Immunosuppression with mycophenolate mofetil attenuates hypertension in an experimental model of autoimmune disease

Abstract

Background-Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that predominantly affects women and is associated with prevalent hypertension, renal injury, and cardiovascular disease. Immune system dysfunction is recognized as an important factor in the pathogenesis of hypertension. We recently showed that preventing autoimmunity prevents the development of hypertension in an experimental model of SLE (female NZBWF1 mice). The present study tests the hypothesis that mycophenolate mofetil (MMF), an immunosuppressive therapy used clinically to treat SLE by depleting proliferating B and T lymphocytes, can improve blood pressure control. Methods and Results-Female SLE and control (NZW/LacJ) mice were treated daily for 8 weeks with 60 mg/kg MMF. Circulating CD45R+ B cells were lower in MMF-treated SLE mice after 4 weeks of treatment, but neither CD4+ nor CD8+ T cells were reduced by MMF. Plasma anti-double-stranded DNA IgG autoantibodies, a marker of SLE disease activity, were higher in SLE mice compared with controls and were lower in SLE mice after 8 weeks of MMF. Mean arterial pressure was elevated in SLE mice compared with controls and lower in SLE mice treated with MMF compared with vehicle-treated SLE mice. MMF also reduced both renal injury (urinary albumin excretion and glomerulosclerosis) and the infiltration of CD45R+ B cells and CD3+CD4+ T cells in kidneys from mice with SLE. Conclusions-These data suggest that MMF selectively depleted CD45R+ B cells and lowered subsequent autoantibody production, furthering the concept that autoantibodies mechanistically contribute to the pathogenesis of hypertension.