Adenosine A2a Receptor Blockade Diminishes Wnt/?-Catenin Signaling in a Murine Model of Bleomycin-Induced Dermal Fibrosis.

ABSTRACT: Adenosine A2a receptor (A2aR) stimulation promotes the synthesis of collagens I and III, and we have recently demonstrated that there is crosstalk between the A2aR and WNT/?-catenin signaling pathway. In in vitro studies, A2aR signaling for collagen III expression was mediated by WNT/?-catenin signaling in human dermal fibroblasts; we further verified whether the crosstalk between A2aR and Wnt/?-catenin signaling was involved in diffuse dermal fibrosis in vivo. Wnt-signaling reporter mice (Tcf/Lef:H2B-GFP) were challenged with bleomycin and treated with the selective A2aR antagonist istradefylline (KW6002) or vehicle. Dermal fibrosis was quantitated and nuclear translocation of ?-catenin in fibroblasts was assessed by double-staining for Green fluorescent protein or dephosphorylated ?-catenin or ?-catenin phosphorylated at Ser552, and vimentin. KW6002 significantly reduced skin thickness, skinfold thickness, breaking tension, dermal hydroxyproline content, myofibroblast accumulation, and collagen alignment in bleomycin-induced dermal fibrosis. Also, there was increased expression of Tcf/Lef:H2B-GFP reporter in bleomycin-induced dermal fibrosis, an effect that was diminished by treatment with KW6002. Moreover, KW6002 significantly inhibited nuclear translocation of Tcf/Lef:H2B-GFP reporter, as well as dephosphorylated ?-catenin and ?-catenin phosphorylated at Ser552. Our work supports the hypothesis that pharmacologic blockade of A2aR inhibits the WNT/?-catenin signaling pathway, contributing to its capacity to inhibit dermal fibrosis in diseases such as scleroderma.

SUBMITTER: Zhang J 

PROVIDER: S-EPMC5809334 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature