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      Apolipoprotein E Regulates Primary Cultured Human Mesangial Cell Proliferation


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          Background: The role of apolipoprotein (apo) E in kidney disease is still unclear. Animal studies have been performed, but it is doubtful if the conclusions are applicable to human beings. The objective of this study was to determine how apo E acts on human kidneys using primary cultured normal human mesangial cells (NHMCs) rather than animals used in previous studies. Methods: apo E and its isoforms E2, E3 and E4, or combinations with apo B were cocultured with primary NHMCs in serum-free medium. Premix WST-1 Cell Proliferation Assay System and DNA-Prep Reagent System were used to measure the proliferation and apoptosis of NHMCs, respectively. Results: (1) apo E itself increased NHMC proliferation at 24 h of culture, while it inhibited this proliferation after 48 h. (2) At 72 h of culture, apo E alone inhibited NHMC proliferation at concentrations higher than 0.78 µg/ml in concentration-dependent manner. (3) When co-cultured with both apo E and apo B, NHMC proliferation was higher than that with apo E alone and lower than that with apo B alone. (4) At 72 h of culture, apo E2, E3 and E4 inhibited NHMC proliferation at different intensities, with no proliferative effect observed. (5) Neither apo E nor apo B caused NHMC apoptosis. Conclusion: apo E regulates primary NHMC proliferation by (1) inhibiting NHMC proliferation or reducing NHMC proliferation induced by apo B, which implies that apo E has a protective effect on the kidney, and (2) increasing the proliferation under certain conditions.

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          Most cited references14

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          Apolipoprotein B and apolipoprotein A-I: risk indicators of coronary heart disease and targets for lipid-modifying therapy

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            Apolipoprotein E modulates immune activation by acting on the antigen-presenting cell.

            Apolipoprotein E (ApoE) is synthesized by a variety of cells including macrophages. These cells activate T lymphocytes by antigen presentation, while the T-cell cytokine, interferon-gamma, inhibits macrophage ApoE expression. ApoE inhibits T-cell proliferation in culture but its role in immune responses has been unclear. The ApoE-deficient (E0) mouse permits an evaluation of the immunological role of ApoE. We have analysed T-cell responses to an exogenous antigen (ovalbumin) and polyclonal mitogen (concanavalin A) in E0 and ApoE+/+ mice. Macrophages of E0 mice stimulated T-cell activation more effectively as antigen-presenting cells than macrophages from ApoE+/+ mice. Both proliferation and interferon-gamma secretion were enhanced in T cells activated in the context of antigen-presenting cells from E0 mice. Since the macrophage-T-cell interaction depends on interactions between cell surface molecules, we assessed the expression of such molecules after in vivo stimulation with interferon-gamma. This treatment caused an increased expression of the co-stimulatory surface proteins CD40 and CD80, and also of the major histocompatibility complex class II molecules I-Ab on macrophages of E0 mice compared with ApoE+/+. Our data suggest that ApoE inhibits T-cell activation by reducing the density of immune stimulatory proteins on antigen-presenting cells.
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              Apolipoproteins and lipoprotein receptors in glomeruli in human kidney diseases.

              This study offers morphological evidence of the involvement of lipid abnormalities in human glomerular injury. Renal biopsy tissues from patients with several types of glomerular diseases were immunocytochemically examined using antibodies to apolipoproteins (apo) A-I, B-100, and E, and antibodies to low density lipoprotein (LDL) receptors and scavenger receptors. Immunofluorescent staining showed the predominant deposition of apo B and apo E in the mesangial area in mesangial proliferative types of glomerulonephritis; the distribution and staining intensity of these apolipoproteins correlated with the grade of mesangial proliferation and proteinuria, but were independent of plasma lipid levels. Immunoelectron microscopy revealed that apo B and apo E were distributed in droplets within glomerular epithelial and mesangial cells or in a granular pattern in the expanded mesangial matrix. Apo A-I was mainly localized in the visceral epithelial cells of normal human kidneys. Staining for apo A-I was increased in the glomerular epithelial cells of nephritic kidneys, compared to the pattern in normal human kidneys, and was decreased in the sclerosed areas of glomeruli. An immunogold technique revealed the expression of LDL receptors on the surface membranes of glomerular mesangial and epithelial cells. Dual immunofluorescent staining showed that apo B and LDL receptors were occasionally co-localized in nephritic glomeruli. Scavenger receptor was detected on the plasma membranes of mesangial and visceral epithelial cells. The glomerular expression of scavenger receptor was increased in glomeruli with marked mesangial proliferation. In addition, the expression of this receptor was intense in monocytes/macrophages occasionally infiltrating the glomeruli. Our present findings indicate that in human nephritic kidneys, glomerular epithelial and mesangial cells express both LDL receptors and scavenger receptors. The accumulation of apolipoproteins, whether receptor-mediated or mediated by other mechanisms, can occur independently of plasma lipid levels, and may be associated with mesangial expansion and proteinuria.

                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                January 2006
                23 September 2005
                : 102
                : 2
                : e62-e70
                aSecond Division of Internal Medicine, bDepartment of Molecular Oncology, Medical Faculty, Kagoshima University, and cIkeda Hospital, Kanoya, Kagoshima, Japan
                88402 Nephron Exp Nephrol 2006;102:e62–e70
                © 2006 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.

                : 29 October 2004
                : 20 July 2005
                Page count
                Figures: 8, Tables: 1, References: 23, Pages: 1
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/88402
                Self URI (text/html): https://www.karger.com/Article/FullText/88402
                Self URI (journal page): https://www.karger.com/SubjectArea/Nephrology
                Original Paper

                Cardiovascular Medicine,Nephrology
                Cell cycle,Isoforms,WST-1,Apolipoprotein B,Flow cytometer,DNA stain,Apoptosis,Apolipoprotein E,Human mesangial cell,Proliferation


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