title: Klotho inhibits transforming growth factor-beta1 (TGF-beta1) signaling and suppresses renal fibrosis and cancer metastasis in mice.
abstract: Fibrosis is a pathological process characterized by infiltration and proliferation of mesenchymal cells in interstitial space. A substantial portion of these cells is derived from residing non-epithelial and/or epithelial cells that have acquired the ability to migrate and proliferate. The mesenchymal transition is also observed in cancer cells to confer the ability to metastasize. Here, we show that renal fibrosis induced by unilateral ureteral obstruction and metastasis of human cancer xenografts are suppressed by administration of secreted Klotho protein to mice. Klotho is a single-pass transmembrane protein expressed in renal tubular epithelial cells. The extracellular domain of Klotho is secreted by ectodomain shedding. Secreted Klotho protein directly binds to the type-II TGF-β receptor and inhibits TGF-β1 binding to cell surface receptors, thereby inhibiting TGF-β1 signaling. Klotho suppresses TGF-β1-induced epithelial-to-mesenchymal transition (EMT) responses in cultured cells, including decreased epithelial marker expression, increased mesenchymal marker expression, and/or increased cell migration. In addition to TGF-β1 signaling, secreted Klotho has been shown to inhibit Wnt and IGF-1 signaling that can promote EMT. These results have raised the possibility that secreted Klotho may function as an endogenous anti-EMT factor by inhibiting multiple growth factor signaling pathways simultaneously.
authors.affiliation: From the Departments of Pathology.
authors.forename: Shigehiro
authors.initials: S
authors.lastname: Doi
authors.affiliation: Oncology, and.
authors.forename: Yonglong
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Osamu
authors.initials: O
authors.lastname: Togao
authors.affiliation: From the Departments of Pathology.
authors.forename: Johanne V
authors.initials: JV
authors.lastname: Pastor
authors.affiliation: From the Departments of Pathology.
authors.forename: George B
authors.initials: GB
authors.lastname: John
authors.affiliation: From the Departments of Pathology.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: From the Departments of Pathology.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Shiizaki
authors.affiliation: the Genzyme Corporation, Cambridge, Massachusetts 02142, and.
authors.forename: Russell
authors.initials: R
authors.lastname: Gotschall
authors.affiliation: the Genzyme Corporation, Cambridge, Massachusetts 02142, and.
authors.forename: Susan
authors.initials: S
authors.lastname: Schiavi
authors.affiliation: the Department of Advanced Nephrology, Graduate School of Biomedical Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima-shi, Hiroshima 734-8551, Japan.
authors.forename: Noriaki
authors.initials: N
authors.lastname: Yorioka
authors.affiliation: Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Masaya
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Oncology, and. Electronic address: david.boothman@utsouthwestern.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Boothman
authors.affiliation: From the Departments of Pathology,. Electronic address: makoto.kuro-o@utsouthwestern.edu.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kuro-O
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000090265:Klotho Proteins; D051379:Mice; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D051381:Rats; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D051153:Wnt Proteins; D007334:Insulin-Like Growth Factor I; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625843:Tgfbr1 protein, rat; D005966:Glucuronidase; D000090265:Klotho Proteins