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      Lutheran/basal cell adhesion molecule accelerates progression of crescentic glomerulonephritis in mice

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          Abstract

          Migration of circulating leukocytes from the vasculature into the surrounding tissue is an important component of the inflammatory response. Among the cell surface molecules identified as contributing to leukocyte extravasation is VCAM-1, expressed on activated vascular endothelium, which participates in all stages of leukocyte–endothelial interaction by binding to leukocyte surface expressed integrin VLA-4. However, not all VLA-4-mediated events can be linked to VCAM-1. A novel interaction between VLA-4 and endothelial Lutheran (Lu) blood group antigens and basal cell adhesion molecule (BCAM) proteins has been recently shown, suggesting that Lu/BCAM may have a role in leukocyte recruitments in inflamed tissues. Here, we assessed the participation of Lu/BCAM in the immunopathogenesis of crescentic glomerulonephritis. High expression of Lu/BCAM in glomeruli of mice with rapidly progressive glomerulonephritis suggests a potential role for the local expression of Lu/BCAM in nephritogenic recruitment of leukocytes. Genetic deficiency of Lu/BCAM attenuated glomerular accumulation of T cells and macrophages, crescent formation, and proteinuria, correlating with reduced fibrin and platelet deposition in glomeruli. Furthermore, we found a pro-adhesive interaction between human monocyte α4β1 integrin and Lu/BCAM proteins. Thus, Lu/BCAM may have a critical role in facilitating the accumulation of monocytes and macrophages, thereby exacerbating renal injury.

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          Most cited references49

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          The Epidermal Growth Factor Receptor Promotes Glomerular Injury and Renal Failure in Rapidly Progressive Crescentic Glomerulonephritis; the Identification of Possible Therapy

          Rapidly progressive glomerulonephritis (RPGN) is a clinical a morphological expression of severe glomerular injury. Glomerular injury manifests as a proliferative histological pattern (“crescents”) with accumulation of T cells and macrophages, and proliferation of intrinsic glomerular cells. We show de novo induction of heparin-binding epidermal growth factor-like growth factor (HB-EGF) in intrinsic glomerular epithelial cells (podocytes) from both mice and humans with RPGN. HB-EGF induction increases phosphorylation of the EGFR/ErbB1 receptor in mice with RPGN. In HB-EGF-deficient mice, EGFR activation in glomeruli is absent and the course of RPGN is improved. Autocrine HB-EGF induces a phenotypic switch in podocytes in vitro. Conditional deletion of the Egfr gene from podocytes of mice alleviates the severity of RPGN. Pharmacological blockade of EGFR also improves the course of RPGN, even when started 4 days after the induction of experimental RPGN. This suggests that targeting the HB-EGF/EGFR pathway could also be beneficial for treatment of human RPGN.
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            RANTES and Monocyte Chemoattractant Protein–1 (MCP-1) Play an Important Role in the Inflammatory Phase of Crescentic Nephritis, but Only MCP-1 Is Involved in Crescent Formation and Interstitial Fibrosis

            The involvement of chemokines in inflammation is well established, but their functional role in disease progression, and particularly in the development of fibrosis, is not yet understood. To investigate the functional role that the chemokines monocyte chemoattractant protein–1 (MCP-1) and RANTES play in inflammation and the progression to fibrosis during crescentic nephritis we have developed and characterized a murine model for this syndrome. Significant increases in T-lymphocytes and macrophages were observed within glomeruli and interstitium, paralleled by an induction of mRNA expression of MCP-1 and RANTES, early after disease initiation. Blocking the function of MCP-1 or RANTES resulted in significant decreases in proteinuria as well as in numbers of infiltrating leukocytes, indicating that both MCP-1 and RANTES (regulated upon activation in normal T cells expressed and secreted) play an important role in the inflammatory phase of crescentic nephritis. In addition, neutralization of MCP-1 resulted in a dramatic decrease in both glomerular crescent formation and deposition of type I collagen. These results highlight a novel role for MCP-1 in crescent formation and development of interstitial fibrosis, and indicate that in addition to recruiting inflammatory cells this chemokine is critically involved in irreversible tissue damage.
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              Multiphoton imaging reveals a new leukocyte recruitment paradigm in the glomerulus.

              In contrast with many capillary beds, the glomerulus readily supports leukocyte recruitment. However, little is known regarding the actions of leukocytes following their recruitment to glomeruli. We used multiphoton confocal microscopy to examine leukocyte behavior in the glomerular microvasculature. In normal glomeruli, neutrophils and monocytes were retained in capillaries for several minutes, remaining static or migrating intravascularly. Induction of glomerular inflammation resulted in an increase in the duration of retention of static and migratory leukocytes. In response to immune complex deposition, both static and migratory neutrophils generated oxidants in inflamed glomeruli via a Mac-1-dependent mechanism. Our results describe a new paradigm for glomerular inflammation, suggesting that the major effect of acute inflammation is to increase the duration of leukocyte retention in the glomerulus. Moreover, these findings describe a previously unknown form of multicellular intravascular patrolling that involves both monocytes and neutrophils, which may underlie the susceptibility of the glomerulus to inflammation.
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                Author and article information

                Journal
                Kidney Int
                Kidney Int
                Kidney International
                Nature Publishing Group
                0085-2538
                1523-1755
                May 2014
                15 January 2014
                : 85
                : 5
                : 1123-1136
                Affiliations
                [1 ]Paris Cardiovascular Research Centre, Institut National de la Santé et de la Recherche Médicale (INSERM) , Paris, France
                [2 ]Université Paris Descartes, Sorbonne Paris Cité , Paris, France
                [3 ]Université Paris Diderot, Sorbonne Paris Cité , Paris, France
                [4 ]Unité Mixte de Recherche 995, Institut National de la Santé et de la Recherche Médicale (INSERM) , Paris, France
                [5 ]Institut National de la Transfusion Sanguine (INTS) , Paris, France
                [6 ]Service d'Exploration Fonctionnelles, Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris (AP-HP) , Paris, France
                [7 ]Institut National de la Santé et de la Recherche Médicale (INSERM) U965, Hôpital Lariboisière , Paris, France
                [8 ]Unité Mixte de Recherche 702, Institut National de la Santé et de la Recherche Médicale (INSERM) , Paris, France
                [9 ]Université Pierre et Marie Curie, Sorbonne Universités , Paris, France
                [10 ]Service de Néphrologie, Hôpital Européen Georges Pompidou, Assistance Publique–Hôpitaux de Paris , Paris, France
                Author notes
                [* ]Inserm, PARCC , Paris, France. E-mail: pierre-louis.tharaux@ 123456inserm.fr
                Article
                ki2013522
                10.1038/ki.2013.522
                4008878
                24429403
                c19986b4-21ca-4b94-b80b-a57b52d5bdaa
                Copyright © 2014 International Society of Nephrology

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/

                History
                : 31 August 2013
                : 17 October 2013
                : 24 October 2013
                Categories
                Basic Research

                Nephrology
                adhesion molecule,crescentic glomerulonephritis,endothelium,macrophage
                Nephrology
                adhesion molecule, crescentic glomerulonephritis, endothelium, macrophage

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