1483 Epalrestat, an aldose reductase inhibitor, alleviates bleomycin-induced skin fibrosis in mice: Drug repositioning study for human systemic sclerosis

Systemic sclerosis (SSc) is a connective tissue disease characterized by skin fibrosis and vasculopathy. Our original high-throughputin vitro screening method identified the aldose reductases (AR) inhibitor epalrestat as potential compound with antifibrotic activity among numerous commercial drugs. AR consist of aldo-keto reductase superfamily members, catalyzing NADPH-dependent detoxification various substrates for which biological action contributes to inflammation fibrosis. We aimed examine whether inhibits in bleomycin-induced SSc model mice phenotypical alteration on cultured human normal dermal fibroblasts. Epalrestat-pretreated fibroblasts were stimulated recombinant TGF-β1, followed assessment TGF-β1/Smad signaling fibrogenic molecules. In vitroepalrestat treatment dose-dependently suppressed TGF-β1-dependent increase type I collagen, fibronectin 1, αSMA, other mesenchymal markers, preceded inhibiting over-phosphorylation expression Smad3 Oral administration (3mg/kg/day) gave marked inhibition maintenance vasculature bleomycin-injected mouse skin. The changes pathology corresponded pSmad3 transcription factors, Zeb1 Slug, correlation significant decrease infiltrating CD3+ T cells αSMA-positive cells, compared those control mice. There no adverse effects throughout study. results provide first evidence that may be major pathogenic contributor novel therapeutic target SSc, perspective its epalrestat.