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      Podocin Organizes Ion Channel-Lipid Supercomplexes: Implications for Mechanosensation at the Slit Diaphragm

      , ,

      Cardiorenal Medicine

      S. Karger AG

      TRPC6, Mechanosensor, Slit diaphragm, Podocyte, Podocin

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          Abstract

          The slit diaphragm is part of a three-layered glomerular filter that prevents most proteins from entering the urinary space. As a highly specialized cell-cell contact the slit diaphragm has recently been appreciated as a signaling platform that regulates podocyte cell survival, polarity, endocytosis and cytoskeletal organization. Mutations in genes encoding slit diaphragm proteins contribute to human hereditary glomerular diseases. Recently, it was discovered that transient receptor potential ion channel TRPC6 mutations cause familial glomerular disease. TRPC6 localizes to the slit diaphragm unexpectedly adding an ion channel to the list of signaling molecules functioning at this complex structure. Recent findings highlight a potential role for TRPC6 at the filtration barrier. TRPC6 has been identified as a sensor of mechanically and osmotically induced membrane stretch. In the context of the slit diaphragm signaling network, TRPC6 is clustered and regulated by a podocin-lipid complex that might translate mechanical tension to ion channel action. This review will summarize the most recent findings on protein-lipid supercomplexes at the slit diaphragm and discuss a potential novel function of the slit diaphragm as a mechanosensor.

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          Most cited references 9

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          TRP channels as cellular sensors.

           D Clapham (2003)
          TRP channels are the vanguard of our sensory systems, responding to temperature, touch, pain, osmolarity, pheromones, taste and other stimuli. But their role is much broader than classical sensory transduction. They are an ancient sensory apparatus for the cell, not just the multicellular organism, and they have been adapted to respond to all manner of stimuli, from both within and outside the cell.
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            NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome.

            Familial idiopathic nephrotic syndromes represent a heterogeneous group of kidney disorders, and include autosomal recessive steroid-resistant nephrotic syndrome, which is characterized by early childhood onset of proteinuria, rapid progression to end-stage renal disease and focal segmental glomerulosclerosis. A causative gene for this disease, NPHS2, was mapped to 1q25-31 and we report here its identification by positional cloning. NPHS2 is almost exclusively expressed in the podocytes of fetal and mature kidney glomeruli, and encodes a new integral membrane protein, podocin, belonging to the stomatin protein family. We found ten different NPHS2 mutations, comprising nonsense, frameshift and missense mutations, to segregate with the disease, demonstrating a crucial role for podocin in the function of the glomerular filtration barrier.
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              TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function.

              Progressive kidney failure is a genetically and clinically heterogeneous group of disorders. Podocyte foot processes and the interposed glomerular slit diaphragm are essential components of the permeability barrier in the kidney. Mutations in genes encoding structural proteins of the podocyte lead to the development of proteinuria, resulting in progressive kidney failure and focal segmental glomerulosclerosis. Here, we show that the canonical transient receptor potential 6 (TRPC6) ion channel is expressed in podocytes and is a component of the glomerular slit diaphragm. We identified five families with autosomal dominant focal segmental glomerulosclerosis in which disease segregated with mutations in the gene TRPC6 on chromosome 11q. Two of the TRPC6 mutants had increased current amplitudes. These data show that TRPC6 channel activity at the slit diaphragm is essential for proper regulation of podocyte structure and function.
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                Author and article information

                Journal
                NEE
                Nephron Exp Nephrol
                10.1159/issn.1660-2129
                Cardiorenal Medicine
                S. Karger AG
                978-3-8055-8311-4
                978-3-318-01479-2
                1660-2129
                2007
                June 2007
                06 June 2007
                : 106
                : 2
                : e27-e31
                Affiliations
                Renal Division, University Hospital Freiburg, Freiburg, Germany
                Article
                101789 Nephron Exp Nephrol 2007;106:e27–e31
                10.1159/000101789
                17570936
                © 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: 1, References: 16, Pages: 1
                Categories
                Paper

                Cardiovascular Medicine, Nephrology

                Podocyte, TRPC6, Slit diaphragm, Mechanosensor, Podocin

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