Kidney Week

Abstract: TH-OR057

Rac1 Restrains the Actin-Myosin Cytoskeleton to Enable Mechanosensing and Prevent Cystic Transformation of Postnatal Kidneys

Session Information

• Genetic Diseases with a Focus on ADPKD Mechanisms, Models, and Medicines
  October 22, 2026 | Location: Mile High Ballroom 4D, Convention Center
  Abstract Time: 04:50 PM - 05:00 PM

Category: Development, Stem Cells, and Regenerative Medicine

• 700 Development, Stem Cells, and Regenerative Medicine

Authors

• Bayazid, Al Borhan, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Al Borhan Bayazid, MS, PhD

• Zhang, Richard R., Vanderbilt University Medical Center, Nashville, Tennessee, United States

Richard R. Zhang

• Dong, Xinyu, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Xinyu Dong

• Jannotta, Ryan Michael, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Ryan Michael Jannotta

• Viquez, Olga, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Olga Viquez, PhD

• Pozzi, Ambra, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Ambra Pozzi, PhD, DrPH

• Zent, Roy, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Roy Zent, MD, PhD

• Bock, Fabian, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Fabian Bock, MD, PhD

Background

Multicystic dysplastic kidney (MCDK) is a severe congenital malformation characterized by disrupted nephron architecture and cortical cyst formation. Rac1 is a small Rho GTPase that promotes F-actin cytoskeleton formation. Recent genetic studies have identified familial mutations affecting the Rac1 pathway in children with MCDK. Here we investigate the mechanism whereby the Rac1-dependent actin cytoskeleton prevents cystic-dysplastic transformation of the nephron.

Methods

To investigate the role of Rac1 in kidney development, we generated mice with deletion of Rac1 in the whole nephron and used 3D confocal and electron microscopy to track tubular epithelial differentiation and morphology over time. We also used Rac1 proximal tubular (PT) cells lacking Rac1 and subjected them to fluid shear stress to mimic the mechanical impact of postnatal kidney development.

Results

Unexpectedly, early glomerular and tubular development was largely intact in mice lacking Rac1 in the developing nephron. However, they developed severe multicystic dysplastic kidneys after birth with large proximal tubular cysts and died within a few weeks. Specifically, we found that Rac1-deficient PTs lost polarity, cell structure and markers of differentiation after birth. In vitro, Rac1 KO PT cells failed to form an intact monolayer upon application of fluid shear stress suggesting that Rac1 was required for flow-induced epithelial maturation. Rac1 mutant cells and mice showed upregulation of the contractile actin-myosin cytoskeleton. Direct myosin inhibition restored flow-induced differentiation in cells and partially prevented multicystic kidney dysplasia in Rac1 mutant mice.

Conclusion

These findings show that loss of Rac1 causes a multicystic-dysplastic phenotype mimicking MCDK and identify Rac1 as a critical regulator linking postnatal mechanical cues to tubular epithelial differentiation by controlling actomyosin. These results further suggest that a fatal developmental MCDK-like phenotype can arise despite intact early nephron induction.

Acknowledgment

NIH-NIDDK

Funding

• NIDDK Support