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Abstract
Kidney podocytes’ function depends on fingerlike projections (foot processes) that interdigitate with those from neighboring cells to form the glomerular filtration barrier. The integrity of the barrier depends on spatial control of dynamics of actin cytoskeleton in the foot processes. We determined how imbalances in regulation of actin cytoskeletal dynamics could result in pathological morphology. We obtained 3-D electron microscopy images of podocytes and used quantitative features to build dynamical models to investigate how regulation of actin dynamics within foot processes controls local morphology. We find that imbalances in regulation of actin bundling lead to chaotic spatial patterns that could impair the foot process morphology. Simulation results are consistent with experimental observations for cytoskeletal reconfiguration through dysregulated RhoA or Rac1, and they predict compensatory mechanisms for biochemical stability. We conclude that podocyte morphology, optimized for filtration, is intrinsically fragile, whereby local transient biochemical imbalances may lead to permanent morphological changes associated with pathophysiology.
Highlights
Podocytes, visceral epithelial cells of the kidney glomerulus, enable the selectivity of the glomerular filtration barrier through their specialized morphology
We reconstructed the in situ 3-D geometry of interacting podocytes that would represent core spatial features of a podocyte that permits spatial modeling
SBEM image stacks were processed by manual segmentation and Gaussian filtering to reconstruct podocyte geometry with arborized processes that included nanoscale cell-cell junctions at the foot processes (Fig 1, Supplementary S1 Video)
Summary
Visceral epithelial cells of the kidney glomerulus, enable the selectivity of the glomerular filtration barrier through their specialized morphology. The cytoskeleton of each highly differentiated podocyte is composed of F-actin, microtubules, and intermediate filaments. All three of these cytoskeletal polymers form the cell body and primary processes, but only actin shapes the foot processes (FPs), the delicate fingerlike projections that interdigitate to form the glomerular filtration barrier [1]. The FPs establish contact between podocytes and the glomerular basement membrane, in addition to the cell-cell contact via specialized transmembrane junctions called the slit diaphragm, where plasma is filtered [3]. The limited treatment options for CKD are in part due to the sensitive nature of these highly differentiated cells
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