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      Arginase in Glomerulonephritis

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          Abstract

          Arginase metabolizes L-arginine to L-ornithine and urea. Two arginase isoforms, AI (liver arginase) and AII (ubiquitously expressed, functions unknown), have been identified. It is clear that arginases potentially have important roles in addition to urea generation for high concentrations are present at inflammatory sites. Regulation occurs through cytokines, substrate competition and products of nitric oxide (NO) metabolism. The functions of arginases at inflammatory sites are unknown, but may include regulation of apoptosis and NO production and generation of structural and cellular protein precursors. In glomerulonephritis there is increased arginase activity in nephritic glomeruli following a pattern similar to that in wound healing. The level can be further increased by NO inhibition suggesting substrate competition. The potential sources in the inflamed glomerulus include infiltrating leucocytes and mesangial cells, and the predominant isoform expressed is AI (AII predominates under physiological conditions). The recent identification of different isoforms of arginase has been an important step towards understanding the significance of arginase activity in glomerulonephritis.

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          Most cited references 6

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          Arginase induction by suppressors of nitric oxide synthesis (IL-4, IL-10 and PGE2) in murine bone-marrow-derived macrophages.

          The present study addresses the regulatory mechanisms involved in the arginine metabolism of macrophages by arginase and nitric oxide synthase. Induction of both enzymes with LPS or by mixed lymphocyte reaction has been reported. Here, we demonstrate that these enzymes can be independently induced in murine bone-marrow-derived macrophages with the appropriate agonists. Arginase expression is specifically triggered by IL-4, IL-10, PGE2 as well as non-toxic or detoxified LPS. Conversely, IFN gamma induces only NO synthesis in these cells. The results demonstrate that the metabolism of arginine in macrophages is controlled by TH1/TH2-dependent cytokines and suggest a regulatory role of arginase on the NO synthesis by intracellular substrate depletion.
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            Coinduction of nitric-oxide synthase and arginase I in cultured rat peritoneal macrophages and rat tissues in vivo by lipopolysaccharide.

            Nitric oxide is synthesized by nitric-oxide synthase from arginine, a common substrate of arginase. Rat peritoneal macrophages were cultured in the presence of bacterial lipopolysaccharide (LPS), and expression of the inducible isoform of nitric-oxide synthase (iNOS) and liver-type arginase (arginase I) was analyzed. mRNAs for iNOS and arginase I were induced by LPS in a dose-dependent manner. iNOS mRNA appeared 2 h after LPS treatment and increased to a near maximum at 8-12 h. On the other hand, arginase I mRNA that was undetectable prior to the treatment began to increase after 4 h with a lag time and reached a maximum at 12 h. Immunoblot analysis showed that iNOS and arginase I proteins were also induced. mRNA for arginase II, an arginase isozyme, was not detected in the LPS-activated peritoneal cells. mRNA for CCAAT/enhancer-binding protein beta (C/EBPbeta), a transactivator of the arginase I gene, was also induced, and the induction was more rapid than that of arginase I mRNA. Changes in iNOS and arginase I mRNAs were also examined in LPS-injected rats in vivo. iNOS mRNA increased rapidly in the lung and spleen, reached a maximum 2-6 h after the LPS treatment, and decreased thereafter. Arginase I mRNA was induced markedly and more slowly in both tissues, reaching a maximum in 12 h. Thus, arginase I appears to have an important role in down-regulating nitric oxide synthesis in murine macrophages by decreasing the availability of arginine, and the induction of arginase I is mediated by C/EBPbeta.
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              Co-induction of arginase and nitric oxide synthase in murine macrophages activated by lipopolysaccharide.

              In view of studies showing that not only nitric oxide synthase (NOS) activity but arginase activity is induced in rodent macrophages by lipopolysaccharide (LPS), the objective of this study was to investigate the co-induction of these two enzymes and to ascertain whether common mechanisms are involved. RAW 264.7 cells were activated by 2 micrograms LPS/ml and incubated for up to 48 hr. Inducible NOS (iNOS) and inducible arginase II (AII) activities were monitored, respectively, by measuring NO2-/NO3- accumulation in cell culture media and formation of urea (as CO2) from L-arginine by cell lysates. AII activity increased linearly up to at least 48 hr, whereas NO2-/NO3- formation reached a plateau well before 48 hr. Immunoprecipitation experiments revealed that AII accounted for 90-100% of arginase activity in LPS-activated macrophages. The inhibitor of NF-kappa B activation, pyrrolidine dithiocarbamate, inhibited the induction of iNOS but not AII. Moreover, whereas IFN-gamma caused iNOS induction, AII induction was nearly abolished by IFN-gamma, perhaps by inhibiting transcription of the AII gene. These observations indicate that co-induction of iNOS and AII occurs by distinct transcriptional mechanisms, AII induction could diminish NO production by decreasing L-arginine availability, and IFN-gamma can prevent AII induction.
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                Author and article information

                Journal
                EXN
                Nephron Exp Nephrol
                10.1159/issn.1660-2129
                Cardiorenal Medicine
                S. Karger AG
                1660-2129
                2000
                June 2000
                10 May 2000
                : 8
                : 3
                : 128-134
                Affiliations
                aDepartment of Molecular Genetics, Sir Alexander Fleming Building, Imperial College School of Medicine, and bDepartment of Histopathology, Imperial College School of Medicine at St.Mary’s Campus, London, UK
                Article
                20660 Exp Nephrol 2000;8:128–134
                10.1159/000020660
                10810229
                © 2000 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: 54, Pages: 7
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/20660
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