The Hippo-Salvador signaling pathway regulates renal tubulointerstitial fibrosis

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 repor...

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Veröffentlicht in:Scientific reports 2016-08, Vol.6 (1), p.31931, Article 31931
Hauptverfasser: Seo, Eunjeong, Kim, Wan-Young, Hur, Jeongmi, Kim, Hanbyul, Nam, Sun Ah, Choi, Arum, Kim, Yu-Mi, Park, Sang Hee, Chung, Chaeuk, Kim, Jin, Min, Soohong, Myung, Seung-Jae, Lim, Dae-Sik, Kim, Yong Kyun
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Sprache:eng
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Zusammenfassung: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.
ISSN:2045-2322
2045-2322
DOI:10.1038/srep31931