Abstract
BackgroundEndothelin-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.MethodsWe 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.ResultsDermal 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.ConclusionsET-1–ETB receptor signaling is involved in skin sclerosis and in collagen synthesis by dermal fibroblasts.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-1011-4) contains supplementary material, which is available to authorized users.
Highlights
Endothelin-1 (ET-1) is important in the pathogenesis of systemic sclerosis (SSc)
ETB receptor–knockout (ETBKO) mice were smaller than with DβH gene promoter–regulated ETB receptor transgene (DβH-ETB) (WT) mice of the same age, and ETBKO mice gained less body weight than did WT mice when treated with phosphate-buffered saline (PBS)
The endothelin type B (ETB) receptor is associated with dermal fibroblast activation and collagen synthesis in response to BLM or ET-1 Because fibroblasts play a critical role in fibrosis, we examined the characteristics of dermal fibroblasts from WT and ETBKO mice
Summary
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. This study was conducted to evaluate the profibrotic function of ETB receptor signaling in a murine model of bleomycin (BLM)-induced scleroderma. The pathogenesis of SSc has been studied in a bleomycin (BLM)-induced scleroderma model [2, 3]. ET-1 plays a critical role in vascular impairment and fibrosis in SSc patients. ET-1 binds two receptor subtypes, the endothelin type A (ETA) and endothelin type B (ETB) receptors [8]. ETA receptor signaling is critical for dermal fibroblast activation [12]. The role of ETB receptor signaling in fibrogenesis is less clear
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