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      Peroxisome Proliferator-Activated Receptor-Gamma Is Expressed by Rat Peritoneal Mesothelial Cells: Its Potential Role in Peritoneal Cavity Local Defense


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          Background/Aims: Peritoneal mesothelial cells (PMCs) play an important role in peritoneal inflammatory and immune response. It was reported that the peroxisomal proliferator-activated receptor-γ (PPARγ) ligand could effectively reduce inflammatory processes. However, the expression and function of PPARγ in PMCs has not been reported. This study was to investigate the expression of PPARγ in rat PMCs and the effect of PPARγ activation on the production of CD40 and ICAM-1 induced by lipopolysaccharide (LPS). Methods: Rat PMCs (RPMCs) were harvested from the peritoneal cavity of Sprague-Dawley rats and maintained under defined in vitro conditions. The cells were treated separately with LPS, 15d-PGJ<sub>2</sub>, and ciglitazone at different time points. The mRNA and protein expression of PPARγ, CD40 and ICAM-1 were detected by RT-PCR and Western blot, respectively. The intracellular distribution of PPARγ was detected by immunocytochemistry. Results: RPMCs expressed PPARγ both at the mRNA and protein level. The specific signals for PPARγ were mainly localized in the nucleus with weak staining in the cytoplasm. Stimulation of RPMCs with LPS resulted in a time-dependent increase in the expression of PPARγ with the peak of mRNA at 3 h and protein at 12 h. Thereafter the expression of PPARγ gradually attenuated. The mRNA expressions for CD40, ICAM-1 and protein expression of ICAM-1 were significantly upregulated following stimulation with LPS. Both 15d-PGJ<sub>2</sub> and ciglitazone decreased the expression of CD40 mRNA and ICAM-1 protein. However, ciglitazone was less effective than 15d-PGJ<sub>2</sub>. Conclusions: There is constitutive expression of PPARγ in cultured RPMCs and PPARγ ligands which strongly inhibit LPS-induced CD40 and ICAM-1 production in RPMCs. It suggested that PPARγ might play a part in the local defense of the peritoneal cavity by downregulating inflammatory mediators, which may play a potential role in preventing peritoneal fibrosis induced by peritonitis. Further in vivo study is needed to demonstrate the long-term effects.

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          Nonsteroidal anti-inflammatory drugs repress beta-secretase gene promoter activity by the activation of PPARgamma.

          Epidemiological evidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) decrease the risk for Alzheimer's disease (AD). Certain NSAIDs can activate the peroxisome proliferator-activated receptor-gamma (PPARgamma), which is a nuclear transcriptional regulator. Here we show that PPARgamma depletion potentiates beta-secretase [beta-site amyloid precursor protein cleaving enzyme (BACE1)] mRNA levels by increasing BACE1 gene promoter activity. Conversely, overexpression of PPARgamma, as well as NSAIDs and PPARgamma activators, reduced BACE1 gene promoter activity. These results suggested that PPARgamma could be a repressor of BACE1. We then identified a PPARgamma responsive element (PPRE) in the BACE1 gene promoter. Mutagenesis of the PPRE abolished the binding of PPARgamma to the PPRE and increased BACE1 gene promoter activity. Furthermore, proinflammatory cytokines decreased PPARgamma gene transcription, and this effect was supressed by NSAIDs. We also demonstrate that in vivo treatment with PPARgamma agonists increased PPARgamma and reduced BACE1 mRNA and intracellular beta-amyloid levels. Interestingly, brain extracts from AD patients showed decreased PPARgamma expression and binding to PPRE in the BACE1 gene promoter. Our data strongly support a major role of PPARgamma in the modulation of amyloid-beta generation by inflammation and suggest that the protective mechanism of NSAIDs in AD involves activation of PPARgamma and decreased BACE1 gene transcription.
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            The mesothelial cell

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              Modulation of the oxidative stress and inflammatory response by PPAR-gamma agonists in the hippocampus of rats exposed to cerebral ischemia/reperfusion.

              Agonists of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) exert protective effects in several models of ischemia/reperfusion injury, but their role in stroke is less clear. The study investigates the effects of two PPAR-gamma agonists, rosiglitazone and pioglitazone, on oxidative stress and inflammatory response induced by ischemia/reperfusion in the rat hippocampus. Common carotid artery occlusion for 30 min followed by 1 h reperfusion resulted in a significant increase in the generation of reactive oxygen species, nitric oxide and the end products of lipid peroxidation as well as markedly reduced endogenous antioxidant glutathione levels and up-regulated superoxide dismutase activity. Western blot analysis showed that ischemia/reperfusion lead to an increase in cyclooxygenase-2 (COX-2) expression, as well activating p38 and p42/44 mitogen-activated protein kinases (MAPKs) and nuclear factor-kappaB (NF-kappaB). Pre-treatment with either rosiglitazone or pioglitazone significantly reduced oxidative stress, COX-2 protein expression and activation of MAPKs and NF-kappaB. Taken together, the results provide convincing evidence that PPAR-gamma agonists exert protective effects in a rat model of mild forebrain ischemia/reperfusion injury by inhibiting oxidative stress and excessive inflammatory response.

                Author and article information

                Am J Nephrol
                American Journal of Nephrology
                S. Karger AG
                January 2007
                19 January 2007
                : 26
                : 6
                : 602-611
                Department of Nephrology, 1st Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, PR China
                98149 Am J Nephrol 2006;26:602–611
                © 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.

                : 10 March 2006
                : 22 November 2006
                Page count
                Figures: 6, Tables: 1, References: 49, Pages: 10
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/98149
                Self URI (text/html): https://www.karger.com/Article/FullText/98149
                Self URI (journal page): https://www.karger.com/SubjectArea/Nephrology
                Original Report: Laboratory Investigation

                Cardiovascular Medicine,Nephrology
                Peritoneal cavity local defense,Peroxisome proliferator-activated receptor-γ,Peritoneal mesothelial cells, rat,CD40,ICAM-1


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