title: Twisted gastrulation, a BMP antagonist, exacerbates podocyte injury.
abstract: Podocyte injury is the first step in the progression of glomerulosclerosis. Previous studies have demonstrated the beneficial effect of bone morphogenetic protein 7 (Bmp7) in podocyte injury and the existence of native Bmp signaling in podocytes. Local activity of Bmp7 is controlled by cell-type specific Bmp antagonists, which inhibit the binding of Bmp7 to its receptors. Here we show that the product of Twisted gastrulation (Twsg1), a Bmp antagonist, is the central negative regulator of Bmp function in podocytes and that Twsg1 null mice are resistant to podocyte injury. Twsg1 was the most abundant Bmp antagonist in murine cultured podocytes. The administration of Bmp induced podocyte differentiation through Smad signaling, whereas the simultaneous administration of Twsg1 antagonized the effect. The administration of Bmp also inhibited podocyte proliferation, whereas simultaneous administration of Twsg1 antagonized the effect. Twsg1 was expressed in the glomerular parietal cells (PECs) and distal nephron of the healthy kidney, and additionally in damaged glomerular cells in a murine model of podocyte injury. Twsg1 null mice exhibited milder hypoalbuminemia and hyperlipidemia, and milder histological changes while maintaining the expression of podocyte markers during podocyte injury model. Taken together, our results show that Twsg1 plays a critical role in the modulation of protective action of Bmp7 on podocytes, and that inhibition of Twsg1 is a promising means of development of novel treatment for podocyte injury.
authors.affiliation: Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Yamada
authors.affiliation: Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.
authors.forename: Jin
authors.initials: J
authors.lastname: Nakamura
authors.affiliation: Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.
authors.forename: Misako
authors.initials: M
authors.lastname: Asada
authors.affiliation: Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Takase
authors.affiliation: Department of Internal Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
authors.forename: Taiji
authors.initials: T
authors.lastname: Matsusaka
authors.affiliation: TMK Project, Kyoto University Graduate School of Medicine, Kyoto, Kyoto, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Iguchi
authors.affiliation: Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Yamada
authors.affiliation: Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Deaprtment of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.
authors.forename: Atsuko Y
authors.initials: AY
authors.lastname: Higashi
authors.affiliation: Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Okuda
authors.affiliation: Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.
authors.forename: Nariaki
authors.initials: N
authors.lastname: Asada
authors.affiliation: Yachiyo Hospital, Anjyo, Aichi, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Fukatsu
authors.affiliation: Department of Cell Biology, Institute of Nephrology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Niigata, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawachi
authors.affiliation: Institute of Oral Biology, Faculty of Medicine, University of Zurich, Zurich, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Graf
authors.affiliation: Department of Nephrology and Dialysis, Kitano Hospital, Tazuke Kofukai Medical Research Institute, Osaka, Osaka, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Muso
authors.affiliation: Kobe City Medical Center General Hospital, Kobe, Hyogo, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Kita
authors.affiliation: Deaprtment of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Ira
authors.initials: I
authors.lastname: Pastan
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York, United States of America.
authors.forename: Aris N
authors.initials: AN
authors.lastname: Economides
authors.affiliation: Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.
authors.forename: Motoko
authors.initials: M
authors.lastname: Yanagita
mesh_terms: D000818:Animals; D055419:Bone Morphogenetic Protein 7 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D007678:Kidney Glomerulus / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009399:Nephrons / Q000378:metabolism; D050199:Podocytes / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D051785:Smad Proteins / Q000378:metabolism
chemical_list: D055419:Bone Morphogenetic Protein 7; D011506:Proteins; D051785:Smad Proteins; C525820:bmp7 protein, mouse; C473561:twisted gastrulation protein, mouse