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      Sustained Expression of Thrombospondin-1 Is Associated with the Development of Glomerular and Tubulointerstitial Fibrosis in the Remnant Kidney Model

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          Abstract

          Background/Aims: Transforming growth factor-β<sub>1</sub> (TGF-β<sub>1</sub>) has been implicated in the development of progressive nephrosclerosis in the remnant kidney model of chronic renal insufficiency. Thrombospondin-1 (TSP-1) is an extracellular matrix protein which has been recently shown to be capable of converting TGF-β from its latent to its active form. We studied the expression of TSP-1 mRNA and protein during the development of glomerular and tubulointerstitial nephrosclerosis in the renal ablation model particularly in relation to TGF-β<sub>1</sub> expression. Methods: The remnant kidney model in the rat was investigated 3 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 7.5 weeks and 10 weeks after disease induction. Using single and double immunostaining techniques, renal tissues were examined for TSP-1 protein, TGF-β<sub>1</sub>, platelet-derived growth factor BB, extracellular matrix proteins, such as collagens and fibronectin, myofibroblast formation and macrophage influx. TSP-1 mRNA expression was investigated using a radioactive in situ hybridization technique. Results: De novo expression of TSP-1 mRNA and protein occurred in all glomerular cell types as well as in tubular cells, myofibroblasts and some macrophages in areas of tubulointerstitial injury. TSP-1 expression preceded and was sustained during the development of tubulointerstitial and glomerular fibrosis and was frequently localized at sites of increased expression of TGF-β<sub>1</sub>, but not of platelet-derived growth factor BB. Conclusion: In the remnant kidney model, the time course and localization of TSP-1 are consistent with its playing a role as a local activator of TGF-β<sub>1</sub>, thereby potentially participating in the development of nephrosclerosis.

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          Thrombospondin-1 Is a Major Activator of TGF-β1 In Vivo

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            Thrombospondin causes activation of latent transforming growth factor- beta secreted by endothelial cells by a novel mechanism [published erratum appears in J Cell Biol 1993 Sep;122(5):following 1143]

            Thrombospondin (TSP) forms specific complexes with transforming growth factor-beta (TGF-beta) in the alpha granule releasate of platelets and these TSP-TGF-beta complexes inhibit the growth of bovine aortic endothelial cells (BAE). In these studies, we report that TSP stripped of associated TGF-beta (sTSP) retained growth inhibitory activity which was partially reversed by a neutralizing antibody specific for TGF- beta. Since BAE cells secrete latent TGF-beta, we determined whether sTSP activates the latent TGF-beta secreted by BAE cells. Cells were cultured with or without sTSP and then the conditioned medium was tested for the ability to support TGF-beta-dependent normal rat kidney (NRK) colony formation in soft agar. Medium conditioned with sTSP showed a dose- and time-dependent ability to stimulate BAE-secreted TGF- beta activity, reaching maximal activation by 1-2 h with 0.4 micrograms/ml (0.9 nM) sTSP. The sTSP-mediated stimulation of TGF-beta activity is not dependent on serum factors and is not a general property of extracellular matrix molecules. The sTSP-mediated stimulation of TGF-beta activity was blocked by a mAb specific for sTSP and by neutralizing antibodies to TGF-beta. Activation of BAE cell secreted latent TGF-beta by sTSP can occur in the absence of cells and apparently does not require interactions with cell surface molecules, since in conditioned medium removed from cells and then incubated with sTSP, activation occurs with kinetics and at levels similar to what is seen when sTSP is incubated in the presence of cells. Serine proteases such as plasmin are not involved in sTSP-mediated activation of TGF- beta. Factors that regulate the conversion of latent to active TGF-beta are keys to controlling TGF-beta activity. These data suggest that TSP is a potent physiologic regulator of TGF-beta activation.
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              Diversity of function is inherent in matricellular proteins: an appraisal of thrombospondin 1

               P Bornstein (1995)
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                Author and article information

                Journal
                NEF
                Nephron
                10.1159/issn.1660-8151
                Nephron
                S. Karger AG
                1660-8151
                2235-3186
                2002
                April 2002
                08 April 2002
                : 90
                : 4
                : 460-470
                Affiliations
                aMedizinische Klinik IV, Universität Erlangen-Nürnberg, Germany, and bDivision of Nephrology, Department of Medicine, University of Washington, Seattle, Wash., USA
                Article
                54735 Nephron 2002;90:460–470
                10.1159/000054735
                11961406
                © 2002 S. Karger AG, Basel

                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.

                Page count
                Figures: 6, References: 26, Pages: 11
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/54735
                Categories
                Original Paper

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