Knockout of endothelin type B receptor signaling attenuates bleomycin-induced skin sclerosis in mice. Issue 1 (December 2016)

• Record Type: Journal Article
• Authors: Akashi, Kengo; Saegusa, Jun; Sendo, Sho; Nishimura, Keisuke; Okano, Takuya; Yagi, Keiko; Yanagisawa, Masashi; Emoto, Noriaki; Morinobu, Akio
• Is Part Of: Arthritis research & therapy. Volume 18:Issue 1(2016)
• Page Start: 1
• Page End: 9
• Publication Date: 2016-12
• Subjects: Systemic sclerosis -- Endothelin type B receptor -- Dermal fibroblast; Arthritis -- Periodicals; Arthritis -- Treatment -- Periodicals; 616.722005
• DOI: 10.1186/s13075-016-1011-4
• Languages: English
• ISSNs: 1478-6362

Abstract

Abstract 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 (ETB KO) 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 ETB KO 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 ETB KO mice compared to WT mice, after BLM treatment. Compared with wild-type, dermal fibroblasts isolated from ETB KO 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.