Kidney Week

Abstract: FR-PO773

TAZ Shows Limited Ability to Substitute for YAP in Preserving Podocytes, Demonstrating Distinct Roles of the Transcriptional Regulators at the Kidney Filtration Barrier

Session Information

• Glomerular Diseases: Mechanisms and Podocyte Biology
  October 25, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology

Authors

• Ester, Lioba, Universitatsklinikum Koln, Koln, Nordrhein-Westfalen, Germany

Lioba Ester, MD

• Wiesner, Eva, Universitatsklinikum Koln, Koln, Nordrhein-Westfalen, Germany

Eva Wiesner, MS, MSc

• Chen, He, Universitatsklinikum Koln, Koln, Nordrhein-Westfalen, Germany

He Chen

• Diefenhardt, Paul, Universitatsklinikum Koln, Koln, Nordrhein-Westfalen, Germany

Paul Diefenhardt, MD

• Brinkkoetter, Paul T., Universitatsklinikum Koln, Koln, Nordrhein-Westfalen, Germany

Paul T. Brinkkoetter, MD

• Benzing, Thomas, Universitatsklinikum Koln, Koln, Nordrhein-Westfalen, Germany

Thomas Benzing, MD, PhD, FASN

• Kann, Martin, Universitatsklinikum Koln, Koln, Nordrhein-Westfalen, Germany

Martin Kann, MD

• Schermer, Bernhard, Universitatsklinikum Koln, Koln, Nordrhein-Westfalen, Germany

Bernhard Schermer, MD

• Cabrita, Inês, Universitatsklinikum Koln, Koln, Nordrhein-Westfalen, Germany

Inês Cabrita, PhD

Background

Podocytes must effectively adapt to considerable mechanical forces at the filtration barrier throughout an organism's lifespan. However, the precise molecular mechanisms governing podocyte adaptation to such mechanical stressors remain elusive. YAP and TAZ, two paralogous transcriptional regulators, have emerged as pivotal mechanotransducers capable of sensing and transducing mechanical stimuli to regulate transcriptional activity.

Methods

We employed conditional deletion targeting Yap (YAP^pKO), Taz (TAZ^pKO), or both (YAP^pKO/TAZ^pKO) specifically in podocytes to delineate the distinct and shared roles of YAP and TAZ in podocyte homeostasis. Utilizing single-nucleus RNA sequencing (snRNA-Seq) analysis of isolated glomeruli, we elucidated overlapping and unique transcriptional responsibilities of these regulators.

Results

Conditional deletion of Yap in podocytes resulted in foot processes effacement and progressive renal failure, whereas Taz deletion did not cause disease. Notably, simultaneous deletion of Yap and Taz led to a neonatal lethal phenotype. Intriguingly, even mice lacking three out of the four Yap and Taz alleles proved non-viable, revealing a compensatory capacity shared between these two regulators. Our snRNA-Seq analysis unveiled an AP-1-dominated stress response as one of the compensatory mechanisms, evident in a subcluster of both YAP- and TAZ-deficient podocytes. Furthermore, dysregulation of Rho-GTPase activity, contributing to actin cytoskeleton de-arrangement, emerged as a primary driver of injury in YAP^pKO podocytes. Lastly, the loss of ERBB4 expression in YAP^pKO, but not in TAZ^pKO, delineated a key distinction between the two regulators, emphasizing a YAP-specific role in regulating ERBB4 signaling to sustain podocyte survival.

Conclusion

Our study comprehensively dissects the distinct and overlapping functions of YAP and TAZ in podocyte homeostasis. Through snRNA-Seq analysis, we identified several pivotal molecular mechanisms, some of which are shared by both regulators while others are dependent solely on YAP. Notably, while YAP can adequately compensate for loss of TAZ, TAZ lacks the capacity to effectively substitute for YAP, resulting in podocyte injury in the absence of YAP.