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      Increased Expression of CD54, CD18, MHC Class II Molecules, and Proliferating Cell Nuclear Antigen in Acute Puromycin Aminonucleoside Nephrosis

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          Abstract

          Cellular infiltration to renal tissues is an important feature during acute puromycin aminonucleoside nephrosis (PAN) in rats. The mechanisms responsible for this infiltration are poorly understood. To elucidate the participation of adhesion molecules in PAN, nephrosis was induced in rats by intraperitoneal puromycin aminonucleoside injection. Controls represent animals injected with a 0.9% saline solution. ICAM-1 (intercellular adhesion molecule 1), CD18 (beta chain of lymphocyte-function-associated antigen), LCA (leukocyte common antigen), ED1 (monocyte/macrophage marker), and proliferating cell nuclear antigen expressions were evaluated in renal tissues 1, 2, and 7 weeks after injection. Frozen sections from PAN rat kidneys showed increased expressions of ICAM-1 and its ligand, and these findings were associated with increased levels of LCA+ and ED1+ cells in glomerulus and interstitium. The kinetics of leukocyte infiltration was similar to the kinetics of ICAM-1 expression: high values at week 2 which returned to normal values at week 7. Increased glomerular and interstitial proliferative activities (proliferating cell nulear antigen positive cells) were also found at week 2 of nephrosis. There was a correlation between ICAM-1 expression and numbers of LCA+ and ED1+ cells and between numbers of LCA+ cells and proliferating cells in glomerulus and interstitium. Correlations between glomerular and tubular ICAM-1 expression, interstitial leukocyte infiltration, and glomerular, interstitial, and tubular proliferative activities with the proteinuria were also observed during the nephrotic phase. In addition, increased lymphocyte binding to PAN renal tissues was observed, and this binding was diminished by anti-LFA-1β monoclonal antibody pretreatment of lymphocytes. A similar result was found with anti-ICAM-1 monoclonal antibody pretreatment of renal tissues. Our results suggest that increased expression of ICAM-1 and proliferative activity could be important determinants in the renal hypercellularity found in this experimental model.

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          Most cited references 7

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          A cell adhesion molecule, ICAM-1, is the major surface receptor for rhinoviruses.

          Rhinoviruses, which cause common colds, possess over 100 serotypes, 90% of which (the major group) share a single receptor. Lymphocyte function associated molecule 1 (LFA-1) mediates leukocyte adhesion to a wide variety of cell types by binding to intercellular adhesion molecule 1 (ICAM-1). We demonstrate identity between the receptor for the major group of rhinoviruses and ICAM-1. A major group rhinovirus binds specifically to purified ICAM-1 and to ICAM-1 expressed on transfected COS cells, and binding is blocked by three ICAM-1 monoclonal antibodies (MAb) that block ICAM-1-LFA-1 interaction, but not by an ICAM-1 MAb that does not block ICAM-1-LFA-1 interaction. This suggests that the ICAM-1 contact site(s) for LFA-1 and rhinoviruses is proximal or identical. In addition, ICAM-1 MAb block the cytopathic effect in HeLa cells mediated by representative major but not minor group rhinoviruses. ICAM-1 is induced by soluble mediators of inflammation, suggesting that the host immune response to rhinovirus may facilitate spread to uninfected cells.
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            Urinary free fatty acids bound to albumin aggravate tubulointerstitial damage.

            Evidence indicates that urinary protein is associated with tubulointerstitial damage and thus it is an aggravating factor for chronic renal disease. As free fatty acids (FFAs) are bound to serum albumin, we hypothesized that FFAs were overloaded to the proximal tubule in massive proteinuria and thus caused tubulointerstitial damage. To test this hypothesis, massive proteinuria was provoked in mice and the renal damage examined. Mice were intraperitoneally injected with bovine serum albumin (BSA) replete with FFAs (r-BSA group, N = 10), FFA-depleted BSA (d-BSA group, N = 10), or saline (saline group, N = 9) for 14 days. The kidneys of the r-BSA group showed severe tubulointerstitial damage and those of the d-BSA group showed mild tubulointerstitial damage. Urinary excretion of both total protein and mouse albumin were significantly higher in the r-BSA group than in the d-BSA group. To examine the proximal tubular uptake of albumin, the BSA content in the cultured mouse proximal tubules was measured by ELISA after 90 minutes of incubation with each BSA. In terms of the BSA content in the proximal tubules, there was no significant difference between the r-BSA and the d-BSA groups. These results indicate that r-BSA and d-BSA were similarly reabsorbed into the proximal tubule and that r-BSA causes severe tubulointerstitial damage. It is the FFAs bound to albumin, rather than albumin itself, which cause severe tubulointerstitial damage by being reabsorbed into the proximal tubule. To our knowledge, this is the first in vivo observation in which FFAs have caused severe tubulointerstitial injury.
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              Proximal tubular cells promote fibrogenesis by TGF-beta1-mediated induction of peritubular myofibroblasts.

              In proteinuric nephropathies with increasingly severe defects of the glomerular filtering barrier, interstitial fibrogenesis is a major effector of scarring. An early event in this process is the peritubular accumulation of myofibroblasts that express alpha-smooth muscle actin (alpha-SMA) and contribute to abnormal matrix production. Common trigger factors are poorly understood. Enhanced protein trafficking may play a role by up-regulating inflammatory and fibrogenic genes in proximal tubular cells. The remnant kidney model in rats was used to (1) analyze interactions between activated proximal tubular cells, peritubular cells expressing the myofibroblast marker, and inflammatory cells at time intervals (days 7, 14, and 30) after surgery, and (2) evaluate the effects of angiotensin-converting enzyme inhibitor (ACEi) on protein trafficking, fibrogenic signaling, and alpha-SMA expression. Abnormal uptake of ultrafiltered proteins by proximal tubular cells (IgG staining) occurred at an early stage (day 7) and was subsequently associated with macrophage and alpha-SMA+ cell accumulation into the peritubular interstitium. alpha-SMA+ cells clustered with macrophages into the interstitium. These changes were associated with appearance of transforming growth factor-beta1 (TGF-beta1) mRNA in proximal tubular cells and in the infiltrating cells with time. At day 30, focal alpha-SMA staining also was found in the tubular cells and in peritubular endothelial cells on semithin ultracryosections. ACEi prevented both proteinuria and abnormal protein accumulation in tubular cells, as well as the inflammatory and fibrogenic reaction with peritubular alpha-SMA expression. Profibrogenic signaling from both proximal tubular cells on challenge with filtered protein and inflammatory cells is implicated as a key candidate trigger of progressive tubulointerstitial 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
                2003
                June 2003
                17 November 2004
                : 94
                : 2
                : e55-e65
                Affiliations
                aCentro de Cirugía Experimental e bInstituto de Investigaciones Clínicas ‘Dr. Americo Negrette’, Facultad de Medicina, Universidad del Zulia, Maracaibo, Venezuela
                Article
                71284 Nephron Exp Nephrol 2003;94:e55–e65
                10.1159/000071284
                12845231
                © 2003 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: 4, Tables: 7, References: 59, Pages: 1
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/71284
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                Original Paper

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