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      Glucose-Induced Changes in the Phenotype of Human Peritoneal Mesothelial Cells: Effect of L-2-Oxothiazolidine Carboxylic Acid

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          Abstract

          Background: During peritoneal dialysis, mesothelial cells are chronically exposed to high concentrations of glucose. Therefore, the cytotoxic effect of glucose may alter the function and reactivity of these cells. Methods: For 4 weeks, human peritoneal mesothelial cells were cultured in vitroin medium supplemented with 45 m M glucose or 45 m M mannitol or with 45 m M glucose and 1 m M L-2-oxothiazolidine-4-carboxylic acid (OTZ), the latter being a precursor for glutathione synthesis. Peroxidation of the mesothelial cell lipids, synthetic activity and reaction of these cells to peritoneal dialysis fluids were studied. Results: In contrast to mannitol, glucose enhanced the peroxidation of the cellular lipids (+65%, p < 0.01) an effect that was prevented by OTZ. Synthesis of hyaluronan and vascular endothelial growth factor was reduced in mesothelial cells treated with glucose by 36% (p < 0.01) and 44% (p < 0.05), respectively; both glucose effects were reversed when cells were incubated with glucose plus OTZ. Monocyte chemoattractant protein-1 synthesis by cells exposed to glucose was increased by 31% (p < 001), and again that effect was prevented by OTZ. Glucose and mannitol stimulated synthesis of fibronectin (+32%, p < 0.05). Mesothelial cells chronically exposed to glucose became activated after subsequent exposure to the dialysis fluid, as reflected by the increased release of interleukin (IL)-6, in contrast to control mesothelial cells, in which IL-6 synthesis was suppressed. Conclusions: Chronic exposure of mesothelial cells to glucose changes their synthetic activity and their reaction after exposure to dialysis fluids. Some of these effects are prevented by OTZ, which suggests that glucose-induced free radicals are responsible for a change in mesothelial cell phenotype under the conditions of peritoneal dialysis.

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          Most cited references 7

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          Peritoneal dialysis and epithelial-to-mesenchymal transition of mesothelial cells.

          During continuous ambulatory peritoneal dialysis, the peritoneum is exposed to bioincompatible dialysis fluids that cause denudation of mesothelial cells and, ultimately, tissue fibrosis and failure of ultrafiltration. However, the mechanism of this process has yet to be elucidated. Mesothelial cells isolated from effluents in dialysis fluid from patients undergoing continuous ambulatory peritoneal dialysis were phenotypically characterized by flow cytometry, confocal immunofluorescence, Western blotting, and reverse-transcriptase polymerase chain reaction. These cells were compared with mesothelial cells from omentum and treated with various stimuli in vitro to mimic the transdifferentiation observed during continuous ambulatory peritoneal dialysis. Results were confirmed in vivo by immunohistochemical analysis performed on peritoneal-biopsy specimens. Soon after dialysis is initiated, peritoneal mesothelial cells undergo a transition from an epithelial phenotype to a mesenchymal phenotype with a progressive loss of epithelial morphology and a decrease in the expression of cytokeratins and E-cadherin through an induction of the transcriptional repressor snail. Mesothelial cells also acquire a migratory phenotype with the up-regulation of expression of alpha2 integrin. In vitro analyses point to wound repair and profibrotic and inflammatory cytokines as factors that initiate mesothelial transdifferentiation. Immunohistochemical studies of peritoneal-biopsy specimens from patients undergoing continuous ambulatory peritoneal dialysis demonstrate the expression of the mesothelial markers intercellular adhesion molecule 1 and cytokeratins in fibroblast-like cells entrapped in the stroma, suggesting that these cells stemmed from local conversion of mesothelial cells. Our results suggest that mesothelial cells have an active role in the structural and functional alteration of the peritoneum during peritoneal dialysis. The findings suggest potential targets for the design of new dialysis solutions and markers for the monitoring of patients. Copyright 2003 Massachusetts Medical Society
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            Antioxidants, diabetes and endothelial dysfunction.

            While a damaged endothelium is recognised to be a key accessory to diabetic macroangiopathy, awareness is developing that impairments concerning endothelium- and nitric oxide (NO)-dependent microvascular function, may contribute to several other corollaries of diabetes, such as hypertension, dyslipidaemia and in vivo insulin resistance. There are now several reports describing elevations in specific oxidant stress markers in both insulin resistance syndrome (IRS) and diabetes, together with determinations of reduced total antioxidant defence and depletions in individual antioxidants. Such a pro-oxidant environment in diabetes may disrupt endothelial function through the inactivation of NO, resulting in the attenuation of a fundamental anti-atherogenic and euglycaemic vascular influence. Indeed, experimental and clinical data suggest that the supplementation of insulin resistant or diabetic states with antioxidants such as vitamin E, normalises oxidant stress and improves both endothelium-dependent vasodilation and insulin sensitivity. However, the promising potential efficacy of antioxidant therapy in cardiovascular disease and diabetes, in either a primary or secondary preventative role, awaits definitive clinical demonstration.
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              Vascular endothelial growth factor production and regulation in human peritoneal mesothelial cells.

              Vascular endothelial growth factor (VEGF) was recently found in peritoneal effluents of peritoneal dialysis (PD) patients. It was suggested that human peritoneal mesothelial cells (HMC) contribute to the intraperitoneal production of VEGF, which may augment vascular permeability, vasodilation and neoangiogenesis in the peritoneal membrane. The present study was designed to assess the influence of proinflammatory cytokines, thrombin, d-glucose and glycated albumin in the regulation of VEGF synthesis in primary HMC cultures. VEGF antigen concentrations were measured in the cell supernatant by ELISA and VEGF mRNA expression was evaluated by real time RT-PCR. Incubation of HMC with interleukin-1alpha (IL-1alpha; 10 to 100 U/mL), tumor necrosis factor-alpha (TNF-alpha; 500 to 1000 U/mL) or thrombin (1 to 10 U/mL) resulted in a time (24 to 72 hours) and concentration dependent increase in VEGF synthesis. In contrast, d-glucose (30 to 90 mmol/L), which is commonly used as an osmotic agent in peritoneal dialysis, was not able to up-regulate VEGF expression. High glucose levels even decreased VEGF production. However, exposure of HMC to Amadori-modified glycated albumin, which is generated in the peritoneal cavity in the presence of glucose-based dialysis solutions, resulted in a dose and time dependent increase in VEGF mRNA expression and antigen secretion. These results demonstrate, to our knowledge for the first time, that glycated serum albumin, not glucose, increases VEGF production in HMC. HMC play an important role as a source of intraperitoneal VEGF synthesis, and VEGF expression also is up-regulated in the presence of proinflammatory cytokines and thrombin. Additionally, these results confirm clinical data that the continuous exposure of the peritoneal membrane to glucose-based dialysis solutions is an important stimulus for VEGF expression. However, it is not glucose per se, but nonenzymatic glycation products like glycated albumin that up-regulate VEGF expression.
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                Author and article information

                Journal
                AJN
                Am J Nephrol
                10.1159/issn.0250-8095
                American Journal of Nephrology
                S. Karger AG
                0250-8095
                1421-9670
                2003
                December 2003
                21 November 2003
                : 23
                : 6
                : 471-476
                Affiliations
                aDepartment of Pathophysiology, Poznan Medical School, Poznan, Poland; bDivison of Nephrology, University of Toronto, Toronto, Canada
                Article
                74667 Am J Nephrol 2003;23:471–476
                10.1159/000074667
                14605496
                © 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: 2, References: 27, Pages: 6
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/74667
                Categories
                Original Report: Laboratory Investigation

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