title: Knockout of endothelin type B receptor signaling attenuates bleomycin-induced skin sclerosis in mice.
abstract: Endothelin-1 (ET-1) is important in the pathogenesis of systemic sclerosis (SSc). ET-1 binds two receptors, endothelin type A (ETA) and endothelin type B (ETB). Dual ETA/ETB receptor antagonists and a selective ETA receptor antagonist are used clinically to treat SSc, and the effect of these antagonists on fibroblast activation has been described. However, the role of ETB receptor signaling in fibrogenesis is less clear. This study was conducted to evaluate the profibrotic function of ETB receptor signaling in a murine model of bleomycin (BLM)-induced scleroderma.
  
  
  
  We used ETB receptor-knockout (ETBKO) mice, which are genetically rescued from lethal intestinal aganglionosis by an ETB receptor transgene driven by the human dopamine β-hydroxylase (DβH)-gene promoter, and wild-type mice with DβH-ETB (WT). BLM or phosphate-buffered saline (PBS) was administered subcutaneously by osmotic minipump, and skin fibrosis was assessed by dermal thickness, subcutaneous fat atrophy, and myofibroblast count in the dermis. Dermal fibroblasts isolated from ETBKO and WT mice were cultured in vitro, stimulated with BLM or ET-1, and the expression of profibrotic genes was compared by quantitative PCR.
  
  
  
  Dermal thickness, subcutaneous fat atrophy, and myofibroblast counts in the dermis were significantly reduced in ETBKO mice compared to WT mice, after BLM treatment. Compared with wild-type, dermal fibroblasts isolated from ETBKO mice showed lower gene expressions of α-smooth muscle actin and collagen 1α1 in response to BLM or ET-1 stimulation in vitro.
  
  
  
  ET-1-ETB receptor signaling is involved in skin sclerosis and in collagen synthesis by dermal fibroblasts.
authors.affiliation: Department of Rheumatology and Clinical Immunology, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Akashi
authors.affiliation: Department of Rheumatology and Clinical Immunology, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Saegusa
authors.affiliation: Department of Rheumatology and Clinical Immunology, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
authors.forename: Sho
authors.initials: S
authors.lastname: Sendo
authors.affiliation: Department of Rheumatology and Clinical Immunology, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Nishimura
authors.affiliation: Department of Clinical Pharmacy, Kobe Pharmaceutical University, Kobe, Japan.|Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Okano
authors.affiliation: Department of Clinical Pharmacy, Kobe Pharmaceutical University, Kobe, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Yagi
authors.affiliation: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Yanagisawa
authors.affiliation: Department of Clinical Pharmacy, Kobe Pharmaceutical University, Kobe, Japan.|Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Noriaki
authors.initials: N
authors.lastname: Emoto
authors.affiliation: Department of Rheumatology and Clinical Immunology, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan. morinobu@med.kobe-u.ac.jp.
authors.forename: Akio
authors.initials: A
authors.lastname: Morinobu
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D001761:Bleomycin / Q000633:toxicity; D024042:Collagen Type I / Q000378:metabolism; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D044023:Receptor, Endothelin B / Q000378:metabolism*; D012595:Scleroderma, Systemic / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology*; D012867:Skin / Q000378:metabolism / Q000473:pathology
chemical_list: D000903:Antibiotics, Antineoplastic; D024042:Collagen Type I; C000602969:EDNRB protein, mouse; D019332:Endothelin-1; D044023:Receptor, Endothelin B; D001761:Bleomycin
keywords: Dermal fibroblast; Endothelin type B receptor; Systemic sclerosis