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      Arkadia-Smad7-Mediated Positive Regulation of TGF-β Signaling in a Rat Model of Tubulointerstitial Fibrosis

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          Abstract

          Background/Aims: Upregulation of transforming growth factor beta (TGF-β)/Smad signaling has been implicated in the primary pathogenesis of renal fibrosis. The ubiquitin-proteasome pathway has an important influence on TGF-β signaling through regulating Smad degradation. As E3 ubiquitin ligases, both Arkadia and Smurf2 are involved in this prosess. In this study, we focused on Arkadia, Smurf2, Smad7, and TGF-β type I receptor (TβRI), principal molecules in the regulation of TGF-β signaling, to understand the regulatory mechanism of ubiquitin-proteasomal degradation of TGF-β signaling in the pathogenesis of renal fibrosis. Methods: A unilateral ureteral obstruction (UUO) model was employed, and sham-operated rats were used as controls. Renal lesions and the expression of Arkadia, Smurf2, Smad7, TβRI, TGF-β1, and type 1 collagen (COL-1) were detected by Western blot, immunoprecipitation, immunohistochemistry, and/or reverse transcription-polymerase chain reaction. Results: The results indicated progressive tubulointerstitial fibrosis, high expression levels of Arkadia, Smurf2, TβRI, TGF-β1 mRNA, type 1 collagen mRNA, and Smad7 mRNA, and low levels of Smad7 protein in the kidneys of rats with unilateral ureteral obstruction, in which Smurf2 interacted with both Smad7 and TβRI, and Arkadia only interacted with Samd7 but not with TβRI. Conclusion: Reduction of Smad7 resulting from ubiquitin-dependent degradation may be mainly attributed to Arkadia, and Arkadia-Smad7-mediated positive regulation of TGF-β signaling may play a promoting role in the progression of tubulointerstitial fibrosis.

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          Most cited references 18

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          Transforming growth factor beta in tissue fibrosis.

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            Smurf1 interacts with transforming growth factor-beta type I receptor through Smad7 and induces receptor degradation.

            Smad7 is an inhibitory Smad that acts as a negative regulator of signaling by the transforming growth factor-beta (TGF-beta) superfamily proteins. Smad7 is induced by TGF-beta, stably interacts with activated TGF-beta type I receptor (TbetaR-I), and interferes with the phosphorylation of receptor-regulated Smads. Here we show that Smurf1, an E3 ubiquitin ligase for bone morphogenetic protein-specific Smads, also interacts with Smad7 and induces Smad7 ubiquitination and translocation into the cytoplasm. In addition, Smurf1 associates with TbetaR-I via Smad7, with subsequent enhancement of turnover of TbetaR-I and Smad7. These results thus reveal a novel function of Smad7, i.e. induction of degradation of TbetaR-I through recruitment of an E3 ligase to the receptor.
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              Smad7 Binds to Smurf2 to Form an E3 Ubiquitin Ligase that Targets the TGFβ Receptor for Degradation

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                Author and article information

                Journal
                AJN
                Am J Nephrol
                10.1159/issn.0250-8095
                American Journal of Nephrology
                S. Karger AG
                0250-8095
                1421-9670
                2007
                April 2007
                07 March 2007
                : 27
                : 2
                : 176-183
                Affiliations
                Department of Nephrology, Second Xiangya Hospital of the Central South University, Changsha, China
                Article
                100518 Am J Nephrol 2007;27:176–183
                10.1159/000100518
                17347560
                © 2007 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: 4, References: 23, Pages: 8
                Categories
                Original Report: Laboratory Investigation

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