The podocyte cytoskeleton—key to a functioning glomerulus in health and disease

Abstract

Almost all mammalian cell types have morphologies that are uniquely tailored to their physiological functions. This immense variation in cell shape depends on an underlying network of dynamic and interconnected actin and microtubule polymers. The glomerular podocyte is an archetypal example of such specialization, with a complex cytoskeleton underlying its delicate architectural features. Dynamic control of this cytoskeletal matrix seems to center around the slit diaphragm, a complex of proteins at the cell-cell junction between adjacent podocyte foot processes. This junction includes molecules that are unique to the podocyte that probably determine the correct morphology of the cell, and are targets of disease processes that disrupt the intricate balance of signaling that controls the cytoskeletal matrix. This Review will outline the most recent concepts and advances in our understanding of this critical aspect of glomerular biology, as well as discussing how an improved understanding of the podocyte cytoskeleton is starting to shape advances in delineating the pathogenesis of common glomerular diseases.

A Homozygous Missense Mutation in the Ciliary Gene TTC21B Causes Familial FSGS

“…Cytoskeleton alterations may affect cellular motility, a suggested mechanism underlying podocyte foot process effacement. 15 Despite no obvious cytoskeleton alteration in undifferentiated cells, here we showed that in challenging conditions, undifferentiated podocytes depleted for IFT139 exhibited a decrease in cell migration that could not be rescued by expressing the p.P209L mutant ( Figure 3E). Altogether, these results suggest that the p.P209L mutant may destabilize mature podocyte architecture by affecting cytoskeleton dynamics.…”

“…[13][14][15] Because IFT139 is redistributed along the microtubule network in mature podocytes, we studied the effect of the p.P209L mutant on cytoskeleton organization in differentiated podocytes. Interestingly, the depletion of IFT139 led to increased cell surface associated with actin cytoskeleton alterations, such as short and misorganized stress fibers and microtubule rearrangement into bike wheel-like shape.…”

Pathogenesis of common glomerular diseases – role of the podocyte cytoskeleton

“…7 Although some studies suggest that detectable movement of podocytes in vitro and in vivo occur, 15 direct and solid evidence still needs to be provided. Endocytosis is another mechanism by which podocytes prevent filter clog.…”

“…122 Rac1 activation is generally associated with a migratory phenotype of the cells, 123 which is believed to contribute to foot-process effacement and proteinuria. 7,124 In addition, Rac1 may contribute to proteinuria via modulation of the mineral corticoid receptor. 125 Thus, HIV viral proteins are likely to cause podocyte phenotypic changes via multiple pathways, contributing to proteinuria.…”

“…2 The mature podocyte presents both epithelial features (established cell polarity with an apical and basal side) and mesenchymal features (de novo expression of vimentin, an intermediate filament protein, loss of epithelial markers such as desmosomal proteins and E-cadherin, and partial motility). 7 In addition, podocytes have long been compared in analogy to smooth-muscle cells, such as capillary pericytes due to similar functional analogies, including spontaneous and angiotensin-induced contraction, as well as glucose uptake. 8 A fully differentiated podocyte consists of a cell body (located in the urinary space), major processes, numerous microtubules, and foot processes branching from major processes and binding to the GBM by means of integrins and α-and β-dystroglycans.…”