文章基本信息

标题：Disease-causing mutation in α-actinin-4 promotes podocyte detachment through maladaptation to periodic stretch
本地全文：下载
作者：Di Feng ; Jacob Notbohm ; Ava Benjamin 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2018
卷号：115
期号：7
页码：1517-1522
DOI：10.1073/pnas.1717870115
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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.
关键词：kidney ; podocyte ; cytoskeleton ; α-actinin-4 ; actin