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      All-trans-Retinoic Acid Inhibits the Development of Mesangial Proliferative Glomerulonephritis in Interleukin-6 Transgenic Mice

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          Abstract

          All-trans-retinoic acid (ATRA), a vitamin A derivative, was reported to suppress the interleukin-6 (IL-6) production and to downregulate the IL-6 receptor (IL-6R) and/or its signal transducer glycoprotein 130. We investigated the in vivo antinephritic effect of ATRA on IL-6 transgenic mice which had developed mesangial proliferative glomerulonephritis (PGN) as well as its in vitro inhibitory effect on the proliferation of rat mesangial cells. In vivo experiments on IL-6 transgenic mice showed that ATRA administration suppressed proteinuria and hematuria and reduced the IL-6 concentrations; furthermore, histological examination demonstrated that it improved PGN. In vitro experiments using rat mesangial cells demonstrated that ATRA inhibited cell growth in a dose-dependent manner within a range from 10<sup>–4</sup> to 10<sup>–6</sup> M. This inhibition by ATRA was partially counteracted by the addition of IL-6. RT-PCR assay results showed that ATRA also reduced IL-6R, but not the glycoprotein 130 expression in mesangial cells. These findings indicate that, by blocking of the IL-6 function, ATRA may be therapeutically effective in PGN.

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          Most cited references 14

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          IgG1 plasmacytosis in interleukin 6 transgenic mice.

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            Cloning of murine alpha and beta retinoic acid receptors and a novel receptor gamma predominantly expressed in skin.

            In addition to having profound effects on embryonic pattern formation, retinoic acid (RA) has striking effects on differentiation and maintenance of epithelial cells in vivo and in vitro Skin is a major target organ for retinoids both in its normal and pathological states. The discovery of two human nuclear receptors for RA (hRAR alpha and hRAR beta) acting as transcriptional RA-inducible enhancer factors has provided a basis for understanding how RA controls gene expression. To investigate the specific role that RARs might play during development and in adult tissues, we have cloned the mouse RAR alpha and RAR beta (mRAR alpha and mRAR beta). Their amino-acid sequences are much more homologous to those of hRAR alpha and hRAR beta, respectively, than to each other, which suggests strongly that RAR alpha- and beta-subtypes have different functions. Most interestingly we have discovered a novel RAR subtype (mRAR gamma) whose expression in adult mouse seems to be highly restricted to skin, whereas RAR alpha and RAR beta are expressed in a variety of adult tissues. Furthermore, both mRAR alpha and mRAR gamma RNAs are readily detected in undifferentiated F9 embryocarcinoma (EC) cells, whereas mRAR beta messenger RNA is induced at least 30-fold in RA-differentiated F9 cells.
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              Anti-interleukin 6 (IL-6) receptor antibody suppresses Castleman's disease like symptoms emerged in IL-6 transgenic mice.

              Transgenic mice carrying human IL-6 cDNA fused with a murine major histocompatibility class-I promoter (H-2L(d)) were serially administered with anti-interleukin-6 receptor (IL-6R) monoclonal antibody (mAb), MR16-1, from the age of 4 weeks to estimate its efficacy on a variety of disorders developed in these mice, most of which are similar to the disorders associated with Castleman's disease. In the control mice treated with isotype-matched mAb, a massive and multiple IgG1 plasmacytosis, mesangial proliferative glomerulonephritis, leukocytosis, thrombocytosis, anemia and abnormalities of blood chemical parameters have developed in accordance with the elevation of serum IL-6, and 50% of mice have died of renal failure by 18 weeks of age. In contrast, the treatment with MR16-1 prevented all these symptoms and prolonged the lifetime of the majority of the mice. Thus, the constitutive overexpression of IL-6 caused various disorders, and the treatment with anti-IL-6R mAb completely prevented from these symptoms. These results clearly confirm that IL-6 indeed plays an essential role in the pathogenesis of a variety of disorders. Furthermore, anti-IL-6R mAb could provide novel therapy for Castleman's disease and MR16-1 should be a useful tool to estimate therapeutic potential of IL-6 antagonists in a variety of murine models for human disease. Copyright 2003 Elsevier Science Ltd.
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                Author and article information

                Journal
                NEE
                Nephron Exp Nephrol
                10.1159/issn.1660-2129
                Cardiorenal Medicine
                S. Karger AG
                1660-2129
                2005
                May 2005
                23 March 2005
                : 100
                : 1
                : e54-e62
                Affiliations
                aDepartment of Molecular Medicine, Osaka University Graduate School of Medicine, Osaka, bFirst Department of Internal Medicine, Nara Medical University, Kashihara, cDepartment of Medical Science I, School of Health and Sport Sciences, Osaka University, Osaka, and dLaboratory of Immune Regulation, Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan
                Article
                84655 Nephron Exp Nephrol 2005;100:e54–e62
                10.1159/000084655
                15795517
                © 2005 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: 7, References: 32, Pages: 1
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/84655
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