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      Angiotensin II Type 1 and Type 2 Receptors Reciprocally Modulate Pro-inflammatory/ Pro-Fibrotic Reactions in Activated Splenic Lymphocytes

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          Abstract

          Angiotensin II (Ang II) type 1 receptor (AT<sub>1</sub>R) has been confirmed to confer renoprotection in the progressive, immune-mediated nephritis in animal models as well as in humans. However, the relative contributions of direct AT<sub>1</sub>R blockade, indirect counteractivation of Ang II type 2 receptor (AT<sub>2</sub>R), or both, to renoprotection through AT<sub>1</sub>R antagonism remains to be clarified. Immunohistochemical studies in the nephritic kidney revealed that tubular epithelial cells and infiltrating immune cells were positive for AT<sub>1</sub>R and AT<sub>2</sub>R. In the present study, we investigated the action of Ang II on both receptors on immune cells. A subpopulation of lipopolysaccharide-activated splenic lymphocytes (mixed lymphocyte populations) was positive for AT<sub>1</sub>R and AT<sub>2</sub>R. Ang II alone could not induce gene expression of a pro-inflammatory chemokine JE or a pro-fibrotic cytokine transforming growth factor-β1 in those cells. However, Ang II could significantly suppress the expression of both genes in those cells under AT<sub>1</sub>R blockade, and this action was mediated through AT<sub>2</sub>R. Conversely, the pro-inflammatory/pro-fibrotic gene expression could be enhanced by AT<sub>2</sub>R blockade, and this was mediated through AT<sub>1</sub>R. AT<sub>1</sub>R and AT<sub>2</sub>R expressed in activated immune cells can modulate pro-inflammatory and pro-fibrotic reactions reciprocally. In advanced immune-mediated nephritic kidneys, AT<sub>1</sub>R antagonism likely confers renoprotection via activation of AT<sub>2</sub>R.

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          Most cited references 7

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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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            Macrophage signaling and respiratory burst.

            Macrophages are key defenders of the lung and play an essential role in mediating the inflammatory response. Critical to this is the activation of the NADPH oxidase. Through receptor-mediated interactions, extracellular stimuli activate pathways that signal for the phosphorylation and assembly of the NADPH oxidase. Once the NADPH oxidase is activated, it produces superoxide and H2O2 in a process known as the respiratory burst. The involvement of O2.- and H2O2 in the antimicrobicidal function of macrophages has been assumed for many years, but it is now clear that the H2O2 produced by the respiratory burst functions as a second messenger and activates major signaling pathways in the alveolar macrophage. Both the nuclear factor-kappaB and activator protein-1 transcription factors are activated by H2O2 produced by the respiratory burst, and, since these control the inducible expression of genes whose products are part of the inflammatory response, this may be a critical link between the respiratory burst and other inflammatory responses. The c-Jun N-terminal kinase (JNK) and extracellular-regulated kinase (ERK) pathways, two members of the mitogen-activated protein kinase family, are also activated by the respiratory burst. JNK is activated by both exogenous and endogenously produced H2O2. Studies with ERK have shown that specific agonists of the respiratory burst, but not bolus H2O2, can activate this pathway. The ERK pathway also modulates the expression of genes via phosphorylation of the transcription factor Elk-1 that controls the production of the c-Fos transcription factor. Although an understanding of the mechanism of redox signaling is in its infancy, it is becoming clear that the reactive oxygen species produced by the respiratory burst have a profound effect on intracellular signaling pathways and ultimately in modulating gene expression.
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              Upregulation of renin-angiotensin system during differentiation of monocytes to macrophages.

              We have demonstrated that accumulated macrophages in human coronary arteries strongly express angiotensin converting enzyme in accordance with the development of atheromatous plaques. However, there are few reports on the regulation of the renin-angiotensin system in macrophages and in monocytes as their source. To examine whether the renin-angiotensin system is upregulated during the differentiation of monocytes to macrophages, and whether it is further regulated by angiotensin II and cytokines. We used a human leukemia cell line, THP-1, for monocytes. Differentiated THP-1, induced by adding phorbol 12-myristate 13-acetate for 24 h, were used as macrophages. Expression of messenger RNA of the renin-angiotensin system components was measured by quantitative reverse-transcriptase polymerase chain reaction. Angiotensin converting enzyme activity and subtype-specific angiotensin-binding sites of cultured cells, and angiotensin II production in the culture medium were measured. Macrophages expressed all components of the renin-angiotensin system except chymase. Cellular angiotensin converting enzyme activity and angiotensin II in the medium were increased 3.2- and 4.5-fold during differentiation, respectively. Expression of angiotensin II type 1 (AT1) and type 2 (AT2) receptors was increased 6.2-and 6.4-fold during differentiation, and was sustained for 7 days. Incubation with angiotensin II for 24 h caused downregulation of both AT1 and AT2 receptor messenger RNA, but the expression levels were still more than threefold higher compared with monocytes. The density of binding sites of AT1 and AT2 receptors in macrophages was 0.26 +/- 0.02 and 0.15 +/- 0.01 fmol/10(6) cells, respectively. The renin-angiotensin system is markedly activated during monocyte/macrophage differentiation, and may participate in the development of atherosclerosis.
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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
                2004
                June 2004
                06 July 2004
                : 24
                : 3
                : 322-329
                Affiliations
                Department of Nephrology, Saitama Medical College, Saitama, Japan
                Article
                78496 Am J Nephrol 2004;24:322–329
                10.1159/000078496
                15148459
                © 2004 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: 25, Pages: 8
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/78496
                Categories
                Original Report: Laboratory Investigation

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