Rac1 promotes kidney collecting duct repair by mechanically coupling cell morphology to mitotic entry
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Prolonged obstruction of the ureter, which leads to injury of the kidney collecting ducts, results in permanent structural damage, while early reversal allows for repair. Cell structure is defined by the actin cytoskeleton, which is dynamically organized by small Rho guanosine triphosphatases (GTPases). In this study, we identified the Rho GTPase, Rac1, as a driver of postobstructive kidney collecting duct repair. After the relief of ureteric obstruction, Rac1 promoted actin cytoskeletal reconstitution, which was required to maintain normal mitotic morphology allowing for successful cell division. Mechanistically, Rac1 restricted excessive actomyosin activity that stabilized the negative mitotic entry kinase Wee1. This mechanism ensured mechanical G2-M checkpoint stability and prevented premature mitotic entry. The repair defects following injury could be rescued by direct myosin inhibition. Thus, Rac1-dependent control of the actin cytoskeleton integrates with the cell cycle to mediate kidney tubular repair by preventing dysmorphic cells from entering cell division.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | eadi7840 |
| Tidsskrift | Science Advances |
| Vol/bind | 10 |
| Udgave nummer | 6 |
| Antal sider | 24 |
| ISSN | 2375-2548 |
| DOI | |
| Status | Udgivet - 2024 |
Bibliografisk note
Funding Information:
We are grateful to the cell imaging shared resource (CISR), our flow cytometry cores at Vanderbilt and the Nashville VA, and our pathology core (Translational Pathology Shared Resource), and we would like to thank J. Schafer, C. Warren, B. Matlock, and D. Flaherty for technical assistance. All scientific illustrations including the graphical abstract were created with Biorender.com [Figs. 2 (A and J), 4C, 6K, and 11C; and figs. S5A, S10A, S30A, and S31). These studies were supported by NIH grants K08 DK134879 (to F.B.), DK069921 (to R.Z.), DK088327 (to R.Z.), DK127589 (to R.Z.), R01 HL163195 (to E.P.), K08 DK135931-01 (to J.P.A.), DP5OD033412 (to A.S.T.), R01 DK119212 (to A.P.), P30 DK114809 (to A.P.), and R01 DK056942 (to A.F.); VA Merit awards I01-BX002196 (to R.Z.) and 1I01BX002025 (t A.P.); American Society of Nephrology Kidney Cure Ben J. Lipps Fellowship (to F.B.); and a Kidney Cure Pre-Doctoral Fellowship (to X.D.), Vanderbilt Faculty Research Scholar Award (to F.B.). Microscopy was performed using the Vanderbilt Cell Imaging Shared Resource (supported by NIH grant P30-CA068485 and the Department of Veteran Affairs), Flow cytometry experiments were performed in the Nashville VA flow cytometry core (U.S. Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN) and the VMC Flow Cytometry Shared Resource (supported by the Vanderbilt Ingram Cancer Center, P30-CA68485, and the Vanderbilt Digestive Disease Research Center, DK058404). Routine histological processing was performed in our Translational Pathology Shared Resource that is supported by NCI/NIH Cancer Center support grant P30-CA068485.
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