title: Kidney-specific knockout of Sav1 in the mouse promotes hyperproliferation of renal tubular epithelium through suppression of the Hippo pathway.
abstract: We have previously reported that Salvador homologue 1 (SAV1), a component of the Hippo pathway, is significantly down-regulated in high-grade clear cell renal cell carcinoma (ccRCC) due to 14q copy number loss, and that this down-regulation contributes to the proliferation and survival of renal tubular epithelial cells through activation of Yes-associated protein 1 (YAP1), a downstream target of the Hippo pathway. However, the impact of SAV1 loss on the proliferation and survival of kidney cells in vivo remained to be determined. To address this issue, we generated kidney-specific Sav1-knockout (Cdh16-Cre;Sav1(fl/fl) ) mice. Sav1 deficiency enhanced the proliferation of renal tubular epithelial cells in Cdh16-Cre;Sav1(fl/fl) mice, accompanied by nuclear localization of Yap1, suggesting suppression of the Hippo pathway. Sav1 deficiency in renal tubules also caused structural and cellular abnormalities of the epithelial cells, including significant enlargement of their nuclei. Furthermore, Cdh16-Cre;Sav1(fl/fl) mice developed both glomerular and tubular cysts. Although lining cells of the glomerular cysts showed no atypia, those of the tubular cysts showed variations in cell size and nuclear shape, which became more severe as the mice aged. In aged Cdh16-Cre;Sav1(fl/fl) mice, we observed focal disruption of proximal tubules and perivascular lymphocytic infiltration. In conclusion, Sav1 is required for the maintenance of growth, nuclear size and structure of renal tubules under physiological conditions, and its deficiency leads to the acquisition of enhanced proliferation of renal epithelial cells through suppression of Hippo signalling.
authors.affiliation: Department of Molecular Pathology, Faculty of Medicine, Oita University, Yufu, Japan.|Department of Urology, Faculty of Medicine, Oita University, Yufu, Japan.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Kai
authors.affiliation: Department of Molecular Pathology, Faculty of Medicine, Oita University, Yufu, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Tsukamoto
authors.affiliation: Department of Molecular Pathology, Faculty of Medicine, Oita University, Yufu, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Hijiya
authors.affiliation: Section of Physiology, Department of Integrative Aging Neuroscience, National Center for Geriatrics and Gerontology, Obu, Japan.
authors.forename: Akinori
authors.initials: A
authors.lastname: Tokunaga
authors.affiliation: Department of Molecular Pathology, Faculty of Medicine, Oita University, Yufu, Japan.
authors.forename: Chisato
authors.initials: C
authors.lastname: Nakada
authors.affiliation: Department of Molecular Pathology, Faculty of Medicine, Oita University, Yufu, Japan.
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Uchida
authors.affiliation: Department of Diagnostic Pathology, Faculty of Medicine, Oita University, Yufu, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Daa
authors.affiliation: Department of Microbiology, Faculty of Medicine, Oita University, Yufu, Japan.
authors.forename: Hidekatsu
authors.initials: H
authors.lastname: Iha
authors.affiliation: Department of Molecular Pathology, Faculty of Medicine, Oita University, Yufu, Japan.|Department of Urology, Faculty of Medicine, Oita University, Yufu, Japan.
authors.forename: Mika
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Department of Urology, Faculty of Medicine, Oita University, Yufu, Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Nomura
authors.affiliation: Department of Urology, Faculty of Medicine, Oita University, Yufu, Japan.
authors.forename: Fuminori
authors.initials: F
authors.lastname: Sato
authors.affiliation: Department of Urology, Faculty of Medicine, Oita University, Yufu, Japan.
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Mimata
authors.affiliation: Animal Resource Center for Infectious Diseases, Research Institute for Microbial Diseases, Suita, Japan.
authors.forename: Masahito
authors.initials: M
authors.lastname: Ikawa
authors.affiliation: Division of Molecular Medicine, Aichi Cancer Institute, Nagoya, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Seto
authors.affiliation: Department of Molecular Pathology, Faculty of Medicine, Oita University, Yufu, Japan.|Department of Biology, Faculty of Medicine, Oita University, Yufu, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Matsuura
authors.affiliation: Department of Molecular Pathology, Faculty of Medicine, Oita University, Yufu, Japan.
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Moriyama
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D018262:Adenocarcinoma, Clear Cell / Q000209:etiology; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000172:deficiency*; D049109:Cell Proliferation / Q000502:physiology*; D053595:Embryonic Stem Cells / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D000090683:Hippo Signaling Pathway; D007680:Kidney Neoplasms / Q000209:etiology; D007684:Kidney Tubules / Q000378:metabolism*; D008822:Mice, Transgenic; D009393:Nephritis / Q000209:etiology; D010750:Phosphoproteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015820:Cadherins; C491946:Cdh16 protein, mouse; D018797:Cell Cycle Proteins; D010750:Phosphoproteins; C485935:Sav1 protein, mouse; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D017346:Protein Serine-Threonine Kinases
keywords: Hippo pathway; SAV1; YAP1; clear cell renal cell carcinoma; knockout mouse, atypical renal tubule