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      Gene Expression Analysis Detected a Low Expression Level of C1s Gene in ICR-Derived Glomerulonephritis (ICGN) Mice

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          Background: ICR-derived glomerulonephritis (ICGN) strain is a novel inbred strain of mice with a hereditary nephrotic syndrome. Deletion mutation of tensin 2 (Tns2), a focal adhesion molecule, has been suggested to be responsible for nephrotic syndrome in ICGN mice; however, the existence of other associative factors has been suggested. Methods and Results: To identify additional associative factors and to better understand the onset mechanism of nephrotic syndrome in ICGN mice, we conducted a comprehensive gene expression analysis using DNA microarray. Immune-related pathways were markedly altered in ICGN mice kidney as compared with ICR mice. Furthermore, the gene expression level of complement component 1, s subcomponent (C1s), whose human homologue has been reported to associate with lupus nephritis, was markedly low in ICGN mouse kidney. Real-time quantitative reverse transcription-polymerase chain reaction confirmed a low expression level of C1s in ICGN mouse liver where the C1s protein is mainly synthesized. A high serum level of anti-dsDNA antibody and deposits of immune complexes were also detected in ICGN mice by enzyme-linked immunosorbent assay and immunohistochemical analyses, respectively. Conclusion: Our results suggest that the immune system, especially the complement system, is associated with nephrotic syndrome in ICGN mice. We identified a low expression level of C1s gene as an additional associative factor for nephrotic syndrome in ICGN mice. Further studies are needed to elucidate the role of the complement system in the onset of nephrotic syndrome in ICGN mice.

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            The mitogen-activated protein kinase and JAK-STAT signaling pathways are required for an oncostatin M-responsive element-mediated activation of matrix metalloproteinase 1 gene expression.

            Both astrocytes in the central nervous system and fibroblasts in somatic tissues are not only the major sources of extracellular matrix components but also of matrix metalloproteinases (MMPs), a family of enzymes directly involved in extracellular matrix breakdown. We have analyzed the regulation of the expression of MMPs and TIMPs (tissue inhibitors of metalloproteinases) in human primary astrocytes stimulated with oncostatin M (OSM) and other extracellular mediators in comparison with normal human dermal fibroblasts. It was found that OSM induced/enhanced transcription of MMP-1 (interstitial collagenase) and MMP-3 (stromelysin 1) in astrocytes, and MMP-1, MMP-9 (gelatinase B), and TIMP-1 in fibroblasts. Analysis of the signal transduction leading to activation of the MMP-1 gene revealed the presence of an OSM-responsive element (OMRE) encompassing the AP-1 binding site and the signal transducer and activator of transcription (STAT) binding element, which mediate activation by OSM. OMRE is also present in the TIMP-1 gene promoter and, although there are some differences in these two motifs, both appear to be targets for the simultaneous action of OSM-induced nuclear effectors. The induced enhancement of transcription by synergistically acting AP-1 and STAT binding elements in response to OSM is Raf-dependent. Cross-talk between the mitogen-activated protein kinase and JAK-STAT pathways is required to achieve maximal induction of the OMRE-driven transcription by OSM.
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              Differential Regulation of Cathepsin S and Cathepsin L in Interferon γ–treated Macrophages

              Cathepsin S (catS) and cathepsin L (catL) mediate late stages of invariant chain (Ii) degradation in discrete antigen-presenting cell types. Macrophages (Mφs) are unique in that they express both proteases and here we sought to determine the relative contribution of each enzyme. We observe that catL plays no significant role in Ii cleavage in interferon (IFN)-γ–stimulated Mφs. In addition, our studies show that the level of catL activity is significantly decreased in Mφs cultured in the presence of IFN-γ whereas catS activity increases. The decrease in catL activity upon cytokine treatment occurs despite the persistence of high levels of mature catL protein, suggesting that a specific inhibitor of the enzyme is up-regulated in IFN-γ–stimulated peritoneal Mφs. Similar inhibition of activity is observed in dendritic cells engineered to overexpress catL. Such enzymatic inhibition in Mφs exhibits only partial dependence upon Ii and therefore, other mechanisms of catL inhibition are regulated by IFN-γ. Thus, during a T helper cell type 1 immune response catL inhibition in Mφs results in preferential usage of catS, such that major histocompatibility complex class II presentation by all bone marrow–derived antigen-presenting cell is regulated by catS.

                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                November 2013
                23 August 2013
                : 123
                : 3-4
                : 34-45
                aDrug Safety Research Laboratories, Astellas Pharma Inc., Osaka, bLaboratory of Animal Models for Human Diseases, National Institute of Biomedical Innovation, Ibaraki, and cAnimal Resource Center, The University of Tokyo, Kasama, Japan
                Author notes
                *Kotaro Tamura, Drug Safety Research Laboratories, Astellas Pharma Inc., 2-1-6, Kashima, Yodogawa-ku, Osaka 532-8514 (Japan), E-Mail
                354057 Nephron Exp Nephrol 2013;123:34-45
                © 2013 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: 4, Tables: 6, Pages: 12
                Original Paper


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