Yap/Taz Deletion in Gli+ Cell-Derived Myofibroblasts Attenuates Fibrosis

Abstract

In damaged kidneys, increased extracellular matrix (ECM) and tissue stiffness stimulate kidney fibrosis through incompletely characterized molecular mechanisms. The transcriptional coactivators yes-associated protein (Yap) and transcriptional coactivator with PDZ-binding motif (Taz) function as mechanosensors in cancer cells and have been implicated in the regulation of myofibroblasts in the kidney. We hypothesized that the development of kidney fibrosis depends on Yap-induced activation and proliferation of kidney fibroblasts. In mice, Yap expression increased in renal fibroblasts after unilateral ureteral obstruction (UUO), in association with worsening of interstitial fibrosis. In cultured fibroblasts, inhibition of Yap/Taz signaling blocked TGF-1-induced fibroblast-to-myofibroblast transformation and ECM production, whereas constitutive activation of Yap promoted fibroblast transformation and ECM production even in the absence of TGF-1. Moreover, in the absence of TGF-1, fibroblasts seeded on a stiffened ECM transformed into myofibroblasts in a process dependent on the activation of Yap. In mice with UUO, the Yap inhibitor verteporfin reduced interstitial fibrosis. Furthermore, Gli1 cell-specific knockout of in mice suppressed UUO-induced ECM deposition, myofibroblast accumulation, and interstitial fibrosis. In a UUO-release model, induction of Gli1 cell-specific knockout partially reversed the development of interstitial fibrosis. Thus, in the kidney, Yap is a tissue mechanosensor that can be activated by ECM and transforms fibroblasts into myofibroblasts; the interaction of Yap/Taz and ECM forms a feed-forward loop resulting in kidney fibrosis. Identifying mechanisms that interrupt this profibrotic cycle could lead to the development of anti-fibrosis therapy.

Deregulation of Hippo–TAZ pathway during renal injury confers a fibrotic maladaptive phenotype

“…Our demonstration that TGF-b1 elevated renal TAZ protein abundance in tubular and interstitial cells in transgenic mice with conditional renal tubular induction of TGF-b1 are consistent with those in a recent study that demonstrated that TGF-b1 stimulates TAZ expression via myocardin-related transcription factor (MRTF) transcription factor-dependent pathways in C3H/10T1/2 pericytelike fibroblast cells (47). Another recent study with mice with YAP/TAZ depletion in the glioma-associated proteinpositive fibroblast population further confirmed the crucial role of these Hippo nuclear transducers in obstructive nephropathy (48). Figure 8.…”

Liver stiffness correlates with serum osteopontin and TAZ expression in human liver cirrhosis

“…It has been suggested that TAZ may act as a mechanoregulator of the transformation of mechanical into biochemical signals, such as OPN . The role of OPN in liver fibrosis and its relationship with the stages of fibrosis is becoming clear .…”

Src‐mediated crosstalk between FXR and YAP protects against renal fibrosis

“…The functional role of YAP was recently translated to myofibroblast activation and the induction of fibrosis. The YAP inhibitor verteporfin suppresses the development of renal fibrosis, and deletion of YAP/PDZ-binding motif signaling in UUO-induced fibrosis could at least partially reverse the condition (22,41). Our results show that p-S127-YAP was regulated by the suppression of Src activity by activated FXR so that the hippo pathway was regulated and the YAP target genes were down-regulated.…”