Abstract: FR-PO243

Inhibition of YAP Exacerbates Podocytes Apoptosis and Disease Progression in Adriamycin-Induced Focal Segmental Glomerulosclerosis

Session Information

Category: Cell Biology

  • 202 Apoptosis, Proliferation, Autophagy, Cell Senescence, Cell Transformation

Authors

  • Zhuang, Qiyuan, Shanghai Medical College, Fudan University, Shanghai, China
  • Li, Fang, AUGUSTA UNIVERSITY, AUGUSTA, Georgia, United States
  • Chen, Jianchun, Vanderbilt University, Nashville, Tennessee, United States
  • Wu, Huijuan, Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China
Background

Focal Segmental Glomerulosclerosis (FSGS) is a common chronic glomerular disease with poor clinical outcomes, of which the main manifestation is nephrotic syndrome. Podocyte lost via apoptosis is one important mechanism underlying the pathogenesis of FSGS. Recently, Yes-associated-protein (YAP), one key downstream effector of Hippo pathway, was recognized as an activator for multiple gene transcriptional factors in nucleus to control cell proliferation, differentiation and apoptosis. However, the potential role of YAP activation in development and progression of FSGS remains unclear.

Methods

The localization, expression and phosphorylation of YAP were examined in kidney samples from patients with FSGS, adriamycin-induced FSGS mT/mG transgenic mouse model and the primary cultured podocytes treated with adriamycin.

Results

We first found that increases of podocyte apoptosis is closely correlated with the expression level of phospho-YAP at serine 397 which is associated with YAP degradation during the progression of FSGS. And then, we found that YAP distributed uniformly in the nucleus and cytoplasm in the podocytes of vehicle treated mouse kidney or in the primary cultured podocytes. Administration of adriamycin to the mice or exposure the primary cultures to adriamycin acutely induced YAP nuclear translocation, an indicator of YAP activation, followed by continuously exporting from the nucleus to the cytoplasm. Accordingly, our data also revealed that the expression of phospho-YAP at serine 127 in the podocytes was acutely decreased and then increased in response to Adriamycin treatment. In addition, administration of verteporfin, a YAP inhibitor, accelerated podocytes apoptosis and segmental glomerulosclerosis and deteriorated renal function in early phase after adriamycin treatment.

Conclusion

Our findings suggest that YAP activation in podocytes is an important endogenous anti-apoptotic mechanism during the progression of FSGS, and targeting YAP could be a potential therapeutic choice for treatment of FSGS.

Funding

  • Government Support - Non-U.S.