Blog
About

0
views
0
recommends
+1 Recommend
1 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found

      Differential Regulation of Toll-Like Receptor 4 Gene Expression in Renal Cells by Angiotensin II: Dependency on AP1 and PU.1 Transcriptional Sites

      Read this article at

      ScienceOpenPublisherPubMed
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Background: Toll-like receptor 4 (TLR4) is involved in the sensing of lipopolysaccharide and, therefore, plays a central role in innate immune responses to Gram-negative bacteria. Interestingly, TLR4 expression occurs within the kidney. We have previously demonstrated that angiotensin II (ANG II) upregulates TLR4 expression on mesangial cells. However, the factors controlling transcriptional activation of the Tlr4 gene in mesangial cells are not known, and the specificity of this response for other renal cells is unclear. Methods: Cultured murine proximal tubular cells (mouse cortical tubule cell line; MCT cells), murine mesangial cells (MMCs), and murine podocytes were treated with ANG II. The expression of ANG II receptor mRNA and TLR4 mRNA and protein was determined by polymerase chain reaction and Western blotting. The transcriptional activity of wild-type and mutant mouse TLR4 promoter reporter constructs was determined upon transient transfection of the three cell types. Results: Although MMCs, podocytes, and syngeneic proximal MCT cells similarly expressed ANG II receptors, ANG II stimulated TLR4 mRNA and protein expression in MMCs and podocytes only. A mouse TLR4 promoter construct (–518/+129), previously shown to contain all important transcriptional regulatory elements in various cell types, was activated by ANG II in MMCs and podocytes, but not in MCT cells. Mutation of a proximal PU.1-binding consensus site or an AP1 site abolished ANG-II-mediated transcriptional activation of the TLR4 promoter. Finally, basal transcription of the Tlr4 gene depended in all three cell lines on an intact AP1 site and additionally on the proximal PU.1 site in MMCs. Conclusions: ANG II stimulates TLR4 transcription through AP1 and PU.1 sites in a cell-specific manner. Since the intrarenal ANG II concentrations are enhanced in many pathophysiological situations, ANG-II-stimulated transcription of TLR4 on MMCs and podocytes may contribute to renal inflammation.

          Related collections

          Most cited references 13

          • Record: found
          • Abstract: found
          • Article: not found

          Rearrangements of the cytoskeleton and cell contacts induce process formation during differentiation of conditionally immortalized mouse podocyte cell lines.

          Mature podocytes are among the most complex differentiated cells and possess a highly branched array of foot processes that are essential to glomerular filtration in the kidney. Such differentiated podocytes are unable to replicate and culturing of primary podocytes results in rapid growth arrest. Therefore, conditionally immortalized mouse podocyte clones (MPC) were established, which are highly proliferative when cultured under permissive conditions. Nonpermissive conditions render the majority of MPC cells growth arrested within 6 days and induce many characteristics of differentiated podocytes. Both proliferating and differentiating MPC cells express the WT-1 protein and an ordered array of actin fibers and microtubules extends into the forming cellular processes during differentiation, reminiscent of podocyte processes in vivo. These cytoskeletal rearrangements and process formation are accompanied by the onset of synaptopodin synthesis, an actin-associated protein marking specifically differentiated podocytes. In addition, focal contacts are rearranged into an ordered pattern in differentiating MPC cells. Most importantly, electrophysiological studies demonstrate that differentiated MPC cells respond to the vasoactive peptide bradykinin by changes in intracellular calcium concentration. These results suggest a regulatory role of podocytes in glomerular filtration. Taken together, these studies establish that conditionally immortalized MPC cells retain a differentiation potential similar to podocytes in vivo. Therefore, the determinative steps of podocyte differentiation and process formation are studied for the first time using an inducible in vitro model.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Toll-like receptors in the pathogenesis of human disease.

            Members of the Toll-like receptor (TLR) family are key regulators of both innate and adaptive immune responses. The function of TLRs in various human diseases has been investigated by comparison of the incidence of disease among people having different polymorphisms in genes that participate in TLR signaling. These studies have shown that TLR function affects several diseases, including sepsis, immunodeficiencies, atherosclerosis and asthma. As this body of data grows, it will provide new insights into disease pathogenesis as well as valuable information on the merits of various therapeutic options.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Ets-1 is a critical regulator of Ang II-mediated vascular inflammation and remodeling.

              Ang II is a central mediator of vascular inflammation and remodeling. The transcription factor Ets-1 is rapidly induced in vascular smooth muscle and endothelial cells of the mouse thoracic aorta in response to systemic Ang II infusion. Arterial wall thickening, perivascular fibrosis, and cardiac hypertrophy are significantly diminished in Ets1-/- mice compared with control mice in response to Ang II. The induction of 2 known targets of Ets-1, cyclin-dependent kinase inhibitor p21CIP and plasminogen activator inhibitor-1 (PAI-1), by Ang II is markedly blunted in the aorta of Ets1-/- mice compared with wild-type controls. Expression of p21CIP in VSMCs leads to cellular hypertrophy, whereas expression of p21CIP in endothelial cells is associated with cell cycle arrest, apoptosis, and endothelial dysfunction. PAI-1 promotes the development of perivascular fibrosis. We have identified monocyte chemoattractant protein-1 (MCP-1) as a novel target for Ets-1. Expression of MCP-1 is similarly reduced in Ets1-/- mice compared with control mice in response to Ang II, which results in significantly diminished recruitment of T cells and macrophages to the vessel wall. In summary, our results support a critical role for Ets-1 as a transcriptional mediator of vascular inflammation and remodeling in response to Ang II.
                Bookmark

                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
                2007
                May 2007
                08 May 2007
                : 27
                : 3
                : 308-314
                Affiliations
                aClinic of Internal Medicine III, University of Jena, Jena, Germany; bInfectious Diseases Service, Department of Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
                Article
                102551 Am J Nephrol 2007;27:308–314
                10.1159/000102551
                17495427
                © 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: 4, Tables: 1, References: 19, Pages: 7
                Categories
                Original Report: Laboratory Investigation

                Comments

                Comment on this article