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      Effects of Rapamycin on Active Heymann Nephritis

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          Abstract

          Background/Aim: The effects of rapamycin (RAPA) were examined in active Heymann nephritis (HN), an experimental model of human membranous nephropathy (MN). Current opinion on the therapy of MN is controversial, and medications used for its treatment have not yielded the expected results. Methods: In a two-part study, we examined the effects of RAPA (1.5 mg/kg/day) during the induction phase of HN and on the evolving disease. In both parts, control groups of immunized rats not treated with RAPA and control groups of unimmunized rats were observed and sacrificed concurrently with the treated groups. Results: During the induction phase no significant changes in proteinuria were observed in the group treated with RAPA, in comparison to those in the untreated group (p < 0.001). During the evolving disease RAPA significantly lowered proteinuria (p < 0.001). The characteristic pathohistologic changes and IgG depositions along the glomerular basement membrane were considerably diminished, and infiltration of CD8+ cells completely prevented. Conclusion: RAPA demonstrated beneficial effects on disease progression, given either in the induction phase or during evolving HN. It would be desirable to investigate the effect of RAPA on patients with MN.

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          Most cited references 17

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          Rapamune (RAPA, rapamycin, sirolimus): mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression.

          Rapamune is a novel immunosuppressive agent in Phase III clinical trial in renal transplantation. Its unique mechanism of action has created great interest in its use as a biochemical probe of signal transduction pathways that has provided insight into its molecular mechanism of action. This article reviews the current state of our understanding of the mechanism of action of rapamune.
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            Rapamycin prolongs survival and arrests pathophysiologic changes in murine systemic lupus erythematosus.

            To evaluate the effects of oral rapamycin (RAPA), a macrolide immunosuppressant that has been shown to interfere with T cell activation events, on the course of spontaneous disease progression in the MRL/MpJ/lpr/lpr (MRL/l) mouse model of lupus. RAPA treatment (6, 12, or 25 mg/kg 3 times per week) was evaluated by monitoring survival rates, autoantibody levels, and urinary albumin levels. Additionally, concanavalin A responsiveness, interleukin-2 (IL-2) production, lymphoid organ size, and histopathology were evaluated ex vivo. RAPA prevented the typical rise in anti-double-stranded DNA antibody and urinary albumin levels and prolonged survival. Spleen and lymph node sizes were significantly decreased, inflammatory changes in the lung, liver, kidney, spleen, lymph node, and thymus were significantly reduced, and T cell mitogen-stimulated splenocyte proliferation and IL-2 production were restored. Data from 3 independent experiments demonstrated that RAPA significantly reduced or prevented many pathologic features of lupus normally seen in the MRL/l mouse, and suggest that RAPA may be useful as a therapeutic agent in SLE in humans.
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              Rapamycin ameliorates proteinuria-associated tubulointerstitial inflammation and fibrosis in experimental membranous nephropathy.

              Proteinuria is a risk factor for progression of chronic renal failure. A model of proteinuria-associated tubulointerstitial injury was developed and was used to examine the therapeutic effect of rapamycin. Two studies were performed. In study A, proteinuric rats were given sheep anti-Fx1A to induce experimental membranous nephropathy; control rats received normal sheep serum. Four weeks later, groups were subdivided and underwent laparotomy alone (two kidneys), nephrectomy alone (one kidney), or nephrectomy with polectomy (0.6 kidney). Renal function and morphology were evaluated 4 wk later. Whereas control rats never developed proteinuria, anti-Fx1A induced severe proteinuria. Proteinuria was unaffected by renal mass reduction. Proteinuric rats developed tubulointerstitial disease that was most severe in rats with 0.6 kidneys. Renal function (GFR) was reduced by loss of renal mass and was reduced further in proteinuric rats with 0.6 kidneys. In study B, the effect of rapamycin on the expression of candidate proinflammatory and profibrotic genes and the progression of proteinuria-associated renal disease were examined. All rats received an injection of anti-Fx1A and were nephrectomized and then divided into groups to receive rapamycin or vehicle. Gene expression, renal morphology, and GFR were evaluated after 4, 8, and 12 wk. Rapamycin reduced expression of the proinflammatory and profibrotic genes (monocyte chemotactic protein-1, vascular endothelial growth factor, PDGF, TGF-beta(1), and type 1 collagen). Tubulointerstitial inflammation and progression of interstitial fibrosis that were present in vehicle-treated rats were ameliorated by rapamycin. Rapamycin also completely inhibited compensatory renal hypertrophy. In summary, rapamycin ameliorates the tubulointerstitial disease associated with chronic proteinuria and loss of renal mass.
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                Author and article information

                Journal
                AJN
                Am J Nephrol
                10.1159/issn.0250-8095
                American Journal of Nephrology
                S. Karger AG
                0250-8095
                1421-9670
                2007
                July 2007
                13 June 2007
                : 27
                : 4
                : 379-389
                Affiliations
                aClinic of Nephrology, Clinical Center of Serbia, bInstitute for Medical Research, and cInstitute of Pathology, Faculty of Medicine, Belgrade, Serbia
                Article
                103918 Am J Nephrol 2007;27:379–389
                10.1159/000103918
                17570905
                © 2007 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: 8, Tables: 2, References: 31, Pages: 11
                Categories
                Original Report: Patient-Oriented, Translational Research

                Cardiovascular Medicine, Nephrology

                Rapamycin, Proteinuria, CD8+ cells, Heymann nephritis

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