Sav1 Loss Induces Senescence and Stat3 Activation Coinciding with Tubulointerstitial Fibrosis

ABSTRACT

Tubulointerstitial fibrosis (TIF) is recognized as a final phenotypic manifestation in the transition from chronic kidney disease (CKD) to end-stage renal disease (ESRD). Here we show that conditional inactivation of Sav1 in the mouse renal epithelium resulted in upregulated expression of profibrotic genes and TIF. Loss of Sav1 induced Stat3 activation and a senescence-associated secretory phenotype (SASP) that coincided with the development of tubulointerstitial fibrosis. Treatment of mice with the YAP inhibitor verteporfin (VP) inhibited activation of genes associated with senescence, SASPs, and activation of Stat3 as well as impeded the development of fibrosis. Collectively, our studies offer novel insights into molecular events that are linked to fibrosis development from Sav1 loss and implicate VP as a potential pharmacological inhibitor to treat patients at risk for developing CKD and TIF.

KEYWORDS:

• fibrosis
• mouse
• renal
• senescence

ACKNOWLEDGMENTS

We thank the UNC Center for Gastrointestinal Biology and Disease Histology Core Facility, the UNC Translational Pathology Laboratory, the UNC Tissue Procurement Facility, and the UNC Animal Histology Core Facility for their help with all the histology results presented in this article.

This work was funded in part by the North Carolina University Cancer Research Fund (UCRF).

We declare that we have no conflicts of interest.