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      Enalaprilat Directly Ameliorates in vitro Cyclosporin Nephrotoxicity in Human Tubulo-Interstitial Cells

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          Abstract

          Background/Aims: Several recent studies have suggested that angiotensin-converting enzyme (ACE) inhibitors ameliorate chronic cyclosporin A (CyA) tubulo-interstitial disease by mechanisms independent of their antihypertensive effects. The aim of the present study was to determine whether ACE inhibition exerts a direct beneficial effect on the tubulo-interstitium in an in vitro model of chronic CyA nephropathy. Methods: Primary cultures of human proximal tubular cells (PTC) and renal cortical fibroblasts (CF) were exposed for 24 h to CyA in the presence or absence of enalaprilat. Parameters of tubulo-interstitial nephrotoxicity were then measured including collagen synthesis (proline incorporation), tubular viability and function (thymidine incorporation, lactate dehydrogenase release, and apical sodium-hydrogen exchange), and secretion of insulin-like growth factor I, transforming growth factor beta 1 (TGFβ<sub>1</sub>), and platelet-derived growth factor. Results: CyA promoted CF collagen synthesis, PTC cytotoxicity (suppressed viability, growth and sodium transport), and tubulo-interstitial fibrogenic cytokine release (CF secretion of insulin-like growth factor I and PTC secretion of TGFβ<sub>1</sub> and platelet-derived growth factor). Enalaprilat completely reversed the stimulatory effects of CyA on CF collagen synthesis (CyA + enalaprilat 6.40 ± 0.50% vs. CyA alone 8.33 ± 0.56% vs. control 6.57 ± 0.62% vs. enalaprilat alone 5.55 ± 0.93%, p < 0.05) and PTC secretion of TGFβ<sub>1</sub> (0.71 ± 0.11, 1.13 ± 0.09, 0.89 ± 0.07, and 0.67 ± 0.09 ng/mg protein/day, respectively, p < 0.05). However, the other manifestations of CyA toxicity were not significantly reversed by concomitant enalaprilat administration. Conclusions: ACE inhibition directly prevents CyA-induced interstitial fibrosis, but not proximal tubule cytotoxicity, independently of haemodynamic and systemic renin-angiotensin system effects. Renoprotection may be partially afforded by directly preventing the tubular secretion of TGFβ<sub>1</sub>.

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          Fibrogenic Effects of Cyclosporin A on the Tubulointerstitium: Role of Cytokines and Growth Factors

          The clinical utility of cyclosporin A (CyA) as an immunosuppressive agent has been significantly limited by the frequent occurrence of chronic nephrotoxicity, characterised by tubular atrophy, interstitial fibrosis and progressive renal impairment. The pathogenesis of this condition remains poorly understood, but has been postulated to be due to either direct cytotoxicity or indirect injury secondary to chronic renal vasoconstriction. Using primary cultures of human proximal tubule cells (PTCs) and renal cortical fibroblasts (CFs) as an in vitro model of the tubulointerstitium, we have been able to demonstrate that clinically relevant concentrations of CyA are directly toxic to these cells and promote fibrogenesis by a combination of suppressed matrix metalloproteinase activity and augmented fibroblast collagen synthesis. The latter effect occurs secondary to the ability of CyA to stimulate autocrine secretion of insulin-like growth factor-I by CFs and paracrine secretion of transforming growth factor-β 1 by PTCs. Many of these pro-fibrotic mechanisms are completely reversed by concurrent administration of the angiotensin-converting enzyme inhibitor, enalaprilat, which has proven efficacy in preventing chronic CyA nephropathy in vivo. These studies highlight the unique potential that human renal cell cultures offer for studying the role of local cytokine networks in tubulointerstitial disease and for developing more effective treatment strategies which specifically target fibrogenic growth factor activity following nephrotoxic injuries.
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            Author and article information

            Journal
            NEF
            Nephron
            10.1159/issn.1660-8151
            Nephron
            S. Karger AG
            1660-8151
            2235-3186
            2000
            December 2000
            01 December 2000
            : 86
            : 4
            : 473-481
            Affiliations
            aDepartment of Renal Medicine, Princess Alexandra Hospital, Brisbane, and bDepartment of Medicine, University of Sydney at Royal North Shore Hospital, Sydney, Australia
            Article
            45837 Nephron 2000;86:473–481
            10.1159/000045837
            11124597
            © 2000 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: 5, Tables: 1, References: 46, Pages: 9
            Product
            Self URI (application/pdf): https://www.karger.com/Article/Pdf/45837
            Categories
            Original Paper

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