Cyclophosphamide modulates Wnt3a/β-catenin signaling in MRL/lpr mice with lupus nephritis.

This study was carried out to analyze the time-dependent changes of Wnt3a/β-catenin signaling during lupus nephritis (LN). At the age of 5 weeks, 30 female MRL/lpr mice and C57BL/6 (C57) mice were randomly grouped. Moreover, 12 females MRL/lpr mice were split into two groups, cyclophosphamide treatment (LN-CTX) and one was untreated. Mice in the LN-CTX group were injected intraperitoneally with cyclophosphamide (CTX) from the age of 16 wk. Urinary protein, serum antinuclear antibodies (ANA), and anti-double-stranded DNA (dsDNA) antibody levels were measured. The detection of renal injury was later confirmed through histopathology, and immunofluorescence analysis. Compared with C57 mice, LN mice had much higher levels of 24-hour urinary protein, ANA and dsDNA antibodies (P<0.05). Histological examination exhibited the proliferation of mesangial cells with the invasion of inflammatory cells, while deposition of immune complex was shown to reach the peak at 28 weeks. The production of Wnt3a and β-catenin proteins and mRNA was significantly increased in the kidneys of LN mice. In contrast, 24-hour urinary protein, ANA and dsDNA antibodies levels decreased significantly and CTX treatment caused a drop in the aforementioned immune response (P<0.05). Renal histopathological changes and immune complex deposition were ameliorated by CTX treatment. the renal levels. Notably, the renal levels of Wnt3a/β-catenin at LN-CTX were found to be lower than that in the untreated LN group. The abnormal activation of the Wnt/β-catenin signaling pathway may play a role in LN formation and thus important molecular target for CTX drug. This research shows that CTX inhibits renal Wnt3a/β-catenin activation in LN mice for the first time, offering a potential molecular mechanism for its renoprotective effects.