Transcriptional Regulators YAP and TAZ Have Distinct Abilities to Compensate for One Another in Podocytes

Key Points Podocyte-specific knockout of YAP but not TAZ led to proteinuria. Knockout of more than two alleles of YAP and TAZ resulted in neonatal death, revealing compensation between the two cotranscription factors. Although YAP fully compensated for the loss of TAZ, TAZ did not entirely compensate for YAP functions related to Rho-GTPase and ERBB4 signaling. Background Kidney function depends on the filtration of enormous volumes of plasma, exposing the filtration barrier to mechanical forces. Podocytes must adapt to these forces for the lifetime of an organism as they cannot self-renew. The molecular mechanisms of podocyte adaptation to mechanical stress remain unclear. YAP and TAZ are key mechanotransducers that relay mechanical stimuli to control transcription. Methods We made use of podocyte-specific knockout mouse models for Yap (YAP pKO ), Taz (TAZ pKO ), or both (YAP pKO /TAZ pKO ) and analyzed single-nucleus RNA sequencing data of isolated glomeruli to delineate the distinct and shared roles of YAP and TAZ in podocyte homeostasis. Results Here, we found that YAP and TAZ have only partially overlapping functions and compensatory potential in podocytes in vivo . YAP pKO mice displayed podocyte damage and progressive kidney failure. By contrast, TAZ pKO animals did not develop any overt disease, while the combined deletion of Yap and Taz caused a neonatal lethal phenotype. Single-nucleus RNA sequencing analysis revealed that in both YAP pKO and TAZ pKO mice, a subpopulation of podocytes showed a similar stress response driven by activator protein 1, revealing a protective compensatory mechanism. However, TAZ failed to compensate sufficiently for the loss of YAP, resulting in dysregulation of Rho-GTPases and subsequently the actin cytoskeleton in diseased YAP pKO . Furthermore, we observed loss of ERBB4 expression exclusively in YAP pKO, underscoring the role of ERBB4 signaling as additional layer of YAP-specific regulation in maintaining podocyte survival. Conclusions In summary, we identified common and distinct roles for the two transcriptional regulators in podocyte homeostasis. YAP and TAZ can compensate for the loss of the other in podocytes to preserve viability. Still, although YAP can entirely compensate for the loss of TAZ securing podocyte health, TAZ fails to maintain all the YAP-specific functions leading to podocyte injury.