Previous reports found that vitamin D analog Paricalcitol can inhibit β-catenin, we tested whether parcial-citol could ameliorate glucose-induced podocyte injury. The podocytes MPC5 cells were treated and divided into 6 groups: low glucose (L), low glucose with mannitol (L+D), high glucose group (H), high glucose + Paricalcitol (H+P), high glucose + losartan (H+losartan) and High glucose + LiCl group (H+Licl). The podocyte injury induced by high glucose and the effect of Paricalcitol on it were evaluated by measuring the cell proliferation and cell apoptosis rates. The nuclear translocation of VDR and β-catenin were evaluated. The upregulated TGF-β and Col IV indicated podocyte injury induced by high glucose, with increased cell apoptosis rate and decreased proliferation rate. After treated with Paricalcitol, elevated WT and nephrin was observed, while the TGF-β and Col IV was down-regulated. It promoted VDR nuclear translocation and blocked β-catenin nuclear translocation. Administration of LiCl, a WNT/β-catenin Signaling pathway agonist, could reverse the effects of Paricalcitol, suggesting that Paricalcitol led to suppression of β-catenin-mediated gene transcription. In response to high glucose, podocytes can undergo a spectrum of changes that may involve apoptosis, slow proliferation, and cell injury. Paricalcitol prevented this podocyte injury by inhibiting Wnt/β-catenin signaling. © 2017, E-Century Publishing Corporation. All rights reserved.