Abstract
BACKGROUND: Thrombospondin-1 (TSP1), a multifunctional, extracellular matrix protein, regulates cellular attachment, proliferation, migration, and differentiation in vitro, and is expressed de novo in many inflammatory diseases, including glomerulonephritis (GN).
METHODS: We investigated the role of TSP1 in the autologous phase of an accelerated model of anti-glomerular basement membrane (GBM) GN in mice deficient in TSP1. The model, induced by the injection of rabbit anti-mouse GBM antibody, is characterized by the development of proteinuria and glomerular damage over a 21-day observation period in wild-type mice.
RESULTS: Mice deficient in TSP1 developed significantly less proteinuria than their wild-type controls 21 days after induction of disease (5,793 +/- 5,456 vs. 24,293 +/- 15,336 microg albumin/mg creatinine; p = 0.002). Serum creatinine levels were significantly higher in the wild-type mice than in the TSP1 deficient animals (29.03 +/- 2.34 vs. 16.39 +/- 2.87 micromol/l; p = 0.005). Other disease indices as crescent formation, fibrin deposition and macrophage influx, were also diminished in the TSP1 knockout animals. The numbers of interstitial CD4+ and CD8+ T cells were generally less in TSP1-deficient mice and reached statistical significance in CD4+ (p = 0.01) and CD8+ T cells (p = 0.02). The difference in outcome of the disease was not due to the difference in deposition/production of heterologous and autologous antibodies in the two groups of animals.
CONCLUSION: This study suggests a proinflammatory role of TSP1 in an experimental model of GN.