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 µg 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 µmol/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.

Journal Section:
Original Paper
Keywords:
Thrombospondin-1, Transgenic mice, Glomerulonephritis
1.
Couser WG: Pathogenesis of glomerular damage in glomerulonephritis. Nephrol Dial Transplant 1998;13(suppl 1):10–15.
2.
Hricik DE, Chung-Park M, Sedor JR: Glomerulonephritis. N Engl J Med 1998;339:888–899.
[PubMed]
https://doi.org/10.1056/NEJM199809243391306
3.
Wilson C: Renal response to immunologic glomerular injury; in Brenner B (ed): The Kidney, ed 5. Philadephia, Saunders, 1996, pp 1253–1391.
4.
Hugo C: The role of thrombospondin in renal disease. Kidney Blood Press Res 2000;23:210–212.
[PubMed]
5.
Nishikawa K, Andres G, Bhan AK, McCluskey RT, Collins AB, Stow JL, Stamenkovic I: Hyaluronate is a component of crescents in rat autoimmune glomerulonephritis. Lab Invest 1993;68:146–153.
[PubMed]
6.
Petterson EA: Cold-insoluble globulin (fibronectin, LETS protein) in normal and diseased human glomeruli: Papain-sensitive attachment to normal glomeruli and deposition in crescents. Clin Immunol Immunopathol 1978;11:425–436.
[PubMed]
https://doi.org/10.1016/0090-1229(78)90170-8
7.
Nickeleit V, Zagachin L, Nishikawa K, Peters JH, Hynes RO, Colvin RB: Embryonic fibronectin isoforms are synthesized in crescents in experimental autoimmune glomerulonephritis. Am J Pathol 1995;147:965–978.
[PubMed]
8.
McGregor B, Colon S, Mutin M, Chignier E, Zech P, McGregor J: Thrombospondin in human glomerulopathies: A marker of inflammation and early fibrosis. Am J Pathol 1994;144:1281–1287.
[PubMed]
9.
Lawler J: The functions of thrombospondin-1 and -2. Curr Opin Cell Biol 2000;12:634–640.
[PubMed]
https://doi.org/10.1016/S0955-0674(00)00143-5
10.
Wight TN, Raugi GJ, Mumby SM, Bornstein P: Light microscopic immunolocation of thrombospondin in human tissues. J Histochem Cytochem 1985;33:295–302.
[PubMed]
11.
Bornstein P: Diversity of function is inherent in matricellular proteins: An appraisal of thrombospondin 1. J Cell Biol 1995;130:503–506.
[PubMed]
https://doi.org/10.1083/jcb.130.3.503
12.
Roberts DD: Regulation of tumor growth and metastasis by thrombospondin-1. FASEB J 1996;10:1183–1191.
[PubMed]
13.
Yabkowitz R, Dixit VM, Guo N, Roberts DD, Shimizu Y: Activated T-cell adhesion to thrombospondin is mediated by the alpha 4 beta 1 (VLA-4) and alpha 5 beta 1 (VLA-5) integrins. J Immunol 1993;151:149–158.
[PubMed]
14.
Wilson KE, Li Z, Kara M, Gardner KL, Roberts DD: Beta 1 integrin- and proteoglycan-mediated stimulation of T lymphoma cell adhesion and mitogen-activated protein kinase signaling by thrombospondin-1 and thrombospondin-1 peptides. J Immunol 1999;163:3621–3628.
[PubMed]
15.
Marinides GN, Suchard SJ, Mookerjee BK: Role of thrombospondin in mesangial cell growth: Possible existence of an autocrine feedback growth circuit. Kidney Int 1994;46:350–357.
[PubMed]
16.
Hugo C, Pichler R, Meek R, Gordon K, Kyriakides T, Floege J, Bornstein P, Couser WG, Johnson RJ: Thrombospondin 1 is expressed by proliferating mesangial cells and is up-regulated by PDGF and bFGF in vivo. Kidney Int 1995;48:1846–1856.
[PubMed]
17.
Hugo C, Shankland SJ, Pichler RH, Couser WG, Johnson RJ: Thrombospondin 1 precedes and predicts the development of tubulointerstitial fibrosis in glomerular disease in the rat. Kidney Int 1998;53:302–311.
[PubMed]
https://doi.org/10.1046/j.1523-1755.1998.00774.x
18.
