Regulation of the Actin Cytoskeleton in Podocytes

Abstract

Podocytes are an integral part of the glomerular filtration barrier, a structure that prevents filtration of large proteins and macromolecules into the urine. Podocyte function is dependent on actin cytoskeleton regulation within the foot processes, structures that link podocytes to the glomerular basement membrane. Actin cytoskeleton dynamics in podocyte foot processes are complex and regulated by multiple proteins and other factors. There are two key signal integration and structural hubs within foot processes that regulate the actin cytoskeleton: the slit diaphragm and focal adhesions. Both modulate actin filament extension as well as foot process mobility. No matter what the initial cause, the final common pathway of podocyte damage is dysregulation of the actin cytoskeleton leading to foot process retraction and proteinuria. Disruption of the actin cytoskeleton can be due to acquired causes or to genetic mutations in key actin regulatory and signaling proteins. Here, we describe the major structural and signaling components that regulate the actin cytoskeleton in podocytes as well as acquired and genetic causes of actin dysregulation.

WITHDRAWN: Dexamethasone reduces podocyte injury through the PTEN-PI3K/Akt signaling pathway

“…Podocytes are the largest intrinsic cell in the kidney.Early podocyte damage is reversible.Once the damaging factor is removed,the cytoskeleton proteins are repaired, and the foot processes still form a cross-connected pattern to perform their functions; however, if the damaging factor continues to act on podocytes,the podocyte damage irreversible [7][8] .The worst consequence is that the proliferative capacity of the podocytes is limited. Once damage occurs, podocytes cannot continue to perform their functions through self-compensation, forming a vicious circle and accelerating the damage of other podocytes, ultimately leading to the occurrence and development of proteinuria.…”

MRTF: Basic Biology and Role in Kidney Disease

“…Precise cytoskeletal control, in turn, is a prerequisite for normal renal structure and function. For example, the delicate morphology of podocyte foot processes, the structural basis of the filtration barrier, is fundamentally dependent upon subtle and highly regulated F-actin organization [ 2 , 3 , 4 , 5 ]. The cytoskeleton is also the structural basis of cell motility.…”

3D Visualization of the Podocyte Actin Network using Integrated Membrane Extraction, Electron Microscopy, and Deep Learning

“…Given the complexity of our datasets, the separate time for sample preparation and imaging for each of them, and internal differences observed across the four biological samples that we used, applying one single deep learning classifier model to all injury models resulted in loss of accuracy. Although several strategies exist to compensate for this problem of "overfitting" [18], we achieved satisfactory segmentation by generating classifiers for each of our datasets. The approach allowed for the supervised segmentation of podocyte structures with high accuracy as compared to manual segmentation, the latter validated by choosing smaller datasets from each condition and validating results using manual segmentation.…”

“…When injured, podocytes undergo foot process effacement (FPE), a massive change in shape including loss of the intricate foot processes and the replacement of these with a sheet of cell membrane covering the GBM. Although a role of the actin cytoskeleton in these processes is evident from the large list of actin-associated genes whose mutation leads to FPE, the pathways leading to FPE in injury remain unclear [16][17][18].…”