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      Differential Expression of Mcp-1 and Its Receptor CCR2 in Glucose Primed Human Mesangial Cells

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          Abstract

          Background: Glomerular mononuclear cell infiltration is associated with the development of a diffuse glomerulosclerosis in patients with diabetic nephropathy. Monocyte chemoattractant protein-1 (MCP-1) plays an important role in the recruitment and accumulation of monocytes and lymphocytes within the glomerulus. In the present study, we examined whether the ambient glucose concentration alters the expression of MCP-1 and its receptor CCR2 in primary human mesangial cells (HMC). Methods: MCP-1 mRNA expression was assessed by Northern blot and CCR2 mRNA expression by RT-PCR analysis. MCP-1 protein production was determined by ELISA. Migration studies were performed to assess functional MCP-1 receptor expression. Results: Exposure of HMC to 30 m M D-glucose led to a 30% increase in MCP-1 mRNA expression as compared to 5 m M D-glucose and osmotic controls while there was no difference in MCP-1 protein production. Simultaneously, CCR2 mRNA expression was down-regulated in HMC exposed to 30 m M D-glucose. 5 m M D-glucose primed HMC showed a dose-dependent migration towards MCP-1 that was dose-dependently inhibited by pertussis toxin, the broad-spectrum chemokine antagonist vMIP-II as well as the CCR2 receptor antagonist (1–8del)MCP-1 – demonstrating functional activity of MCP-1 receptor expression in primary HMC. In accordance with the downregulatory effects of 30 m M D-glucose on CCR2 mRNA expression no migratory response towards MCP-1 was observed under these conditions. The additional proinflammatory stimulus TNFα increased MCP-1 protein production in 30 as compared to 5 m M D-glucose primed HMC (2,194 ± 568 vs. 1,422 ± 379 pg MCP-1/10<sup>4</sup> cells × ml in 30 vs. 5 m M D-glucose primed HMC +24 h TNFα 500 U/ml, p = 0.002). However, this was not associated with an increased MCP-1 mRNA transcription. The 30 m M D-glucose induced downregulation of CCR2 mRNA expression was prevented in the presence of TNFα. Conclusion: High ambient glucose does not affect mesangial MCP-1 release and decreases its CCR2 receptor expression. However, in the presence of an inflammatory stimulus these effects of high glucose are reversed and an autocrine pathway of MCP-1 develops in mesangial cells.

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          Most cited references 12

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          Chemokine receptors: gateways to inflammation and infection.

           V Schall,  B Premack (1996)
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            Costimulation of fibroblast collagen and transforming growth factor beta1 gene expression by monocyte chemoattractant protein-1 via specific receptors.

            Recent studies indicate potential roles of monocyte chemotactic protein-1 (MCP-1) in recruitment of monocytes to sites of inflammation. However, their increased expression does not always correlate with monocyte influx, suggesting other possible biological activities for this member of the C-C chemokine family. In view of its potential role in regulating extracellular matrix expression in fibrotic disorders, the effects of MCP-1 on lung fibroblast collagen expression were evaluated. Isolated rat lung fibroblasts were treated with increasing doses of MCP-1 for variable periods of time and examined for effects on collagen synthesis and expression of procollagen alpha1(I) mRNA expression. The results show that MCP-1 was able to stimulate collagen expression in these cells in a dose-dependent manner but required over 24 h for significant elevation to occur. In view of this delayed time course, the possibility of mediation via endogenous transforming growth factor beta (TGFbeta) was tested by the ability of anti-TGFbeta antibody to inhibit this MCP-1 stimulation of collagen expression. Significant but incomplete inhibition by this antibody was observed. Pretreatment of the cells with antisense but not by sense or missense TGFbeta1 oligodeoxyribonucleotides caused essentially complete inhibition of this MCP-1 stimulatory effect. Furthermore, MCP-1 treatment was found to also stimulate TGFbeta secretion and mRNA expression, which was also abolished by pretreatment with antisense TGFbeta1 oligodeoxyribonucleotides. The kinetics of TGFbeta expression indicates that significant increase preceded that for collagen expression. Binding studies using 125I-labeled MCP-1 indicated the presence of specific and saturable binding sites with a dissociation constant consistent with the dose response curves for stimulation of fibroblast collagen synthesis and TGFbeta activity by MCP-1. These results taken together suggest that MCP-1 stimulates fibroblast collagen expression via specific receptors and endogenous up-regulation of TGFbeta expression. The latter then results in autocrine and/or juxtacrine stimulation of collagen gene expression.
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              Possible relationship of monocyte chemoattractant protein-1 with diabetic nephropathy.

              Monocyte chemoattractant protein-1 (MCP-1) is a specific chemokine to recruit and activate monocytes from the circulation to inflammatory site. In diabetic nephropathy, similar to other glomerulonephropathies, infiltration and activation of monocytes/macrophages in glomerulus have been implicated in the development of glomerular injury. The aim of the present study was to examine a possible relationship of MCP-1 with diabetic nephropathy and to investigate the role of glycated albumin (Gly-Alb) as well as high concentration of glucose (HG) on MCP-1 production by cultured human mesangial cells. MCP-1 in serum or urine and urinary albumin (Alb) as well as several clinical parameters such as plasma glucose, serum Gly-Alb, and hemoglobin A1c (HbA1c) were measured after overnight fasting in 16 control subjects and 54 diabetic patients. The relationships between the levels of urinary Alb and urinary or serum MCP-1 and also between the values of respective clinical parameter and urinary MCP-1 levels were analyzed. Next, using cultured human mesangial cells, we investigated the role of Gly-Alb and/or HG on the gene and protein expression of MCP-1. Urinary levels (ng/g creatinine), but not serum levels, of MCP-1 increased in accordance with the extent of albuminuria. In all subjects, there were significant correlations between the urinary levels of Alb and MCP-1 (r = 0.746, P < 0.0001) and between the levels of serum Gly-Alb and urinary MCP-1 (r = 0.475, P < 0.0001). In cultured human mesangial cells, the gene and protein expression of MCP-1 was dose and time dependently up-regulated by Gly-Alb. HG slightly but significantly stimulated MCP-1 expression. The combination of Gly-Alb and HG showed the greatest stimulation in more than an additive manner on MCP-1 production. This study suggests that facilitated MCP-1 production by mesangial cells in diabetic milieu contributes to the initiation and progression of diabetic nephropathy.
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                Author and article information

                Journal
                NEF
                Nephron
                10.1159/issn.1660-8151
                Nephron
                S. Karger AG
                1660-8151
                2235-3186
                2002
                October 2002
                18 October 2002
                : 92
                : 4
                : 797-806
                Affiliations
                aDivision of Nephrology, University of Aachen, and bDepartment of Pharmacology, Medizinische Hochschule, Hannover, Germany; cInstitute of Nephrology, University of Wales College of Medicine, Cardiff, UK; dPharmazentrum Frankfurt, Clinic of J.W. Goethe University, Frankfurt, Germany
                Article
                65448 Nephron 2002;92:797–806
                10.1159/000065448
                12399623
                © 2002 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: 43, Pages: 10
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/65448
                Categories
                Original Paper

                Cardiovascular Medicine, Nephrology

                CCR2, Glucose, Mesangial cell, Monocyte chemoattractant protein-1

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