Disease-causing mutation in α-actinin-4 promotes podocyte detachment through maladaptation to periodic stretch

Di Feng, Jacob Notbohm, Ava Benjamin, Shijie He, Minxian Wang, Lay-Hong Ang, Minaspi Bantawa, Mehdi Bouzid, Emanuela Del Gado, Ramaswamy Krishnan, Martin R Pollak

Research output: Contribution to journalArticlepeer-review

Abstract

α-Actinin-4 (ACTN4) bundles and cross-links actin filaments to confer mechanical resilience to the reconstituted actin network. How this resilience is built and dynamically regulated in the podocyte, and the cause of its failure in ACTN4 mutation-associated focal segmental glomerulosclerosis (FSGS), remains poorly defined. Using primary podocytes isolated from wild-type (WT) and FSGS-causing point mutant Actn4 knockin mice, we report responses to periodic stretch. While WT cells largely maintained their F-actin cytoskeleton and contraction, mutant cells developed extensive and irrecoverable reductions in these same properties. This difference was attributable to both actin material changes and a more spatially correlated intracellular stress in mutant cells. When stretched cells were further challenged using a cell adhesion assay, mutant cells were more likely to detach. Together, these data suggest a mechanism for mutant podocyte dysfunction and loss in FSGS—it is a direct consequence of mechanical responses of a cytoskeleton that is brittle.
Original languageEnglish
Pages (from-to)1517-1522
Number of pages6
JournalProceedings of the National Academy of Sciences
Volume115
Issue number7
Early online date29 Jan 2018
DOIs
Publication statusPublished - 13 Feb 2018

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