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  • Review Article
  • Published:

Podocyte–actin dynamics in health and disease

Nature Reviews Nephrology volume 12, pages 692–710 (2016)Cite this article

Subjects

Key Points

  • The actin cytoskeleton of podocytes reflects their physiological functions and underlies their unique morphology, which can adjust in response to environmental changes to maintain filtration barrier integrity

  • Podocyte focal adhesions and slit diaphragms are signalling networks that interact with the actin cytoskeleton, maintain balance between intracellular and extracellular signals, and regulate podocyte function and morphology

  • The cell-surface expression of components of the focal adhesion and slit diaphragm is controlled by actin-dependent endocytic pathways, which have been identified as crucial regulators of filtration barrier integrity

  • Mutations in proteins that connect actin dynamics, focal adhesions, slit diaphragms and endocytic pathways might cause glomerular disorders characterized by glomerular basement abnormalities, podocyte foot process effacement and proteinuria

  • New insights into how defects in podocyte anchoring lead to distinct forms of glomerular diseases will pave the way for more effective therapies, creating the possibility of personalized nephrology care

Abstract

Genetic studies of hereditary forms of nephrotic syndrome have identified several proteins that are involved in regulating the permselective properties of the glomerular filtration system. Further extensive research has elucidated the complex molecular basis of the glomerular filtration barrier and clearly established the pivotal role of podocytes in the pathophysiology of glomerular diseases. Podocyte architecture is centred on focal adhesions and slit diaphragms — multiprotein signalling hubs that regulate cell morphology and function. A highly interconnected actin cytoskeleton enables podocytes to adapt in order to accommodate environmental changes and maintain an intact glomerular filtration barrier. Actin-based endocytosis has now emerged as a regulator of podocyte integrity, providing an impetus for understanding the precise mechanisms that underlie the steady-state control of focal adhesion and slit diaphragm components. This Review outlines the role of actin dynamics and endocytosis in podocyte biology, and discusses how molecular heterogeneity in glomerular disorders could be exploited to deliver more rational therapeutic interventions, paving the way for targeted medicine in nephrology.

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Figure 1: Architecture and anatomical structure of the glomerular filtration barrier.
Figure 2: Podocyte dysfunction is a common feature of renal injury.
Figure 3: Integrative signalling networks enable interactions between podocyte focal adhesions, the slit diaphragm and actin dynamics.
Figure 4: Endocytic vesicles in podocytes.
Figure 5: Endocytic pathways in podocytes.

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Acknowledgements

We thank M. Passera and K. Mierke (Istituto di Ricerche Farmacologiche Mario Negri, Bergamo, Italy), for helping to edit the manuscript before submission. L.P.'s research is supported by a fellowship from Fondazione Aiuti per la Ricerca sulle Malattie Rare (ARMR), Bergamo, Italy.

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  1. IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Kilometro Rosso Science and Technology Park, Via Stezzano 87, Bergamo, 24126, Italy

    Luca Perico, Sara Conti, Ariela Benigni & Giuseppe Remuzzi

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  1. Luca Perico
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Contributions

L.P. gathered data for the article and wrote the first draft of the manuscript. S.C. provided the images and helped to prepare the first draft. L.P., A.B. and G.R. contributed substantially to discussion of the article's content. A.B and G.R. reviewed and edited the manuscript before submission.

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Correspondence to Giuseppe Remuzzi.

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Glossary

Podocyte

Glomerular epithelial cell that resides on the visceral side of the Bowman capsule and wraps around glomerular capillaries. Podocytes are an integral component of the glomerular filtration barrier.

Permselectivity

The ability to restrict the permeation of macromolecules on the basis of their molecular size, charge and structural configuration.

Monogenic diseases

Pathological conditions that result from modifications in a single gene occurring in all cells of the body.

Anoikis

An apoptotic process that is induced by inadequate or inappropriate interaction between a cell and the underlying extracellular matrix.

Apoptosis

A form of cell death in which a programmed sequence of events leads to the elimination of a cell without the release of harmful substances that might affect neighbouring cells.

Hypertrophy

A process by which cells can increase their size. Hypertrophy can result in the enlargement of an organ or tissue without increasing the number of constituent cells.

Ectodomain

Part of a transmembrane protein that extends into the outer extracellular space.

Endoderm

The innermost primary germ layer of the embryo, which develops into the gastrointestinal tract, the lungs, the urinary bladder and part of the urethra.

Epiblast

The primordial outer layer of the embryo before the segregation of the germ layers.

Actin stress fibres

Contractile actin bundles found in non-muscle cells. They are composed of actin microfilaments and various crosslinking proteins, such as α-actinin.

Podocyturia

The presence of podocytes in the urine as a consequence of detachment from the glomerular basement membrane during pathological conditions.

Shunt pathways

An occasional, non-selective pathway consisting of non-selective pores that are larger in size than other pores of the slit diaphragm. This pathway might be responsible for the appearance of plasma proteins, such as albumin, in urine.

Occluding junctions

These cell junctions (also known as tight junctions) are formed by the fusion of integral proteins of the lateral cell membranes of adjacent epithelial cells, and limit permeability.

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Perico, L., Conti, S., Benigni, A. et al. Podocyte–actin dynamics in health and disease. Nat Rev Nephrol 12, 692–710 (2016). https://doi.org/10.1038/nrneph.2016.127

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