Epalrestat (EPS), an aldose reductase inhibitor, is widely prescribed to manage diabetic neuropathies. It is generally believed that EPS is beneficial to diabetic patients because it can protect endothelial cells, Schwann cells, or other neural cells from oxidative stress. However, several clinical studies revealed that EPS therapy led to liver dysfunction, which limited its clinical applications. Currently, the underlying mechanism by which EPS causes liver dysfunction is unknown. The present study aimed to investigate the mechanism responsible for EPS-induced liver injury. In mouse liver, EPS 1) increased oxidative stress, indicated by increased expression of MnSOD, Ho-1 and Nqo1, 2) induced inflammation, indicated by infiltration of inflammatory cells, and induced expression of TNFalpha, CD11b, and CD11c, as well as 3) predisposed to induce fibrosis, evidenced by increased mRNA and protein expression of early pro-fibrotic biomarker genes pro-collagen I and alpha-smooth muscle actin, and by increased collagen deposition. In cultured mouse and human hepatoma cells, EPS treatment induced oxidative stress, decreased cell viability, and triggered apoptosis evidenced by increased Caspase-3 cleavage/activation. In addition, EPS increased mRNA and protein expression of cytoglobin in mouse liver, indicating that EPS activated hepatic stellate cells. Furthermore, EPS treatment in cultured human hepatic stellate cells increased cell viability. In summary, EPS induced oxidative stress in mouse liver and hepatoma cells. EPS induced liver inflammation and tended to promote liver fibrogenesis. Therefore, cautions should be exercised during EPS therapy.

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