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Contributed by Martin R. Pollak, December 29, 2017 (sent for review October 13, 2017; reviewed by Wilhelm Albert Kriz and Dimitrije Stamenovic)
Significance
Point mutations in α-actinin-4 (ACTN4) cause a form of kidney disease in humans. Although we know these mutations affect kidney podocytes, the mechanism by which they lead to podocyte dysfunction remains unclear. Here, we show that homozygous mutant Actn4 podocytes developed irrecoverable reductions in their contraction and irreparable disruptions in their actin cytoskeletons when subjected to periodic stretch. This maladaptive response is akin to failure of a brittle material under deformation. Our results clarify the mechanism by which mutations in ACTN4 leave the podocyte more vulnerable to detachment in the progression of kidney disease.
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.
Footnotes
↵1R.K. and M.R.P. contributed equally to this work.
- ↵2To whom correspondence should be addressed. Email: mpollak{at}bidmc.harvard.edu.
Author contributions: D.F., R.K., and M.R.P. designed research; D.F., A.B., and L.-H.A. performed research; J.N., S.H., M.W., M. Bantawa, M. Bouzid, and E.D.G. contributed new reagents/analytic tools; D.F., E.D.G., R.K., and M.R.P. analyzed data; and D.F., R.K., and M.R.P. wrote the paper.
Reviewers: W.A.K., University of Heidelberg; and D.S., Boston University.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1717870115/-/DCSupplemental.
Published under the PNAS license.
Biophysical effect of α-actinin-4 mutations
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