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      Contributions of Intrinsic Renal Cells to Crescentic Glomerulonephritis

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      Cardiorenal Medicine

      S. Karger AG

      T cell, Cytokine, Cell-mediated immunity, Macrophage

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          Abstract

          The pro-inflammatory contributions of leukocytes, particularly macrophages and T cells, to the immunopathogenesis of proliferative forms of glomerulonephritis (GN) have been clearly established by various techniques, including in vivo depletion studies in experimental models. The evidence for an active pro-inflammatory role for intrinsic renal cells in GN has relied on studies demonstrating their production of pro-inflammatory mediators in vitro and during the development of GN. Until recently,the specific in vivo contributions of mediators from intrinsic renal cells to inflammatory injury in GN have proven difficult to define. Utilising ‘chimeric’ mice as a tool, several studies have explored the involvement of intrinsic renal cells via their production of cytokines and other key pro-inflammatory molecules. These studies provide evidence of important functional contributions of intrinsic renal cells to inflammatory injury in GN via their expression of cytokines, cytokine receptors, MHC-II and co-stimulatory molecules. They suggest a sequence of interactions between cytokines from leukocytes and intrinsic renal cells and important contributions of glomerular epithelial cell proliferation to crescent formation.

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          Most cited references 11

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          Role of intrinsic renal cells versus infiltrating cells in glomerular crescent formation.

          Studies were undertaken to characterize the cellular composition that occurs in glomeruli and the tubulointerstitium of a passive model of complement-independent crescentic nephritis in mice. Glomerulonephritis was induced by the injection of antibody to whole rabbit glomeruli, and tissue was examined histologically at 7, 14 and 28 days. Mice developed proteinuria, glomerular crescents, and progressive glomerulosclerosis and tubulointerstitial fibrosis. The majority of the cells within the crescents appeared to be intrinsic ezrin-positive epithelial cells of visceral or parietal origin. Many of the ezrin positive cells were proliferating and expressing the PDGF receptor. Despite expression of the macrophage adhesive protein, osteopontin, the early crescents were devoid of infiltrating macrophages, T cells or myofibroblasts, which could be explained by the finding that the Bowman's capsule remained intact. Tubulointerstitial damage also occurred, and included tubular dilation and atrophy, periglomerular and patchy interstitial infiltration and interstitial fibrosis with increased interstitial deposition of type IV collagen and laminin. Interstitial infiltrating cells included macrophages, CD4+ T lymphocytes, CD8+ T lymphocytes, and activated myofibroblasts. Tubular osteopontin expression was increased in the areas of tubulointerstitial damage and was associated with interstitial macrophage infiltration. We describe an experimental model of complement-independent murine crescentic nephritis associated with tubulointerstitial injury. Proliferating glomerular epithelial cells are the main cellular components of the crescents in this model.
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            Intrinsic renal cells are the major source of tumor necrosis factor contributing to renal injury in murine crescentic glomerulonephritis.

            Macrophages are prominent participants in crescentic glomerulonephritis (GN) and have been suggested to be the major source of TNF in this cell-mediated form of glomerular inflammation. Intrinsic renal cells also have the capacity to produce TNF. For dissecting the contribution of local versus bone marrow (BM)-derived TNF in inflammatory renal injury, TNF chimeric mice were created by transplanting normal wild-type (WT) BM into irradiated TNF-deficient recipients (WT-->TNF-/- chimeras) and vice versa (TNF-/- -->WT chimeras). A model of crescentic GN induced by an intravenous injection of sheep anti-murine glomerular basement membrane antibody was studied in WT mice, mice with complete TNF deficiency (TNF-/-), and chimeric mice. Crescentic GN was attenuated in TNF-/- mice with fewer crescents (crescents, 13.7 +/- 1.7% of glomeruli) and reduced functional indices of renal injury (serum creatinine, 15.2 +/- 0.8 micromol/L). Similar protection (crescents, 14.3 +/- 1.9% of glomeruli; serum creatinine, 18.9 +/- 1.1 micromol/L) was observed in chimeric mice with intact BM but absent renal-derived TNF (WT-->TNF-/- chimeras), suggesting a minor contribution of infiltrating leukocytes to TNF-mediated renal injury. Chimeric mice with TNF-deficient leukocytes but intact intrinsic renal cell-derived TNF (crescents, 20.5 +/- 2.0% of glomeruli; serum creatinine, 21.6 +/- 1.4 micromol/L) developed similar crescentic GN to WT mice (crescents, 22.3 +/- 1.4% of glomeruli; serum creatinine, 24.8 +/- 1.9 micromol/L). Cutaneous delayed-type hypersensitivity after subdermal challenge with the nephritogenic antigen was attenuated in the absence of BM cell-derived TNF but unaffected in WT-->TNF-/- chimeric mice. These studies suggest that intrinsic renal cells are the major cellular source of TNF contributing to inflammatory injury in crescentic GN.
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              The cyclin-dependent kinase inhibitor p27Kip1 safeguards against inflammatory injury.

              The cyclin-dependent kinase inhibitor p27Kip1 controls cell proliferation in response to normal mitogenic stimuli. We show here that p27Kip1 also safeguards against excessive cell proliferation in specific pathophysiologic settings. We used experimental glomerulonephritis as a paradigm for immune mediated inflammation and ureteral obstruction as a model for non-immune mediated inflammation. Renal function was substantially decreased in nephritic p27-/- mice compared with control mice, and this was associated with increased glomerular cell proliferation, apoptosis and matrix protein accumulation. Tubular epithelial cell proliferation and apoptosis was also increased in p27-/- mice following ureteral obstruction. p27Kip1 may have a general role in protecting cells and tissues from inflammatory injury.
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                Author and article information

                Journal
                NEE
                Nephron Exp Nephrol
                10.1159/issn.1660-2129
                Cardiorenal Medicine
                S. Karger AG
                1660-2129
                2005
                December 2005
                09 September 2005
                : 101
                : 4
                : e173-e177
                Affiliations
                Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Australia
                Article
                88165 Nephron Exp Nephrol 2005;101:e173–e177
                10.1159/000088165
                16155400
                © 2005 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: 1, References: 19, Pages: 1
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/88165
                Categories
                Minireview

                Cardiovascular Medicine, Nephrology

                Macrophage, Cell-mediated immunity, Cytokine, T cell

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