TY - JOUR
T1 - Knockout of endothelin type B receptor signaling attenuates bleomycin-induced skin sclerosis in mice
AU - Akashi, Kengo
AU - Saegusa, Jun
AU - Sendo, Sho
AU - Nishimura, Keisuke
AU - Okano, Takuya
AU - Yagi, Keiko
AU - Yanagisawa, Masashi
AU - Emoto, Noriaki
AU - Morinobu, Akio
N1 - Publisher Copyright:
© 2016 Akashi et al.
PY - 2016/5/21
Y1 - 2016/5/21
N2 - Background: 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. Methods: 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. Results: 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. Conclusions: ET-1-ETB receptor signaling is involved in skin sclerosis and in collagen synthesis by dermal fibroblasts.
AB - Background: 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. Methods: 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. Results: 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. Conclusions: ET-1-ETB receptor signaling is involved in skin sclerosis and in collagen synthesis by dermal fibroblasts.
KW - Dermal fibroblast
KW - Endothelin type B receptor
KW - Systemic sclerosis
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U2 - 10.1186/s13075-016-1011-4
DO - 10.1186/s13075-016-1011-4
M3 - Article
C2 - 27209208
AN - SCOPUS:84969504557
SN - 1478-6354
VL - 18
JO - Arthritis Research and Therapy
JF - Arthritis Research and Therapy
IS - 1
M1 - 113
ER -