Abstract P348: Immunosuppression with Cyclophosphamide Attenuates Renal Injury but Not Hypertension in an Experimental Model of Autoimmune Disease

Abstract

Cardiovascular disease is the major cause of mortality among patients with the autoimmune disorder systemic lupus erythematosus (SLE). Our laboratory previously showed that immunosuppression with mycophenolate mofetil, a common therapy in patients with SLE, attenuates the development of hypertension in an experimental model of SLE. Cyclophosphamide is another common therapy for patients with SLE that has contributed to improved disease management; however, its impact on the development of hypertension associated with SLE is not clear. We tested whether treatment with cyclophosphamide (25 mg/kg, once/week, IP injection) for four weeks attenuates hypertension in an established female mouse model of SLE with hypertension (30 week old NZBWF1 females). Plasma anti-dsDNA IgG levels, pathogenic for the disease, were lower in cyclophosphamide-treated SLE mice compared to vehicle-treated SLE mice (161 ± 43, n=19 vs 501 ± 114, n=21, p<0.05 units/mL), suggesting efficacy of the therapy to suppress aberrant immune system function. Mean arterial pressure (MAP) was assessed by carotid artery catheters in conscious mice. Treatment did not attenuate the development of hypertension (136 ± 3 mmHg, n=15) when compared to vehicle treated SLE mice (131 ± 4 mmHg, n=13, p=0.69]; however, urinary albumin excretion (72.2 ± 68 mg/day, n=21, mg/day) was lower in cyclophosphamide treated animals (0.06 ± 0.02 mg/day, n=13). Corresponding with the reduction in autoantibodies, preliminary data suggest that cyclophosphamide treatment lowered circulating CD45R + B cells (15.87 ± 8.49%, n=10 vs 26.96 ± 4.72%, n=8). Paradoxically, circulating CD11b + Ly6G + neutrophils were increased in cyclophosphamide treated SLE mice compared to vehicle treated (39.26 ± 4.92%, n=10 vs 20.58 ± 6.01%, n=8, p=0.06). These data suggest that cyclophosphamide treatment attenuates autoantibody production and renal disease during SLE, but that the potential to impact MAP may be blunted by the increase in circulating neutrophils.