Abstract: SA-PO220

Yap Dependent Mechanotransduction Determines the Podocyte’s Response to Injury

Session Information

  • Glomerular: Cell Biology
    November 04, 2017 | Location: Hall H, Morial Convention Center
    Abstract Time: 10:00 AM - 10:00 AM

Category: Glomerular

  • 1003 Glomerular: Cell Biology

Authors

  • Rinschen, Markus M., University Hospital Cologne, Cologne, Germany
  • Huber, Tobias B., University Medical Center Hamburg, Hamburg, Germany
  • Benzing, Thomas, University Hospital Cologne, Cologne, Germany
  • Schermer, Bernhard, University Hospital Cologne, Cologne, Germany
Background

Podocytes, terminally differentiated cells of the kidney filtration barrier, are subjected to considerable mechanical strain by physiological filtration pressure, which can even be increased by severe hypertension. When injury causes cytoskeletal reorganization and morphological alterations of these cells, the filtration barrier may become compromised and allow proteins to leak into the urine (proteinuria). The activities of the transcriptional co-activators YAP and TAZ are tightly controlled by the Hippo signaling pathway and are sensitive to mechanical cues.

Methods

We used time-resolved quantitative proteomics in the in vivo and in vitro PAN model of podocyte injury.

Results

We show that podocyte injury stimulates YAP activity and the expression of YAP-dependent target genes in a rat model of glomerular disease prior to the development of proteinuria. In contrast, injury of cultured human and mouse podocyte cell lines reduced YAP and TAZ activity when the cells were grown on stiff substrates. However, culturing these cells on soft matrix or inhibiting stress fiber formation recapitulated the damage-induced YAP upregulation observed in vivo, indicating a mechanotransduction-dependent mechanism of YAP activation in podocytes. YAP overexpression in cultured podocytes enhanced the abundance of extracellular matrix–related proteins. YAP activity was increased in mouse models of diabetic nephropathy, and expression of the YAP target CTGF was observed in renal biopsies from patients with glomerular disease. Whereas overexpression of human YAP in mice induced mild proteinuria, pharmacological inhibition of the interaction between YAP and its partner TEAD in rats ameliorated glomerular disease and reduced damage-induced mechanosignaling in glomeruli.

Conclusion

We conclude that perturbation of the mechanosensitive Hippo signaling pathway is a potential therapeutic target for treating some glomerular diseases.

Funding

  • Government Support - Non-U.S.