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      C-Type Natriuretic Peptide Inhibits Proliferation and Monocyte Chemoattractant Protein-1 Secretion in Cultured Human Mesangial Cells

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          Abstract

          Background: Mesangial cell proliferation and matrix accumulation are hallmarks of various progressive glomerular diseases. We examined whether C-type natriuretic peptide (CNP) that is known to regulate the proliferation of vascular smooth muscle cells could modulate these pathological processes using human glomerular mesangial cells (GMCs) in culture. Methods: Proliferation of GMCs cultured with different concentrations of CNP-22 for 48 h was determined by a colorimetric assay using a tetrazorium salt. Monocyte chemoattractant protein-1 (MCP-1) and type IV collagen secretion into the culture media by GMCs in the presence or absence of CNP-22 were evaluated by ELISA. Expression of mRNA for natriuretic peptide receptor B (NPR-B), a specific receptor for CNP, was examined by reverse transcription polymerase chain reaction (RT-PCR). Results: CNP-22 (1–10 µ M) inhibited serum-induced GMC growth in a dose-dependent manner. The amount of MCP-1 in the culture supernatant was increased approximately 2.4-fold by 5 µg/ml of lipopolysaccharide. This increase was inhibited by CNP-22 at 0.1–1 µ M in a dose-dependent fashion. CNP-22 (10 µ M) inhibited GMC type IV collagen secretion stimulated by 20 ng/ml of platelet-derived growth factor. Expression of NPR-B mRNA was confirmed in GMCs by RT-PCR. Conclusions: CNP suppresses GMC proliferation and MCP-1 and type IV collagen secretion by GMCs. It may have a therapeutic potential against human proliferative glomerular diseases, especially those with the involvement of monocytes.

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          Most cited references 3

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          Activation of MCP-1 gene expression is mediated through multiple signaling pathways.

          Multiple signal transduction pathways including protein kinase C, tyrosine phosphorylation, and an independent third signaling mechanism are involved in the activation of monocyte chemotactic protein-1 gene. Northern blot analysis showed that the incubation of endothelial cell with dioctanoylglycerol induced maximum level of monocyte chemotactic protein-1 transcripts. The TPA-induced monocyte chemotactic protein-1 expression was abolished by treating the cells with both staurosporine and genistein; however, only a portion of the LPS-induced expression was inhibited by staurosporine/genistein. This is in accordance with the observation that LPS induced the expression of monocyte chemotactic protein-1 in desensitized cells. Thus, a third signal transduction pathway other than protein kinase C or tyrosine kinase is involved in the LPS-induced monocyte chemotactic protein-1 expression in human endothelial cell.
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            C-type natriuretic peptide inhibits mesangial cell proliferation and matrix accumulation in vivo

            Local C-type natriuretic peptide (CNP) production and CNP receptor expression have been demonstrated in glomeruli. However, the glomerular (patho-)physiological functions of CNP are largely unknown. We therefore investigated the effects of CNP on mesangial cell proliferation and matrix accumulation in the rat mesangioproliferative anti-Thy 1.1 model. Over seven days rats received a continuous infusion (1 microgram/kg/min) of either CNP (N = 6), an irrelevant control peptide (N = 3) or buffer alone (N = 6). Kidney biopsies were performed on days 2, 4 and 8. Few significant differences between the groups were noted on days 2 and 4. Compared to buffer treated rats on day 8, those receiving CNP showed a 35% reduction of glomerular mitoses, a 62% reduction of glomerular uptake of the thymidine analogue BrdU and a significant reduction in glomerular expression of PDGF B-chain. Double immunoperoxidase staining also revealed blunting of proliferating, activated mesangial cells (515 reduction of alpha-smooth muscle actin-/BrdU-positive cells) and macrophage influx. Moreover, there was a marked reduction of mesangial collagen IV and fibronectin accumulation at the protein and mRNA level. Rats receiving the control peptide were indistinguishable from buffer treated rats. Systemic blood pressure was reduced by 10 to 20% in both CNP and control peptide treated rats on day 8, excluding that the findings were due to hemodynamic effects of CNP. Our findings demonstrate that CNP is involved in the regulation of mesangial cell proliferation and matrix production in vivo. The data suggest the existence of a glomerular natriuretic peptide system that may regulate tissue homeostasis and contribute to resolution of mesangioproliferative diseases.
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              Platelet-derived Growth Factor-stimulated Secretion of Basement Membrane Proteins by Skeletal Muscle Occurs by Tyrosine Kinase-dependent and -independent Pathways

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                Author and article information

                Journal
                NEF
                Nephron
                10.1159/issn.1660-8151
                Nephron
                S. Karger AG
                1660-8151
                2235-3186
                2000
                December 2000
                01 December 2000
                : 86
                : 4
                : 467-472
                Affiliations
                Second Department of Internal Medicine, Hirosaki University School of Medicine, Hirosaki, Japan
                Article
                45836 Nephron 2000;86:467–472
                10.1159/000045836
                11124596
                © 2000 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, References: 34, Pages: 6
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/45836
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