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  • Review Article
  • Published:

The podocyte slit diaphragm—from a thin grey line to a complex signalling hub

Nature Reviews Nephrology volume 9, pages 587–598 (2013)Cite this article

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Abstract

The architectural design of our kidneys is amazingly complex, and culminates in the 3D structure of the glomerular filter. During filtration, plasma passes through a sieve consisting of a fenestrated endothelium and a broad basement membrane before it reaches the most unique part, the slit diaphragm, a specialized type of intercellular junction that connects neighbouring podocyte foot processes. When podocytes become stressed, irrespective of the causative stimulus, they undergo foot process effacement and loss of slit diaphragms—two key steps leading to proteinuria. Thus, proteinuria is the unifying denominator of a broad spectrum of podocytopathies. With the rising prevalence of chronic kidney disease and the fact that glomerular diseases account for the majority of patients with end-stage renal disease, further investigation and elucidation of this unique structure is of paramount importance. This Review recounts how perception of the slit diaphragm has changed over time as a result of intense research, from its first anatomical description as a thin intercellular connection, to an appreciation of its role as a dynamic signalling hub. These observations led to the introduction of novel concepts in podocyte biology, which could pave the way to development of highly desired, specific therapeutic strategies for glomerular diseases.

Key Points

  • The slit diaphragm is a unique intercellular contact point that integrates the structural components of various other cell junction types, including tight, adhesion, gap and neuronal junctions

  • We propose that the slit diaphragm should be classified as a unique category of intercellular junction

  • Slit diaphragm functioning is impaired in all monogenic inherited proteinuric diseases

  • The slit diaphragm executes several highly specialized functions: macromolecular filtering, connecting the slit diaphragm to the actin cytoskeleton and initiating signalling pathways that regulate the plasticity of foot processes

  • The slit diaphragm also mediates calcium signalling, mechanosensation, regulation of the cytoskeleton, cell polarity, cell survival, endocytosis and transcription

  • Further research into this delicate structure holds the potential to discover novel treatment options for proteinuria and chronic kidney diseases

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Figure 1: Timeline of major discoveries relating to the slit diaphragm.
Figure 2: Electron micrographs of the slit diaphragm and surrounding structures.
Figure 3: Molecular components of the podocyte slit diaphragm.
Figure 4: A comprehensive overview of signalling pathways converging at the slit diaphragm.

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Change history

  • 25 November 2012

    In the original 'about the authors section', author affiliations for Christoph Schell and Tobias Huber were not complete. This has been corrected for the online version of the article.

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Acknowledgements

We apologize to all podocyte researchers whose interesting work and ideas could not be described in more detail owing to space limitations. The work in T. B. Huber's laboratory has been generously supported by grant number KFO208 from the DFG (German Research Foundation) to F. Grahammer and T. B. Huber, the Excellence Initiative of the German Federal and State Governments (grant numbers EXC 294 to T. B. Huber and GSC-4 (Spemann Graduate School of Biology and Medicine) to C. Schell and T. B. Huber), the Else Kröner Fresenius Stiftung (F. Grahammer, T. B. Huber), the Fritz Thyssen Stiftung (F. Grahammer, T. B. Huber) and the BMBF (Federal Ministry of Education and Research) Gerontosys II—NephAge (T. B. Huber).

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  1. Renal Division, University Hospital Freiburg, Hugstetter Strasse 55, Freiburg, 79106, Germany

    Florian Grahammer & Tobias B. Huber

  2. Spemann Graduate School of Biology and Medicine (SGBM), Albert-Ludwigs University, Albertstrasse 19a, Freiburg, 79104, Germany

    Christoph Schell

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All authors contributed equally to researching the data for the article, discussions of its content, writing the article and review and/or editing of the manuscript before submission.

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Correspondence to Tobias B. Huber.

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T. B. Huber declares that he receives project-specific grant funding from Pfizer Pharma and has acted as a consultant for Abbott Pharma and Pfizer Pharma. The other authors declare no competing interests.

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Grahammer, F., Schell, C. & Huber, T. The podocyte slit diaphragm—from a thin grey line to a complex signalling hub. Nat Rev Nephrol 9, 587–598 (2013). https://doi.org/10.1038/nrneph.2013.169

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