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      Angiotensin II Blockade Limits Tubular Protein Overreabsorption and the Consequent Upregulation of Endothelin 1 Gene in Experimental Membranous Nephropathy

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          Abstract

          Proteinuric renal diseases are associated with excessive renal synthesis of endothelin 1 (ET-1) either in experimental animals or humans. This has been interpreted as an upregulation of ET-1 gene in proximal tubular cells secondary to overreabsorption of an unusual amount of filtered proteins. Here we used a model of chronic proteinuria, passive Heymann nephritis (PHN), to localize the structure of the kidney responsible for excessive ET-1 expression and synthesis and to clarify whether drugs that reduce glomerular protein trafficking modified the distribution of ET-1 mRNA and the corresponding peptide in the kidney. PHN was induced in Sprague-Dawley rats after injection of rabbit anti-Fx1A antibody. Group 1 (n = 5) was untreated, group 2 (n = 5) was given daily the angiotensin-converting enzyme inhibitor lisinopril (40 mg/l) plus the angiotensin II receptor antagonist L-158,809 (50 mg/l) from day 7 – when rats were already proteinuric – to month 12. An additional group of normal rats (n = 5) was used as controls. Urinary excretion of ET-1 was significantly increased in PHN rats as compared with controls and normalized by the treatment. By in situ hybridization a weak signal for ET-1 mRNA was detectable in glomeruli, distal tubular segments, and proximal tubules of control kidneys. By contrast, a strong labeling was found in the kidneys of rats with PHN which was mainly localized to proximal tubules and renal interstitium. The pattern of renal ET-1-like immunoreactivity was remarkably consistent with ET-1 mRNA expression. In animals with PHN given the angiotensin II blocking therapy, the urinary excretion of proteins normalized, and the structural integrity of the kidney was well preserved. In the kidney tissue taken from these animals, both ET-1 mRNA and protein staining were quite comparable to controls. These data suggest a link between excessive protein tubular reabsorption and enhanced renal ET-1 in chronic nephropathies and provide a novel explanation for the renoprotective effect in vivo of drugs that, by blocking the biological activity of angiotensin II, reduce glomerular protein traffic and possible deleterious effects of excessive tubular protein overloading.

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          Author and article information

          Journal
          EXN
          Nephron Exp Nephrol
          10.1159/issn.1660-2129
          Cardiorenal Medicine
          S. Karger AG
          1660-2129
          1998
          April 1998
          20 March 1998
          : 6
          : 2
          : 121-131
          Affiliations
          a Mario Negri Institute for Pharmacological Research, Bergamo, and b Division of Nephrology and Dialysis, Azienda Ospedaliera, Ospedali Riuniti di Bergamo, Italy; c MRC Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, Que., Canada
          Article
          20519 Exp Nephrol 1998;6:121–131
          10.1159/000020519
          © 1998 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: 31, Pages: 11
          Product
          Self URI (application/pdf): https://www.karger.com/Article/Pdf/20519
          Categories
          Original Paper

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