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Abstract: TH-PO769

YAP and TAZ in Podocytes: Twins Distinguished by Single-Nucleus Transcriptomic Analysis

Session Information

Category: Glomerular Diseases

  • 1403 Podocyte Biology

Authors

  • Ester, Lioba, Universitatsklinikum Koln, Koln, Nordrhein-Westfalen, Germany
  • Cabrita, Inês, Universitatsklinikum Koln, Koln, Nordrhein-Westfalen, Germany
  • Ventzke, Michel Tim, Universitatsklinikum Koln, Koln, Nordrhein-Westfalen, Germany
  • Wiesner, Eva, Universitatsklinikum Koln, Koln, Nordrhein-Westfalen, Germany
  • Chen, He, Universitatsklinikum Koln, Koln, Nordrhein-Westfalen, Germany
  • Benzing, Thomas, Universitatsklinikum Koln, Koln, Nordrhein-Westfalen, Germany
  • Kann, Martin, Universitatsklinikum Koln, Koln, Nordrhein-Westfalen, Germany
  • Schermer, Bernhard, Universitatsklinikum Koln, Koln, Nordrhein-Westfalen, Germany
Background

Podocyte homeostasis and the maintenance of the filtration barrier relies on the balanced activity of YAP and TAZ, the two effectors of the Hippo signaling pathway. Previous studies showed an increase of YAP and TAZ during glomerular disease. Additionally, specific deletion of YAP and TAZ in adult podocytes increases susceptibility to induced injury, suggesting a protective role. However, the exact molecular mechanisms underlying these observations remain unclear. Here, we investigate the individual roles of YAP and TAZ in podocytes in vivo.

Methods

We generated genetic mouse models in which YAP, TAZ, or both were knocked out specifically in podocytes (pKO). The mice were deeply characterized including kidney function, slit diaphragm morphology and survival. To gain insights into pathomechanisms leading to podocyte disease and to differentiate processes unique for YAP or TAZ we performed single nuclei RNA Sequencing (snRNASeq) of isolated glomeruli of mice of different ages and stages of disease.

Results

YAP pKO mice present a heterogenous disease onset until 12 weeks old, with a phenotype resembling focal segmental glomerulosclerosis (FSGS) with proteinuria and reduced slit diaphragm length. TAZ pKO mice displayed a tendency towards a reduced slit diaphragm length without developing proteinuria. Notably, when breeding mice to obtain both YAP and TAZ knockout alleles, no viable offspring was produced with less than two of the four YAP/TAZ alleles, suggesting compensational mechanisms. Immunostainings supported this hypothesis. The snRNASeq analysis revealed similar patterns in the YAP and TAZ pKO mice, further confirming their overlapping functions. Subsequent cell communication network analysis provided first evidence on disturbed signaling pathways that could contribute to the phenotypic differences observed between YAP and TAZ pKO mice.

Conclusion

While YAP and TAZ have a high level of similarity and are considered homologous twins, their roles in podocytes are distinct, as only the specific deletion of YAP leads to FSGS. Strikingly, combined YAP/TAZ activity above a certain threshold is indispensable for podocyte homeostasis, as the combined knock out is not viable. With this study we apply snRNASeq to elucidate shared, unique and compensatory functions of YAP and TAZ in podocyte homeostasis and injury.