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      Inducible Nitric Oxide Synthase Induction in Thy 1 Glomerulonephritis Is Complement and Reactive Oxygen Species Dependent

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          Abstract

          Thy 1 glomerulonephritis (GN) is a rat model of complement-dependent immune mesangial injury with induced glomerular nitric oxide (NO) synthesis. To examine mechanisms of inducible nitric oxide synthase (iNOS) induction, we studied the effects of treatment with the antioxidant N-acetyl-cysteine (NAC) and soluble complement receptor 1 (sCR1). Thy 1 GN was induced by intravenous anti-Thy 1 antibody. Glomeruli were isolated and kidney tissue taken from 30 min to 24 h after induction. Nitrite (NO<sup>–</sup><sub>2</sub>) synthesis, luminol chemiluminescence for reactive oxygen species (ROS), and iNOS and cytokine mRNA were assayed in isolated glomeruli. Mesangial injury (mesangiolysis) and leucocyte infiltration were quantitated on tissue sections. NAC (i.p. 1,000 mg/kg, 1 h prior to anti-Thy 1) reduced glomerular NO<sup>–</sup><sub>2</sub> synthesis (3.5 ± 0.66 vs. untreated 8.2 ± 1.1, p = 0.02), and iNOS mRNA expression, and abolished enhanced chemiluminescence. In vitro incubation of nephritic glomeruli with 20 mM NAC also suppressed nitrite production (4.7 ± 0.8 vs. untreated 12.2 ± 0.7 nmol NO<sup>–</sup><sub>2</sub>/2,000 glomeruli/48 h, p = 0.003), and chemiluminescence. In NAC-treated animals, neutrophil infiltration (0.5 ± 0 vs. untreated 9.6 ± 1.6 glomerulus, p = 0.0005), and macrophage infiltration (1.7 ± 0.4 vs. untreated 12.0 ± 0.1, p = 0.006) were abolished, and mesangiolysis was significantly reduced (45.9 ± 1.3 vs. untreated 34.4 ± 2.1 cells/glomerulus, p = 0.009). NAC did not inhibit anti-Thy 1 antibody deposition. C1q was unaffected, but C3 was reduced. sCR1 treatment prevented iNOS mRNA induction, the enhanced chemiluminescence, and the neutrophil infiltration at 1 h. IL-1β and TNFα mRNAs were not affected by either NAC or sCR1. These results show that NAC inhibits iNOS induction and NO synthesis in this model, and suppresses ROS synthesis and injury. They suggest that complement-dependent ROS generation is the critical initiating event that follows fixation of anti-Thy 1 antibody.

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          Most cited references 4

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          N-acetylcysteine delays the infiltration of inflammatory cells into the lungs of paraquat-intoxicated rats.

          We investigated a possible role for N-acetylcysteine (NAC), a well-known antioxidant and free radical scavenger, against oxidative lung damage as observed in the in vivo model of paraquat-intoxicated rats. The administration of two ip doses of 50 mg/kg NAC to paraquat-intoxicated animals did not change the glutathione status of the lungs, as determined by the measurement of nonprotein sulfhydryl (NP-SH) groups. The administration of NAC did however suppress the paraquat-induced release of chemoattractants for neutrophils in the bronchoalveolar fluid when the lavage was carried out 12 hr after the administration of 30 mg/kg paraquat. Also, in the intoxicated NAC-treated animals, the infiltration of inflammatory cells was significantly reduced, as demonstrated by the examination of the cell composition of the bronchoalveolar lavage (BAL), 24 hr after paraquat. Phorbol myristate acetate-stimulated superoxide anion production from the AM isolated from the BAL of paraquat-intoxicated nontreated animals was lower than that of controls, whereas in the NAC-treated animals, it was close to that of the controls. The obtained results indicate that NAC has a protective effect against oxidative lung damage by delaying inflammation. It also prevents the paraquat-induced reduction of superoxide anion production by stimulated AM. In the present model, however, the NAC administration regimen did not affect the survival rate of paraquat-intoxicated rats.
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            Acute glomerulonephritis after intravenous injection of monoclonal anti-thymocyte antibodies in the rat

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              Pyrrolidine Dithiocarbamate Differentially Affects Interleukin 1β- and cAMP-Induced Nitric Oxide Synthase Expression in Rat Renal Mesangial Cells

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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
                1999
                February 1999
                14 January 1999
                : 7
                : 1
                : 26-34
                Affiliations
                Department of Experimental Pathology, Imperial College School of Medicine, St. Mary’s Campus, London, UK
                Article
                20581 Exp Nephrol 1999;7:26–34
                10.1159/000020581
                9892811
                © 1999 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: 9, References: 42, Pages: 9
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/20581
                Categories
                Original Paper

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