Rac1 promotes kidney collecting duct repair by mechanically coupling cell morphology to mitotic entry

Sci Adv. 2024 Feb 9;10(6):eadi7840. doi: 10.1126/sciadv.adi7840. Epub 2024 Feb 7.

Abstract

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.

MeSH terms

  • Actin Cytoskeleton / metabolism
  • Actins / metabolism
  • Cytoskeleton / metabolism
  • Kidney Tubules, Collecting* / metabolism
  • rac1 GTP-Binding Protein / metabolism

Substances

  • rac1 GTP-Binding Protein
  • Actins