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      Hyperhexosemia Induced Functional and Structural Changes in the Kidneys: Role of Endothelins

      research-article
      , , , ,
      Nephron
      S. Karger AG
      Endothelins, Hyperhexosemia, Kidney, Bosentan, Basement membrane

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          Abstract

          Background/Aims: Glomerular basement membrane (GBM) thickening and mesangial matrix expansion are characteristic features of diabetic nephropathy. The present study investigates the role of endothelins (ETs) in the pathogenesis of such changes in diabetic nephropathy. Methods: Diabetic (streptozotocin-induced, 65 mg/kg), galactose-fed (30%) and control animals were followed up for 1 and 6 months. Animal groups also included diabetic and galactose fed animals on dual ET<sub>A</sub>/ET<sub>B</sub> receptor antagonist bosentan (100 mg/kg). A semi-quantitative reverse transcription polymerase chain reaction method was used to quantify mRNA expression of ET-1, ET-3, ET<sub>A</sub>, ET<sub>B</sub>, fibronectin and collagen α2(IV). Histological analyses of the kidneys and ET-1, ET-3 and fibronectin immunohistochemistry were performed. Morphometric assessment of the GBM after 6 months was performed. Results: Diabetes increased mRNA expression of ET-1, ET-3, ET<sub>A</sub>, ET<sub>B</sub>, fibronectin and collagen α2(IV) after one and six months. In contrast, although increased ET<sub>A</sub> and ET<sub>B</sub> mRNAs were present following galactose feeding both at 1 and 6 months, ET-1, ET-3, fibronectin and collagen α2(IV)mRNAs were increased after 6 months. Both diabetes and galactose feeding caused increased GBM thickening. Furthermore, diabetes caused an increase in mesangial matrix production. Bosentan prevented increased fibronectin and collagen α2(IV) mRNA expression, increased mesangial matrix deposition and GBM thickening. Conclusion: This study has demonstrated that diabetes and galactose feeding induced functional and structural changes in the kidney are mediated via ETs.

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          Endothelins.

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            Pathophysiology of endothelin in the cardiovascular system.

            In this article, we review the basic pharmacological and biochemical features of endothelin and the pathophysiological roles of endothelin in cardiovascular diseases. Development of receptor antagonists has accelerated the pace of investigations into the pathophysiological roles of endogenous endothelin-1 in various diseases, e.g. chronic heart failure, renal diseases, hypertension, cerebral vasospasm, and pulmonary hypertension. In chronic heart failure, the expression of endothelin-1 and its receptors in cardiomyocytes is increased, and treatment with an endothelin receptor antagonist improves survival and cardiac function. Endothelin receptor antagonists also improve other cardiovascular diseases. These results suggest that the interference with endothelin pathway either by receptor blockade or by inhibition of endothelin converting enzyme may provide novel therapeutic drugs strategies for multiple disease states.
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              The structure and specificity of endothelin receptors: Their importance in physiology and medicine

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                Author and article information

                Journal
                NEF
                Nephron
                10.1159/issn.1660-8151
                Nephron
                S. Karger AG
                1660-8151
                2235-3186
                2002
                2002
                13 December 2001
                : 90
                : 1
                : 86-94
                Affiliations
                Department of Pathology, University of Western Ontario, London, Ontario, Canada
                Article
                46319 Nephron 2002;90:86–94
                10.1159/000046319
                11744810
                eed7e6c4-e470-4393-bdb5-b2c39220de02
                © 2002 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.

                History
                Page count
                Figures: 6, References: 45, Pages: 9
                Categories
                Original Paper

                Cardiovascular Medicine,Nephrology
                Endothelins,Hyperhexosemia,Kidney,Bosentan,Basement membrane
                Cardiovascular Medicine, Nephrology
                Endothelins, Hyperhexosemia, Kidney, Bosentan, Basement membrane

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