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Sci Rep. 2016 Aug 23;6:31931. doi: 10.1038/srep31931.

The Hippo-Salvador signaling pathway regulates renal tubulointerstitial fibrosis.

Author information

1
National Creative Research Initiatives Center, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea.
2
Biomedical Research Center, Asan Institute for Life Sciences, Seoul, Korea.
3
Department of Anatomy and Cell Death Disease Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea.
4
Institute of Clinical Medicine Research of Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Bucheon, Korea.
5
Department of Internal Medicine, College of Medicine, The Chungnam National University of Korea, Daejeon, Korea.
6
National Creative Research Initiatives Center for Energy Homeostasis Regulation, Institute of Molecular Biology and Genetics and School of Biological Sciences, Seoul National University, 599 Gwanak-Ro, Gwanak-Gu, Seoul 151-742, Korea.
7
Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul 138-736, Korea.
8
Convergence Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul 138-736, Korea.
9
Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.

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.

PMID:
27550469
PMCID:
PMC4994041
DOI:
10.1038/srep31931
[Indexed for MEDLINE]
Free PMC Article

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