<i>Sav1</i> 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 <i>Sav1</i> in the mouse renal epithelium resulted in upregulated expression of profibrotic genes and TIF. Loss of <i>Sav1</i> 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 <i>Sav1</i> loss and implicate VP as a potential pharmacological inhibitor to treat patients at risk for developing CKD and TIF.