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      Myofibroblast Differentiation: Plasma Membrane Microdomains and Cell Phenotype

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          Abstract

          Myofibroblast differentiation characterizes a prominent cellular phenotype identified in experimental models of progressive kidney disease and human kidney biopsies. Mesangial cells, tubulointerstitial fibroblasts and, perhaps, tubular epithelial cells undergo myofibroblast differentiation, a process characterized by α-actin expression, synthesis of interstitial collagens and a growth response. Inhibition of myofibroblast differentiation could prevent kidney disease progression but may be difficult to accomplish, since inhibition of multiple signaling pathways would be required. Cell biology advances have enabled a better understanding of how information from many microenvironmental stimuli are integrated by spatial compartmentalization of extracellular receptors and cytosolic signaling molecules within specialized plasma membrane domains, such as focal adhesions and lipid rafts. We review this information and hypothesize that myofibroblast differentiation of renal cells can only proceed if the spatial arrangement of intracellular molecules, in large part determined by extracellular matrix-regulated cytoskeletal organization, permits activation of appropriate signaling pathways by soluble molecules interacting with receptors in specialized plasma membrane microdomains. If proven, this hypothesis suggests targeting key molecules within adhesion complexes and rafts (in some cases with drugs that are already clinically available) may provide more effective therapy for kidney disease progression.

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          Most cited references 24

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          Focal adhesion kinase: a regulator of focal adhesion dynamics and cell movement.

          Engagement of integrin receptors with extracellular ligands gives rise to the formation of complex multiprotein structures that link the ECM to the cytoplasmic actin cytoskeleton. These adhesive complexes are dynamic, often heterogeneous structures, varying in size and organization. In motile cells, sites of adhesion within filopodia and lamellipodia are relatively small and transient and are referred to as 'focal complexes,' whereas adhesions underlying the body of the cell and localized to the ends of actin stress fibers are referred to as 'focal adhesions'. Signal transduction through focal complexes and focal adhesions has been implicated in the regulation of a number of key cellular processes, including growth factor induced mitogenic signals, cell survival and cell locomotion. The formation and remodeling of focal contacts is a dynamic process under the regulation of protein tyrosine kinases and small GTPases of the Rho family. In this review, we consider the role of the focal complex associated protein tyrosine kinase, Focal Adhesion Kinase (FAK), in the regulation of cell movement with the emphasis on how FAK regulates the flow of signals from the ECM to the actin cytoskeleton.
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            Molecular basis of renal fibrosis.

             James A. Eddy (2000)
            All progressive renal diseases are the consequence of a process of destructive fibrosis. This review will focus on tubulointerstitial fibrosis, the pathophysiology of which will be divided into four arbitrary phases. First is the cellular activation and injury phase. The tubules are activated, the peritubular capillary endothelium facilitates migration of mononuclear cells into the interstitium where they mature into macrophages, and myofibroblasts/activated fibroblasts begin to populate the interstitium. Each of these cells releases soluble products that contribute to ongoing inflammation and ultimately fibrosis. The second phase, the fibrogenic signaling phase, is characterized by the release of soluble factors that have fibrosis-promoting effects. Several growth factors and cytokines have been implicated, with primary roles suggested for transforming growth factor-beta, connective tissue growth factor, angiotensin II and endothelin-1. Additional factors may participate including platelet-derived growth factor, basic fibroblast growth factor, tumor necrosis factor-alpha and interleukin-1, while interferon-gamma and hepatocyte growth factor may elicit antifibrotic responses. Third is the fibrogenic phase when matrix proteins, both normal and novel to the renal interstitium, begin to accumulate. During this time both increased matrix protein synthesis and impaired matrix turnover are evident. The latter is due to the renal production of protease inhibitors such as the tissue inhibitors of metalloproteinases and plasminogen activator inhibitors which inactivate the renal proteases that normally regulate matrix turnover. Fourth is the phase of renal destruction, the ultimate sequel to excessive matrix accumulation. During this time the tubules and peritubular capillaries are obliterated. The number of intact nephrons progressively declines resulting in a continuous reduction in glomerular filtration.
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              Integrins can collaborate with growth factors for phosphorylation of receptor tyrosine kinases and MAP kinase activation: roles of integrin aggregation and occupancy of receptors

              Integrins mediate cell adhesion, migration, and a variety of signal transduction events. These integrin actions can overlap or even synergize with those of growth factors. We examined for mechanisms of collaboration or synergy between integrins and growth factors involving MAP kinases, which regulate many cellular functions. In cooperation with integrins, the growth factors EGF, PDGF-BB, and basic FGF each produced a marked, transient activation of the ERK (extracellular signal-regulated kinase) class of MAP kinase, but only if the integrins were both aggregated and occupied by ligand. Transmembrane accumulation of total tyrosine-phosphorylated proteins, as well as nonsynergistic MAP kinase activation, could be induced by simple integrin aggregation, whereas enhanced transient accumulation of the EGF-receptor substrate eps8 required integrin aggregation and occupancy, as well as EGF treatment. Each type of growth factor receptor was itself induced to aggregate transiently by integrin ligand-coated beads in a process requiring both aggregation and occupancy of integrin receptors, but not the presence of growth factor ligand. Synergism was also observed between integrins and growth factors for triggering tyrosine phosphorylation of EGF, PDGF, and FGF receptors. This collaborative response also required both integrin aggregation and occupancy. These studies identify mechanisms in the signal transduction response to integrins and growth factors that require various combinations of integrin aggregation and ligands for integrin or growth factor receptors, providing opportunities for collaboration between these major regulatory systems.
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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
                2002
                2002
                09 October 2002
                : 10
                : 5-6
                : 313-319
                Affiliations
                Departments of Medicine and Physiology and Biophysics, Case Western Reserve University, Rammelkamp Center for Education and Research, MetroHealth System Campus, Cleveland, Ohio, USA
                Article
                65309 Exp Nephrol 2002;10:313–319
                10.1159/000065309
                12381915
                © 2002 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: 2, References: 49, Pages: 7
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/65309
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