and in rats with uninephrectomy-induced focal glomerular sclerosis, the mesangial expression of MMP-50/100 was significantly increased. In the first model, double-label immunofluorescence demonstrated identical localization of MMP-50/100 with mesangial immune complex deposits. CONCLUSIONS: We conclude that MMP-50/100 is an intrinsic component of the mesangial matrix, presumably related to the "classic" mesangial cell. Expression of MMP-50/100 is increased in expanded mesangial matrices during development of glomerular disease. Furthermore, MMP-50/100 appears to be involved in the handling of mesangial immune complexes.

Animals↗