Role of thrombospondin-1 in the autologous phase of an accelerated model of anti-glomerular basement membrane glomerulonephritis.
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.


CONCLUSIONS
This study suggests a proinflammatory role of TSP1 in an experimental model of GN.
Klinische Abteilung für Nephrologie, Universitätsklinik für Innere Medizin Innsbruck, Innsbruck, Austria.
Kathrin
K
Hochegger
Sara
S
Knight
Christian
C
Hugo
Gert
G
Mayer
Jack
J
Lawler
Tanya N
TN
Mayadas
Alexander R
AR
Rosenkranz
D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000276:immunology* / Q000473:pathology; D000910:Antibodies, Heterophile / Q000032:analysis; D007518:Isoantibodies / Q000032:analysis; D007700:Kinetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011507:Proteinuria / Q000209:etiology; D019700:Thrombospondin 1 / Q000235:genetics / Q000502:physiology*
D000910:Antibodies, Heterophile; D007518:Isoantibodies; D019700:Thrombospondin 1