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.

Resolution of organ fibrosis

“…Mice with ablation of p16 INK4a do not exhibit SA-β-gal-positive senescent cells and fibrosis is enhanced, consistent with senescence playing an antifibrotic role (106). Interestingly, inducing senescence in renal epithelial cells leads to enhanced fibrosis in aristolochic acid-induced renal fibrosis (107). Since epithelial cells are not major producers of the fibrotic ECM, senescence in these cells is unlikely to terminate fibrogenesis.…”

Protein Acyltransferase DHHC3 Regulates Breast Tumor Growth, Oxidative Stress, and Senescence

“…Regarding STAT3, elevated tyrosine phosphorylation is not only oncogenic, but also may be suppressive by multiple potential mechanisms (ref. 31 and references within), including induction of cell senescence (32, 33). …”

Surviving Acute Organ Failure: Cell Polyploidization and Progenitor Proliferation

“…Indeed, cell cycle arrest upon polyploidization and cellular hyperfunction represents a hypersecretory state that is also associated with a persistent secretion of profibrotic mediators driving fibrogenesis, that is, cell senescence [87]. The association of tissue polyploidization, fibrosis, and senescence, has been demonstrated for the liver [88,89], heart [89,90], and is likely to account also for kidney fibrosis [91]. In all of these organs, polyploidization may also lead to fibrosis and organ dysfunction through another mechanism.…”