title: The Hippo-Salvador signaling pathway regulates renal tubulointerstitial fibrosis.
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.
authors.affiliation: National Creative Research Initiatives Center, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea.|Biomedical Research Center, Asan Institute for Life Sciences, Seoul, Korea.
authors.forename: Eunjeong
authors.initials: E
authors.lastname: Seo
authors.affiliation: Department of Anatomy and Cell Death Disease Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Wan-Young
authors.initials: WY
authors.lastname: Kim
authors.affiliation: National Creative Research Initiatives Center, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea.
authors.forename: Jeongmi
authors.initials: J
authors.lastname: Hur
authors.affiliation: National Creative Research Initiatives Center, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea.|Biomedical Research Center, Asan Institute for Life Sciences, Seoul, Korea.
authors.forename: Hanbyul
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Anatomy and Cell Death Disease Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Sun Ah
authors.initials: SA
authors.lastname: Nam
authors.affiliation: Department of Anatomy and Cell Death Disease Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Arum
authors.initials: A
authors.lastname: Choi
authors.affiliation: Department of Anatomy and Cell Death Disease Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Yu-Mi
authors.initials: YM
authors.lastname: Kim
authors.affiliation: Institute of Clinical Medicine Research of Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Bucheon, Korea.
authors.forename: Sang Hee
authors.initials: SH
authors.lastname: Park
authors.affiliation: Department of Internal Medicine, College of Medicine, The Chungnam National University of Korea, Daejeon, Korea.
authors.forename: Chaeuk
authors.initials: C
authors.lastname: Chung
authors.affiliation: Department of Anatomy and Cell Death Disease Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Jin
authors.initials: J
authors.lastname: Kim
authors.affiliation: 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.
authors.forename: Soohong
authors.initials: S
authors.lastname: Min
authors.affiliation: Biomedical Research Center, Asan Institute for Life Sciences, Seoul, Korea.|Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul 138-736, Korea.|Convergence Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul 138-736, Korea.
authors.forename: Seung-Jae
authors.initials: SJ
authors.lastname: Myung
authors.affiliation: National Creative Research Initiatives Center, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea.
authors.forename: Dae-Sik
authors.initials: DS
authors.lastname: Lim
authors.affiliation: Department of Anatomy and Cell Death Disease Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea.|Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Yong Kyun
authors.initials: YK
authors.lastname: Kim
mesh_terms: D000217:Acyltransferases; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition; D005355:Fibrosis; D017353:Gene Deletion; D005786:Gene Expression Regulation; D000090683:Hippo Signaling Pathway; D006801:Humans; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007684:Kidney Tubules / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; C415864:SAV1 protein, human; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D051176:beta Catenin; D000217:Acyltransferases; C108675:TAFAZZIN protein, human; D017346:Protein Serine-Threonine Kinases