The Hippo-Salvador signaling pathway regulates renal tubulointerstitial fibrosis.

Eunjeong Seo,Chaeuk Chung,Yong Kyun Kim,Hanbyul Kim,Sang Hee Park,Arum Choi,Dae-Sik Lim,Seung-Jae Myung,Jeongmi Hur,Soohong Min,Jin Kim,Sun Ah Nam,Yu-Mi Kim,Wan-Young Kim

doi:10.1038/srep31931

Abstract

Renal tubulointerstitial fibrosis (TIF) is the final pathway of various renal injuries that result in chronic kidney disease. The mammalian Hippo-Salvador signaling pathway has been implicated in the regulation of cell proliferation, cell death, tissue regeneration, and tumorigenesis. Here, we report that the Hippo-Salvador pathway plays a role in disease development in patients with TIF and in a mouse model of TIF. Mice with tubular epithelial cell (TEC)-specific deletions of Sav1 (Salvador homolog 1) exhibited aggravated renal TIF, enhanced epithelial-mesenchymal transition-like phenotypic changes, apoptosis, and proliferation after unilateral ureteral obstruction (UUO). Moreover, Sav1 depletion in TECs increased transforming growth factor (TGF)-β and activated β-catenin expression after UUO, which likely accounts for the abovementioned enhanced TEC fibrotic phenotype. In addition, TAZ (transcriptional coactivator with PDZ-binding motif), a major downstream effector of the Hippo pathway, was significantly activated in Sav1-knockout mice in vivo. An in vitro study showed that TAZ directly regulates TGF-β and TGF-β receptor II expression. Collectively, our data indicate that the Hippo-Salvador pathway plays a role in the pathogenesis of TIF and that regulating this pathway may be a therapeutic strategy for reducing TIF.

Highlights

IntroductionIncludes AXIN (axis inhibition protein), APC (adenomatosis polyposis coli), GSK3β(glycogen synthase kinase 3β) and CK1ɛ(casein kinase 1ɛ) phosphorylates β-catenin, which is routed to the ubiquitin/proteasome degradation pathway
Includes AXIN, APC, GSK3β(glycogen synthase kinase 3β) and CK1ɛ(casein kinase 1ɛ) phosphorylates β-catenin, which is routed to the ubiquitin/proteasome degradation pathway
We investigated whether the Hippo-Salvador pathway regulates cell apoptosis and proliferation during progressive tubulointerstitial fibrosis (TIF) by performing TUNEL assays and immunostaining for PCNA, respectively

Summary

Introduction

Includes AXIN (axis inhibition protein), APC (adenomatosis polyposis coli), GSK3β(glycogen synthase kinase 3β) and CK1ɛ(casein kinase 1ɛ) phosphorylates β-catenin, which is routed to the ubiquitin/proteasome degradation pathway. It has been shown that Wnt/β-catenin signaling is activated in fibrotic kidney diseases and regulates renal fibrosis[12,13,14,15,16]. Activated LATS1/2 directly phosphorylates and inhibits YAP1 and TAZ (yes-associated protein; transcriptional co-activator with PDZ-binding motif), transcriptional co-activators that mainly regulate tissue development and homeostasis[19,20,21,22,23,24,25,26]. We used genetic in vivo and in vitro approaches to demonstrate the role of the Hippo signaling pathway in renal tubules in progressive TIF. We found that genetic deletion of Sav[1] in TECs in vitro and in vivo substantially increased TIF severity through TGF-βand Wnt/β-catenin signaling activation

Methods

Results

Conclusion