Hugo CP, Pichler RP, Schulze-Lohoff E, Prols F, Adler S, Krutsch HC, Murphy-Ullrich JE, Couser WG, Roberts DD, Johnson RJ: Thrombospondin peptides are potent inhibitors of mesangial and glomerular endothelial cell proliferation in vitro and in vivo. Kidney Int 1999;55:2236–2249.
[PubMed]
https://doi.org/10.1046/j.1523-1755.1999.00459.x
19.
Hugo C, Kang DH, Johnson RJ: Sustained expression of thrombospondin-1 is associated with the development of glomerular and tubulointerstitial fibrosis in the remnant kidney model. Nephron 2002;90:460–470.
[PubMed]
https://doi.org/10.1159/000054735
20.
Rosenkranz AR, Mendrick DL, Cotran RS, Mayadas TN: P-selectin deficiency exacerbates experimental glomerulonephritis: A protective role for endothelial P-selectin in inflammation. J Clin Invest 1999;103:649–659.
[PubMed]
21.
Rosenkranz AR, Knight S, Sethi S, Alexander SI, Cotran RS, Mayadas TN: Regulatory interactions of alpha-beta and gamma-delta T cells in glomerulonephritis. Kidney Int 2000;58:1055–1066.
[PubMed]
https://doi.org/10.1046/j.1523-1755.2000.00263.x
22.
Lawler J, Sunday M, Thibert V, Duquette M, George EL, Rayburn H, Hynes RO: Thrombospondin-1 is required for normal murine pulmonary homeostasis and its absence causes pneumonia. J Clin Invest 1998;101:982–992.
[PubMed]
23.
Kitching AR, Holdsworth SR, Ploplis VA, Plow EF, Collen D, Carmeliet P, Tipping PG: Plasminogen and plasminogen activators protect against renal injury in crescentic glomerulonephritis. J Exp Med 1997;185:963–968.
[PubMed]
https://doi.org/10.1084/jem.185.5.963
24.
Haas M: IgG subclass deposits in glomeruli of lupus and nonlupus membranous nephropathies. Am J Kidney Dis 1994;23:358–364.
[PubMed]
25.
Schultz-Cherry S, Murphy-Ullrich JE: Thrombospondin causes activation of latent transforming growth factor-beta secreted by endothelial cells by a novel mechanism. J Cell Biol 1993;122:923–932.
[PubMed]
https://doi.org/10.1083/jcb.122.4.923
26.
Lan HY, Paterson DJ, Atkins RC: Initiation and evolution of interstitial leukocytic infiltration in experimental glomerulonephritis. Kidney Int 1991;40:425–433.
[PubMed]
27.
D’Amico G: Role of interstitial infiltration of leukocytes in glomerular diseases. Nephrol Dial Transplant 1988;3:596–600.
[PubMed]
28.
Crawford SE, Stellmach V, Murphy-Ullrich JE, Ribeiro SM, Lawler J, Hynes RO, Boivin GP, Bouck N: Thrombospondin-1 is a major activator of TGF-beta1 in vivo. Cell 1998;93:1159–1170.
[PubMed]
https://doi.org/10.1016/S0092-8674(00)81460-9
29.
Agah A, Kyriakides TR, Lawler J, Bornstein P: The lack of thrombospondin-1 (TSP1) dictates the course of wound healing in double-TSP1/TSP2-null mice. Am J Pathol 2002;161:831–839.
[PubMed]
30.
Mansfield PJ, Suchard SJ: Thrombospondin promotes chemotaxis and haptotaxis of human peripheral blood monocytes. J Immunol 1994;153:4219–4229.
[PubMed]
31.
Huber AR, Ellis S, Johnson KJ, Dixit VM, Varani J: Monocyte diapedesis through an in vitro vessel wall construct: Inhibition with monoclonal antibodies to thrombospondin. J Leukoc Biol 1992;52:524–528.
[PubMed]
32.
Lan HY, Nikolic-Paterson DJ, Mu W, Atkins RC: Local macrophage proliferation in the progression of glomerular and tubulointerstitial injury in rat anti-GBM glomerulonephritis. Kidney Int 1995;48:753–760.
[PubMed]
© 2004 S. Karger AG, Basel
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
2004
You do not currently have access to this content.