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

This article highlights the evolution in understanding of the podocyte slit diaphragm. Now appreciated as far more than a simple intercellular connection, the slit diaphragm controls the structure and function of the glomerular filtration barrier. However, several slit diaphragm properties remain un...

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Published in:Nature reviews. Nephrology Vol. 9; no. 10; pp. 587 - 598
Main Authors: Grahammer, Florian, Schell, Christoph, Huber, Tobias B.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 01.10.2013
Nature Publishing Group
Subjects:
692/698/272/1684/1587/2101
692/699/1585/2759
Animals
Biology
Care and treatment
Cytoskeleton
Diagnosis
Disease
Endothelium
Glomerular Filtration Barrier - metabolism
Humans
Intercellular Junctions - metabolism
Kidney glomerulus
Kidneys
Medicine
Medicine & Public Health
Mutation
Nephrology
Nephrotic syndrome
Phosphorylation
Physiological aspects
Podocytes - metabolism
Proteins
Renal Insufficiency, Chronic - metabolism
review-article
Signal Transduction - physiology
Transmission electron microscopy
Urine
Germany
ISSN:1759-5061, 1759-507X, 1759-507X
Online Access:Get full text
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Abstract This article highlights the evolution in understanding of the podocyte slit diaphragm. Now appreciated as far more than a simple intercellular connection, the slit diaphragm controls the structure and function of the glomerular filtration barrier. However, several slit diaphragm properties remain unclear: its role in filtration, exact molecular structure, and the complex pathways initiated by this dynamic signalling hub. 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
AbstractList 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. Grahammer, F. et al. Nat. Rev. Nephrol. 9, 587-598 (2013); published online 3 September 2013; doi: 10.1038/nrneph.2013.169
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.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.
This article highlights the evolution in understanding of the podocyte slit diaphragm. Now appreciated as far more than a simple intercellular connection, the slit diaphragm controls the structure and function of the glomerular filtration barrier. However, several slit diaphragm properties remain unclear: its role in filtration, exact molecular structure, and the complex pathways initiated by this dynamic signalling hub. 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
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.
Audience Academic
Author Huber, Tobias B.
Grahammer, Florian
Schell, Christoph
Author_xml – sequence: 1
  givenname: Florian
  surname: Grahammer
  fullname: Grahammer, Florian
  organization: Renal Division, University Hospital Freiburg
– sequence: 2
  givenname: Christoph
  surname: Schell
  fullname: Schell, Christoph
  organization: Spemann Graduate School of Biology and Medicine (SGBM), Albert-Ludwigs University
– sequence: 3
  givenname: Tobias B.
  surname: Huber
  fullname: Huber, Tobias B.
  email: tobias.huber@uniklinik-freiburg.de
  organization: Renal Division, University Hospital Freiburg
BackLink https://www.ncbi.nlm.nih.gov/pubmed/23999399$$D View this record in MEDLINE/PubMed
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Snippet This article highlights the evolution in understanding of the podocyte slit diaphragm. Now appreciated as far more than a simple intercellular connection, the...
The architectural design of our kidneys is amazingly complex, and culminates in the 3D structure of the glomerular filter. During filtration, plasma passes...
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StartPage 587
SubjectTerms 692/698/272/1684/1587/2101
692/699/1585/2759
Animals
Biology
Care and treatment
Cytoskeleton
Diagnosis
Disease
Endothelium
Glomerular Filtration Barrier - metabolism
Humans
Intercellular Junctions - metabolism
Kidney glomerulus
Kidneys
Medicine
Medicine & Public Health
Mutation
Nephrology
Nephrotic syndrome
Phosphorylation
Physiological aspects
Podocytes - metabolism
Proteins
Renal Insufficiency, Chronic - metabolism
review-article
Signal Transduction - physiology
Transmission electron microscopy
Urine
Title The podocyte slit diaphragm—from a thin grey line to a complex signalling hub
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