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      Decreased Degradation of Collagen and Fibronectin following Exposure of Proximal Cells to Glucose

      , , ,

      Cardiorenal Medicine

      S. Karger AG

      Fibronectin, Collagen, Glucose, Diabetes

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          Abstract

          Background/Aims: Thickening and reduplication of the tubular basement membrane has been reported as an early event in diabetic nephropathy. The aim of the work outlined here was to examine the effects and mechanisms involved in the modulation of renal proximal tubular type-IV collagen and fibronectin turnover by glucose. Methods: The effect of glucose on type-IV collagen and fibronectin generation was studied by exposure of primary cultures of human renal proximal tubular cells (HPTC) to elevated D-glucose concentrations. Subsequently the mechanism of modulation of fibronectin generation was examined in a polarised system utilising the porcine proximal tubular cell line LLC-PK1 grown on porous tissue culture inserts. Results: Incubation of confluent growth-arrested HPTC with 25 m M D-glucose led to the accumulation of both type-IV collagen and fibronectin. This increase was not dependent on new gene transcription for either protein. Exposure of HPTC to 25 m M D-glucose also led to the induction of tissue inhibitor of metalloproteinases (TIMP-1 and TIMP-2) and also gelatinase A. There was, however, a net decrease in overall gelatinolytic activity. Incubation of confluent monolayers of LLC-PK1 cells grown on tissue culture inserts with 25 m M D-glucose on either their apical or basolateral aspect led to fibronectin accumulation seen only in the basolateral compartment. Under these experimental conditions, we can demonstrate polyol pathway activation, and furthermore the increase in fibronectin concentration in response to glucose was inhibited by the aldose reductase inhibitor sorbinil. Fibronectin accumulation was also demonstrated following both apical and basolateral addition of 1 m M sorbitol, but not following the addition of 25 m M galactose to either aspect of the cells. Conclusions: These data demonstrate that the glucose-induced accumulation of type-IV collagen and fibronectin was associated with alterations in the degradative pathway of these matrix components. In addition fibronectin generation in response to glucose was non-polar in terms of application of glucose, but polar in terms of fibronectin accumulation. The mechanisms of glucose-induced modulation of fibronectin were mediated by polyol pathway activation, and more specifically related to the metabolism of sorbitol to fructose.

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          Author and article information

          Journal
          EXN
          Nephron Exp Nephrol
          10.1159/issn.1660-2129
          Cardiorenal Medicine
          S. Karger AG
          978-3-8055-6977-4
          978-3-318-00513-4
          1660-2129
          1999
          December 1999
          28 October 1999
          : 7
          : 5-6
          : 449-462
          Affiliations
          Institute of Nephrology, University of Wales College of Medicine, Cardiff Royal Infirmary, Cardiff, Wales, UK
          Article
          20624 Exp Nephrol 1999;7:449–462
          10.1159/000020624
          10559643
          © 1999 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: 13, References: 44, Pages: 14
          Product
          Self URI (application/pdf): https://www.karger.com/Article/Pdf/20624
          Categories
          Paper

          Cardiovascular Medicine, Nephrology

          Collagen, Glucose, Fibronectin, Diabetes

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