Modulation of glomerular structure and function in murine lupus nephritis by methylprednisolone and cyclophosphamide

The effects of methylprednisolone and cyclophosphamide were examined in a murine model of lupus nephritis (MRL-1pr/1pr). Animals were assigned to four groups at 12 weeks of age. Mice in the control group received intraperitoneal saline solution either daily or weekly. Animals in the low-dose methylprednisolone (MPLD) group received 6 mg/kg/day intraperitoneal methylprednisolone; those in the high-dose methylprednisolone (MPHD) group received 12 mg/kg/day intraperitoneal methylprednisolone. Animals in the cyclophosphamide group received 50 mg/kg/wk intraperitoneal cyclophosphamide. Animals surviving to 24 weeks were examined. MPHD and cyclophosphamide treatments were associated with maintenance of normal glomerular filtration rates and the development of only minimal proteinuria. However, detailed morphometric evaluation of the glomerulus revealed glomerular enlargement and mesangial matrix expansion in both groups. Unlike MPHD-treated mice, cyclophosphamide-treated animals demonstrated a marked reduction in the number of osmophilic dense deposits along the glomerular capillary walls. MPLD had little effect on function, despite significant reductions in cell proliferation and anti-double-strand DNA antibodies. Tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) levels were dramatically increased in plasma of control animals. Treatment with methylprednisolone and cyclophosphamide dramatically reduced TNF-alpha but not IL-6. Treatment also reduced renal IL-1 beta, TNF-alpha and transforming growth factor-beta mRNA levels compared with untreated mice. Despite minimal serologic activity and preservation of renal function, neither cyclophosphamide nor methylprednisolone was able to completely suppress disease activity, as measured by increased cytokine production and glomerular structural injury. The inability of treatment to reduce IL-6 levels may explain the resistance to treatment in this model.