Mycophenolate Mofetil Attenuates Hypertension in an Experimental Model of Systemic Lupus Erythematosus

Abstract

Mycophenolate mofetil (MMF) is an immunosuppressive agent that selectively depletes proliferating lymphocytes and is commonly used to prevent organ transplant rejection or treat autoimmune disease. Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disorder that predominately affects women of childbearing age and is associated with a high rate of hypertension, renal injury, and cardiovascular disease. Recent clinical evidence suggests that treatment with MMF can reduce blood pressure in patients with rheumatoid arthritis or psoriasis; however, whether MMF can be effectively utilized in the control of blood pressure during SLE remains unclear. Because immune dysregulation and inflammation have been linked to the pathophysiology of essential hypertension, we hypothesized that MMF will attenuate hypertension and renal injury in an experimental mouse model of SLE. Female SLE (NZBWF1) and control (NZW) mice, aged 26 weeks, were injected intraperitoneally with 5% dextrose (vehicle) or MMF daily at a rate of 60 mg/kg/day for eight weeks. CD45R+ B cells were lower in the peripheral blood of SLE mice treated with MMF for eight weeks (19.5±1.3% SLE‐Vehicle vs. 5.2±1.5% SLE‐MMF, p< 0.01), but the levels of both CD4+ and CD8+ T cells were unchanged. Circulating levels of anti‐dsDNA IgG auto antibodies, a marker of SLE disease activity, were higher in SLE mice as compared to control mice (789±120 vs. 161±57 units/mL, p<0.0001), and were significantly lower in mice treated for eight weeks with MMF (SLE‐MMF: 321±90; p<0.05 vs. SLE‐Vehicle). Urinary albumin excretion, an indicator of glomerular injury, was increased in SLE mice as compared to controls (5.6±1.9 vs. 0.11±0.02 ng/day, p<0.0001), and was lower in SLE mice treated with MMF (SLE‐MMF: 0.38±0.20 ng/day; p<0.001 vs. SLE‐Vehicle). Mean arterial pressure (MAP; mmHg) measured in conscious mice by carotid catheter was higher in SLE mice than in control mice (141±3 vs. 120±3, p<0.05). MAP was significantly lower in SLE mice treated with MMF when compared to vehicle treated SLE mice (SLE‐MMF: 120±5; p<0.001 vs. SLE‐Vehicle). These data suggest that MMF treatment may have added clinical benefit for patients with SLE by helping to control blood pressure, a major contributor to cardiovascular risk in this population. Moreover, given that MMF selectively depleted CD45R+ B cells, these data provide additional evidence that B cells and the production of auto antibodies mechanistically contribute to the pathogenesis of hypertension during SLE.Support or Funding InformationResearch supported by: VA# I01BX002604‐01A2 (MJR), T32HL105324 (EBT), HL051971 (UMMC‐Physiology)