Rac1 promotes kidney collecting duct integrity by limiting actomyosin activity

Bock et al. show that the small Rho GTPase Rac1 is not essential for epithelial branching morphogenesis during kidney collecting duct development. However, Rac1 later maintains epithelial polarity, morphology, and function by Arp2/3-dependent cytoskeletal branching, which restricts actomyosin activity. A polarized collecting duct (CD), formed from the branching ureteric bud (UB), is a prerequisite for an intact kidney. The small Rho GTPase Rac1 is critical for actin cytoskeletal regulation. We investigated the role of Rac1 in the kidney collecting system by selectively deleting it in mice at the initiation of UB development. The mice exhibited only a mild developmental phenotype; however, with aging, the CD developed a disruption of epithelial integrity and function. Despite intact integrin signaling, Rac1-null CD cells had profound adhesion and polarity abnormalities that were independent of the major downstream Rac1 effector, Pak1. These cells did however have a defect in the WAVE2-Arp2/3 actin nucleation and polymerization apparatus, resulting in actomyosin hyperactivity. The epithelial defects were reversible with direct myosin II inhibition. Furthermore, Rac1 controlled lateral membrane height and overall epithelial morphology by maintaining lateral F-actin and restricting actomyosin. Thus, Rac1 promotes CD epithelial integrity and morphology by restricting actomyosin via Arp2/3-dependent cytoskeletal branching.

Automated summary

The study demonstrates that Rac1 is not essential for epithelial branching morphogenesis during kidney collecting duct development, but plays a crucial role in maintaining epithelial integrity, polarity, and function by Arp2/3-dependent cytoskeletal branching. This function of Rac1 involves restricting actomyosin activity. Despite a mild developmental phenotype in mice with selectively deleting Rac1 at the initiation of UB development, aging leads to disruption of epithelial integrity and function in the collecting duct, which is reversible with direct myosin II inhibition. Additionally, Rac1 controls lateral membrane height and overall epithelial morphology by restricting actomyosin and promoting CD epithelial integrity.