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      Mechanisms Underlying the Ameliorative Property of Lisinopril in Progressive Mesangioproliferative Nephritis

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          Abstract

          The present study was performed to clarify the mechanism underlying the beneficial effects of lisinopril on chronic glomerulonephritis. Chronic glomerulonephritis was induced by a single injection of E30 monoclonal antibody (E30) recognizing Thy-1.1 antigen to unilaterally nephrectomized rats. E30 injection resulted in persistent massive proteinuria with a decrease in anionic charge sites on the glomerular basement membrane (GBM) at 8 weeks. Also, renal tissue from rats treated with E30 showed typical glomerulosclerosis and tubulointerstitial fibrosis. Lisinopril exerted a potent antiproteinuric effect and suppressed the progression of both glomerulosclerosis and tubulointerstitial fibrosis. Lisinopril recovered the reduced number of anionic charge sites on GBM, accounting for the positive action against massive proteinuria. Immunostaining for desmin revealed that lisinopril treatment prevented the injury of glomerular epithelial cells (GECs) occurring in the chronic nephritic stage. Also, the level of gene expression of transforming growth factor-β (TGF-β) and plasminogen activator inhibitor-1 (PAI-1) in the renal cortex were reduced, suggesting that lisinopril improved extracellular matrix (ECM) metabolism. These results indicated that proteinuria in Thy-1.1 antibody-induced chronic nephritis is associated with a decrease in anionic charge sites on GBM, and that the antiproteinuric effect of lisinopril is attributable to protection against GEC damage. Suppression of TGF-β and PAI-1 expression contributed to the preventive effect of lisinopril on ECM deposition in renal tissue.

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          Most cited references 5

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          Suppression of experimental glomerulonephritis by antiserum against transforming growth factor beta 1.

          Glomerulonephritis is an inflammation of the kidney characterized by the accumulation of extracellular matrix within the damaged glomeruli, impaired filtration and proteinuria. In its progressive form, the disease destroys kidney function leading to uraemia and death, unless dialysis therapy or kidney transplantation is available. The pathogenesis of glomerulonephritis is incompletely understood, but the eliciting factor is thought often to be an immunological injury to mesangial and/or other resident cells in the glomeruli. We have used an animal model of acute mesangial proliferative glomerulonephritis to show that this disease is associated with increased production and activity of transforming growth factor beta 1 (TGF-beta 1), an inducer of extracellular matrix production. Here we report that administration of anti-TGF-beta 1 at the time of induction of the glomerular disease suppresses the increased production of extracellular matrix and dramatically attenuates histological manifestations of the disease. These results provide direct evidence for a causal role of TGF-beta 1 in the pathogenesis of the experimental disease and suggest a new approach to the therapy of glomerulonephritis.
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            Targeting TGF-beta overexpression in renal disease: maximizing the antifibrotic action of angiotensin II blockade.

            Overproduction of transforming growth factor-beta (TGF-beta) is a key mediator of extracellular matrix accumulation in fibrotic diseases. We hypothesized that the degree of reduction of pathological TGF-beta expression can be used as a novel index of the antifibrotic potential of angiotensin II (Ang II) blockade in renal disease. One day after induction of Thy 1.1 glomerulonephritis, rats were treated with increasing doses of the Ang I converting enzyme (ACE) inhibitor enalapril and/or the Ang II receptor blocker losartan in the drinking water. Six days after disease induction the therapeutic effect on glomerular TGF-beta overexpression was evaluated. Both enalapril and losartan reduced TGF-beta overproduction in a dose-dependent manner, showing a moderate reduction at doses known to control blood pressure in renal forms of hypertension. A maximal reduction in TGF-beta expression of approximately 45% was seen for both drugs starting at 100 mg/liter enalapril and 500 mg/liter losartan, with no further reduction at doses of enalapril up to 1000 mg/liter or losartan up to 2500 mg/liter. Co-treatment with both drugs was not superior to single therapy. Consistent with our hypothesis that reduction in TGF-beta expression is a valid target, other disease measures, including glomerular matrix accumulation, glomerular production and mRNA expression of the matrix protein fibronectin and the protease inhibitor plasminogen-activator-inhibitor type 1 (PAI-1) closely followed TGF-beta expression. The data suggest that these therapies act through very similar pathways and that, in order to more effectively treat renal fibrosis, these drugs must be combined with other drugs that act by different mechanisms.
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              Recovery of Damaged Glomerular Capillary Network with Endothelial Cell Apoptosis in Experimental Proliferative Glomerulonephritis

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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
                August 2002
                15 July 2002
                : 91
                : 4
                : 719-729
                Affiliations
                Shionogi Discovery Research Laboratories, Shionogi & Co., Osaka, and bDepartment of Anatomy, Juntendo University School of Medicine , Bunkyo-ku, Tokyo, Japan
                Article
                65036 Nephron 2002;91:719–729
                10.1159/000065036
                12138278
                © 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.

                Page count
                Figures: 6, Tables: 3, References: 36, Pages: 11
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/65036
                Categories
                Original Paper

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