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

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.

Rostafuroxin Protects from Podocyte Injury and Proteinuria Induced by Adducin Genetic Variants and Ouabain

“…However, podocyte activities and actin cytoskeletal dynamics are known to be integrated in a dynamic signaling hub at the slit diaphragm membrane (Grahammer et al, 2013;New et al, 2013). Alterations in these signaling pathways, frequently caused by genetic mutations within these networks that are responsible for biochemical dysfunctions in proteins and in their related signaling cascades, may progress to glomerular diseases (Wiggins, 2007;Mathieson, 2008).…”

“…Definite protein interaction networks that involve SH2 domain-containing proteins appear to control a wide spectrum of physiologic activities, which include cardiac and renal function, and influence cardiovascular remodeling (Liu et al, 2012;Grahammer et al, 2013). However, podocyte activities and actin cytoskeletal dynamics are known to be integrated in a dynamic signaling hub at the slit diaphragm membrane (Grahammer et al, 2013;New et al, 2013).…”

“…Mutations in several podocyte genes have been associated with monogenic and polygenic syndromes that feature proteinuria (Liu et al, 2001;Wiggins, 2007;Mathieson, 2008;Piscione and Licht, 2011;Grahammer et al, 2013). In this context, we have contributed to unraveling the role of a polymorphism of the cytoskeletal protein adducin and high levels of endogenous ouabain (EO) in hypertension and glomerular podocyte damage, both in animal models and in patients (Bianchi et al, 1994;Bianchi, 2005;Manunta et al, 2009;Ferrandi et al, 2010a,b).…”

“…Proteinuria is the hallmark of a broad spectrum of podocytopathies characterized by podocyte foot process effacement and alterations of the slit diaphragm, a dynamic signaling hub able to initiate complex signaling networks and integrate multiple intercellular signals via actin cytoskeleton (Grahammer et al, 2013).…”

The FERM protein EPB41L5 regulates actomyosin contractility and focal adhesion formation to maintain the kidney filtration barrier

“…focal adhesion | actomyosin | podocyte | FSGS G lomerular epithelial cells or podocytes represent a pericytelike cell type establishing the kidney filtration barrier in combination with endothelial cells and the basement membrane (1,2). These cells exhibit a strictly polarized morphology characterized by a large cell body and extending primary and secondary foot processes, which enclose glomerular capillaries (3).…”