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      PPAR-γ Activation Inhibits Angiotensin II Synthesis, Apoptosis, and Proliferation of Mesangial Cells from Spontaneously Hypertensive Rats

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          Abstract

          Background/Aim: The angiotensin II level is elevated in subjects genetically prone to develop hypertension, triggering renal hypercellularity, cytokine production, and matrix deposition. Angiotensin-converting enzyme inhibition and/or angiotensin II type 1 receptor blockade attenuate renal damage. Rosiglitazone, a peroxisome proliferator-activated receptor gamma agonist possessing antihypertensive and anti-inflammatory properties, was demonstrated to provide better renal protection than angiotensin-converting enzyme inhibitors. We studied the effects of in vivo peroxisome proliferator-activated receptor gamma activation by rosiglitazone on angiotensin II synthesis, proliferation, and apoptosis of mesangial cells of spontaneously hypertensive rats versus normotensive Sprague-Dawley rats. Methods: The animals consumed either a high-sodium diet (8% Na) or a normal-sodium diet (0.5% Na). Half of each group received rosiglitazone at 5 mg/kg/day. After 3 weeks, all rats were sacrificed and the mesangial cells isolated and cultured. Angiotensin II was assessed by radioimmunoassay, apoptosis by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay, and cell proliferation by [<sup>3</sup>H]thymidine incorporation. Results: Only the spontaneously hypertensive rats which consumed the high-sodium diet developed hypertension (185 ± 6 mm Hg vs. basal 128 ± 5 mm Hg; p = 0.0007) which was attenuated by rosiglitazone (to 126 ± 4 mm Hg; p = 0.34). Angiotensin II synthesis, proliferation, and apoptosis were exaggerated in mesangial cell cultures from Sprague-Dawley rats and, more so, spontaneously hypertensive rats fed the high-sodium diet, but were inhibited in cultures from rosiglitazone-treated animals. Conclusions: Peroxisome proliferator-activated receptor gamma activation, in addition to lowering blood pressure, suppresses angiotensin II synthesis and downregulates angiotensin-II-mediated proliferation and apoptosis of mesangial cells. In the context of hypertension-induced renal damage, this would mean that the renoprotective role of rosiglitazone extends beyond glycemic and lipidemic control.

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          Most cited references 17

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          Peroxisome Proliferator-Activated Receptors: Nuclear Control of Metabolism

           B. Desvergne (1999)
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            Proinflammatory actions of angiotensins.

            Many experimental data have suggested that the renin-angiotensin system participates in immune and inflammatory responses. Angiotensin II is involved in several steps of the inflammatory process: mononuclear cells respond to angiotensin II stimulation (cell proliferation and chemotaxis); angiotensin II regulates the recruitment of proinflammatory cells into the site of injury (mediated by the expression of vascular permeability factors, adhesion molecules and chemokines by resident cells); inflammatory cells can produce angiotensin II, and might therefore contribute to the perpetuation of tissue damage. In this review, we summarize the proinflammatory properties of angiotensin II, to demonstrate the novel role of this vasoactive peptide as a true cytokine. We will show the information obtained as a result of the pharmacological blockade of the renin angiotensin system, which has demonstrated that this system is involved in immune and inflammatory diseases. In this aspect, we discuss the molecular mechanism of angiotensin II-induced tissue damage, as well as its contribution to the pathogenesis of several diseases, including atherosclerosis, hypertension and renal damage, showing that angiotensin II plays an active role in the inflammatory response of these diseases.
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              Mesangial cell proliferation inhibitors for the treatment of proliferative glomerular disease.

               Y Kurogi (2002)
              Mesangial cells (MC) serve a number of functions in the renal glomerular capillary including structural support of the capillary tuft, modulation of glomerular hemodynamics, and a phagocytic function allowing removal of macromolecules and immune complexes. The proliferation of MC is a prominent feature of glomerular disease including IgA nephropathy, membranoproliferative glomerulonephritis, lupus nephritis, and diabetic nephropathy. In experimental animal models of nephritis, MC proliferation frequently precedes and is linked to the increase of extracellular matrix in the mesangium and glomerulosclerosis. Reduction of MC proliferation in glomerular disease models by treatment with heparin, low-protein diet, or antibodies to platelet-derived growth factor (PDGF), have been shown to reduce extracellular matrix expansion and glomerulosclerotic changes. Therefore, MC proliferation inhibitors may offer therapeutic opportunities for the treatment of proliferative glomerular disease. It is also known that the MC proliferation is inhibited by many kinds of pharmacological drugs, for example, angiotensin converting enzyme (ACE) inhibitors, leukotriene D(4) (LTD(4)) antagonists, PDGF inhibitors, matrix metalloproteinases (MMP) inhibitors, 3-hydroxy-3 methyl glutaryl-coenzymeA (HMG-CoA) inhibitors, cyclin-dependent kinases (CDK) inhibitors, and others. This review summarizes the recently reported MC proliferation inhibitors with their pharmacological properties on the basis of their chemical structures. Copyright 2002 Wiley Periodicals, Inc.
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                Author and article information

                Journal
                NEE
                Nephron Exp Nephrol
                10.1159/issn.1660-2129
                Cardiorenal Medicine
                S. Karger AG
                1660-2129
                2007
                July 2007
                29 June 2007
                : 106
                : 4
                : e107-e112
                Affiliations
                Nephrology Division, Department of Nephrology, Assaf Harofeh Medical Center, Zerifin, affiliated to Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
                Article
                104834 Nephron Exp Nephrol 2007;106:e107–e112
                10.1159/000104834
                17622738
                © 2007 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: 3, Tables: 1, References: 24, Pages: 1
                Categories
                Original Paper

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