title: Fragility of foot process morphology in kidney podocytes arises from chaotic spatial propagation of cytoskeletal instability.
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.
authors.affiliation: R. D. Berlin Center for Cell Analysis & Modeling, U. Connecticut School of Medicine, Farmington, CT, United States of America.
authors.forename: Cibele V
authors.initials: CV
authors.lastname: Falkenberg
authors.affiliation: Department of Pharmacological Sciences, and Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.
authors.forename: Evren U
authors.identifier: 0000-0001-6137-109X
authors.initials: EU
authors.lastname: Azeloglu
authors.affiliation: Department of Mechanical Engineering, Columbia University, New York, NY, United States of America.
authors.forename: Mark
authors.identifier: 0000-0001-9379-8805
authors.initials: M
authors.lastname: Stothers
authors.affiliation: National Center for Microscopy and Imaging Research, UCSD, San Diego, CA, United States of America.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Deerinck
authors.affiliation: Department of Pharmacological Sciences, and Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.
authors.forename: Yibang
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Pharmacological Sciences, and Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.
authors.forename: John C
authors.initials: JC
authors.lastname: He
authors.affiliation: National Center for Microscopy and Imaging Research, UCSD, San Diego, CA, United States of America.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Ellisman
authors.affiliation: Department of Mechanical Engineering, Columbia University, New York, NY, United States of America.
authors.forename: James C
authors.identifier: 0000-0002-8084-3301
authors.initials: JC
authors.lastname: Hone
authors.affiliation: Department of Pharmacological Sciences, and Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.
authors.forename: Ravi
authors.initials: R
authors.lastname: Iyengar
authors.affiliation: R. D. Berlin Center for Cell Analysis & Modeling, U. Connecticut School of Medicine, Farmington, CT, United States of America.
authors.forename: Leslie M
authors.identifier: 0000-0002-1851-4646
authors.initials: LM
authors.lastname: Loew
mesh_terms: D008841:Actin Cytoskeleton / Q000473:pathology* / Q000502:physiology*; D016764:Cell Polarity; D048429:Cell Size; D022081:Cell Surface Extensions / Q000473:pathology* / Q000502:physiology; D002478:Cells, Cultured; D003198:Computer Simulation; D006801:Humans; D008954:Models, Biological; D017711:Nonlinear Dynamics; D050199:Podocytes / Q000473:pathology* / Q000502:physiology*; D062211:Spatio-Temporal Analysis