Disease-causing mutation in α-actinin-4 promotes podocyte detachment through maladaptation to periodic stretch
| Autor: | Di Feng, Martin R. Pollak, Minxian Wang, Shijie He, Ramaswamy Krishnan, Jacob Notbohm, Emanuela Del Gado, Minaspi Bantawa, Lay-Hong Ang, Ava Benjamin, Mehdi Bouzid |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Contraction (grammar) Mutant 030232 urology & nephrology Mice Transgenic macromolecular substances Podocyte 03 medical and health sciences 0302 clinical medicine Focal segmental glomerulosclerosis Cell Adhesion medicine Animals Humans Point Mutation Actinin Cell adhesion Cytoskeleton Actin Multidisciplinary Glomerulosclerosis Focal Segmental Podocytes Chemistry Biological Sciences medicine.disease Cell biology 030104 developmental biology medicine.anatomical_structure Female Intracellular |
| Zdroj: | Proceedings of the National Academy of Sciences. 115:1517-1522 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1717870115 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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