Fli-1 inhibitors reduce the production of inflammatory cytokines in human renal glomerular endothelial cells and ameliorate lupus nephritis in NZB/W F1 mice

Abstract

Abstract Expression of transcription factor Fli-1 impacts lupus nephritis (LN) development in both human patients and murine models of lupus. We studied the effects of camptothecin and topotecan, Fli-1 inhibitors, on LN in NZB/W F1 mice and renal endothelial cells. Human Renal Glomerular Endothelial Cells (HRGEC) were treated with Fli-1 inhibitors, and inflammatory cytokines were measured after stimulation with IFN-α and IFN-γ. NZB/W F1 female mice were treated with camptothecin, topotecan, cyclophosphamide, or vehicle control. Blood and urine were collected, and autoantibodies and proteinuria were monitored. The expression of Fli-1 in HRGEC, when treated with 0.1 μM or higher concentrations of camptothecin, was significantly reduced. The production of MCP-1 and IP-10, inflammatory cytokines associated with LN development, were significantly lower in the HRGEC treated with camptothecin compared to the HRGEC treated with DMSO at 4 and 24 hours following stimulation with IFN-α and IFN-γ at the concentration of 100 ng/ml. NZB/W F1 mice were treated with camptothecin, topotecan, cyclophosphamide, or PBS control when more than 40% of mice had proteinuria higher than 30 mg/dL. At the age of 37 weeks, 70% of NZB/W F1 mice treated with vehicle had proteinuria higher than 2,000 mg/dL. None of the NZB/W F1 mice treated with camptothecin or topotecan had proteinuria higher than 100 mg/dL. One of the NZB/W F1 mice treated with cyclophosphamide had proteinuria higher than 100 mg/dL. Blood urea nitrogen (BUN) was lower in the sera from NZB/W F1 mice treated with camptothecin, topotecan, or cyclophosphamide compared to that of the mice treated with vehicle. Together, these results indicate that Fli-1 inhibitors are novel therapeutic approaches in treating LN.