Blockade of Angiotensin II with Losartan Attenuates Transforming Growth Factor-β1 Inducible Gene-h3 (βig-h3) Expression in a Model of Chronic Cyclosporine Nephrotoxicity

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Abstract

Background: We recently demonstrated that upregulation of the transforming growth factor (TGF)-β1 inducible gene-h3 (βig-h3) is associated with tubulointerstitial fibrosis (TIF) in a rat model of chronic cyclosporine A (CsA) nephrotoxicity. This study investigated the association between βig-h3 expression and TIF during losartan treatment in this model. Methods: Adult Sprague-Dawley rats kept on a salt-depleted diet (0.05% sodium) were treated daily for 4 weeks with vehicle (olive oil, 1 ml/kg), CsA (15 mg/kg) or both CsA and losartan (10 mg/kg in drinking water). The effect of losartan on βig-h3 expression was evaluated using in situ hybridization, immunohistochemistry and immunoblotting. Histopathology, expressions of TGF-β1 and intrarenal angiotensin II were compared across treatment groups. Results: Concurrent administration of losartan significantly attenuated βig-h3 mRNA and protein expression within the tubulointerstitium of CsA-treated kidneys. This was accompanied by the retardation of TIF (18 ± 5 vs. 39 ± 5%, p < 0.01 vs. CsA) and the expression of TGF-β1 mRNA (336 ± 49 vs. 685 ± 63%, p < 0.01 vs. CsA) and the number of angiotensin II-positive glomeruli (18 ± 5 vs. 38 ± 6, p < 0.05 vs. CsA). Conclusion: Losartan is capable of abrogating the upregulation of TGF-β1 and βig-h3 expression, and this is associated with attenuated tubulointerstitial fibrosis in chronic CsA nephrotoxicity.

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Identification of motifs for cell adhesion within the repeated domains of transforming growth factor-beta-induced gene, betaig-h3.

Yu Park, T. J. Kim, S. H. Kim … (2000)

betaig-h3 is a transforming growth factor-beta-inducible cell adhesion molecule that has four characteristic homologous repeated domains. We made recombinant betaig-h3 proteins, which were highly active in mediating human corneal epithelial (HCE) cell adhesion and spreading. The 2nd and the 4th repeated domains were sufficient to mediate HCE cell adhesion. A sequence analysis showed that aspartic acid (Asp) and isoleucine (Ile) of the 2nd and the 4th domains are highly conserved in many fasciclin 1 homologous (fas-1) domains. Substitution mutational study identified these two amino acids are essential for cell adhesion. Synthetic peptides containing Asp and Ile, NKDIL and EPDIM derived from the 2nd and the 4th domains, respectively, almost completely blocked cell adhesion mediated by not only wild type betaig-h3 but also each of the 2nd and the 4th domains. These peptides alone were fully active in mediating cell adhesion. In addition, we demonstrated the functional receptor for betaig-h3 is alpha(3)beta(1) integrin. These results, therefore, establish the essential motifs within the 2nd and the 4th domains of betaig-h3, which interact with alpha(3)beta(1) integrin to mediate HCE cell adhesion to betaig-h3 and suggest that other proteins containing Asp-Ile in their fas-1 domains could possibly function as cell adhesion molecules.

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Nephrotoxicity of immunosuppressive drugs: long-term consequences and challenges for the future.

L Ceballos, Joan W. Bennett, A Olyaei (2000)

The calcineurin inhibitors cyclosporin A (CsA) and tacrolimus (FK506) are associated with dose- and efficacy-limiting adverse events, including nephrotoxicity, which may diminish their overall benefits for long-term graft survival. Nephrotoxicity is difficult to distinguish from chronic allograft rejection and is a particular problem in the setting of renal transplantation. Minimizing immunosuppressant-induced nephrotoxicity could improve long-term renal allograft survival. However, to obtain significant long-term improvement in renal allograft outcomes, it may be necessary to adopt new immunosuppressive regimens that rely less on calcineurin inhibitors. Recipients of other transplanted organs, as well as patients with autoimmune diseases who require immunosuppressant therapy, could also benefit from this change in immunosuppressive drug strategy because their healthy, native kidneys are particularly susceptible to the nephrotoxic effects of CsA and FK506. CsA- and FK506-sparing regimens, which use reduced doses of CsA and FK506 in combination with other nonnephrotoxic immunosuppressants, may be the best current option for reducing nephrotoxicity. The chemical immunosuppressant mycophenolate mofetil (MMF) has been used as part of CsA- and FK506-sparing regimens that provide improved renal function while maintaining adequate immunosuppression. Such regimens should reduce patient morbidity and mortality. Also, because immunosuppressant-induced nephrotoxicity has been associated with significant financial costs, CsA- and FK506-sparing regimens should result in substantial savings in health care costs.

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cDNA Cloning and Sequence Analysis of βig-h3, a Novel Gene Induced in a Human Adenocarcinoma Cell Line after Treatment with Transforming Growth Factor-β

GREGORY D. PLOWMAN, KELLY BENNETT, LINDA MADISEN … (1992)

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Author and article information

Journal

Journal ID (publisher-id): NEE

Journal ID (nlm-ta): Nephron Exp Nephrol

Journal ID (doi): 10.1159/issn.1660-2129

Title: Cardiorenal Medicine

Publisher: S. Karger AG

ISSN (Electronic): 1660-2129

Publication date Subscription-year: 2005

Publication date (Print): January 2005

Publication date (Electronic): 14 January 2005

Volume: 99

Issue: 1

Pages: e9-e16

Affiliations

Department of ^aInternal Medicine, The Catholic University of Korea, Seoul, and ^bDepartment of Biochemistry, Kyungpook National University School of Medicine, Daegu, Korea; ^cNephrology and Dialysis Unit, the Affiliated Hospital, YanBian University Medical College, YanJi, JiLin, PR China

Article

Publisher ID: 81793 Other ID: Nephron Exp Nephrol 2005;99:e9–e16

DOI: 10.1159/000081793

PubMed ID: 15637465

SO-VID: 5e9f82c3-165c-4455-9138-3303fa341085

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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.

History

Date received : 02 February 2004

Date accepted : 07 July 2004

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Figures: 5, Tables: 2, References: 34, Pages: 1

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Blockade of Angiotensin II with Losartan Attenuates Transforming Growth Factor-β1 Inducible Gene-h3 (βig-h3) Expression in a Model of Chronic Cyclosporine Nephrotoxicity

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Abstract

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Karger: Nephrology

Most cited references 28

Identification of motifs for cell adhesion within the repeated domains of transforming growth factor-beta-induced gene, betaig-h3.

Nephrotoxicity of immunosuppressive drugs: long-term consequences and challenges for the future.

cDNA Cloning and Sequence Analysis of βig-h3, a Novel Gene Induced in a Human Adenocarcinoma Cell Line after Treatment with Transforming Growth Factor-β

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