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      Inhibitory Effect of Pravastatin on Transforming Growth Factor β1-Inducible Gene h3 Expression in a Rat Model of Chronic Cyclosporine Nephropathy

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          Abstract

          Background/Aims: Overexpression of transforming growth factor β1-inducible gene h3 (βig-h3) is associated with renal scarring in several models of renal disease. We investigated the inhibitory effect of pravastatin on βig-h3 expression in a rat model of chronic cyclosporin A (CsA)-induced nephropathy. Methods: Adult Sprague Dawley rats kept on a low salt 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 pravastatin (20 mg/kg in drinking water). The effect of pravastatin on βig-h3 expression was evaluated using in situ hybridization, immunohistochemistry, and immunoblotting. Functional parameters, histopathology (tubulointerstitial fibrosis, TIF, and arteriolopathy), and levels of transforming growth factor β1 (TGF-β1) and endothelial nitric oxide synthase were compared for the different treatment groups. Results: Co-administration of pravastatin significantly inhibited βig-h3 mRNA production and gene expression within the tubulointerstitium of the CsA-treated kidneys, and this paralleled an attenuation of TIF (12.7 ± 2.2 vs. 35.9 ± 5.4%, p < 0.01 vs. CsA) and the expression of TGF-β1 mRNA (279 ± 40 vs. 719 ± 85%, p < 0.01 vs. CsA). Pravastatin treatment reduced endothelial nitric oxide synthase protein levels and reversed the renal dysfunction caused by CsA. Neither CsA nor pravastatin affected total serum cholesterol or triglyceride levels in the treatment groups. Conclusion: Pravastatin thus effectively abrogated the upregulation of βig-h3 gene expression and associated TGF-β1 production, and this was associated with attenuated TIF in this model of chronic CsA-induced nephropathy.

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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
          2005
          December 2005
          22 November 2005
          : 25
          : 6
          : 611-620
          Affiliations
          aDepartment of Internal Medicine, Xenotransplantation Center, KangNam St. Mary’s Hospital, bDepartment of Anatomy, Cell Death Research Center,The Catholic University of Korea, Seoul, cDepartment of Biochemistry, Kyungpook National University School of Medicine, Daegu, Korea; dDepartment of Internal Medicine, Nephrology and Dialysis Unit, the Affiliated Hospital, YanBian University Medical College, JiLin, China
          Article
          89905 Am J Nephrol 2005;25:611–620
          10.1159/000089905
          16308546
          © 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: 4, Tables: 1, References: 51, Pages: 10
          Product
          Self URI (application/pdf): https://www.karger.com/Article/Pdf/89905
          Categories
          Original Report: Laboratory Investigation

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