Cyclophosphamide Treatment Attenuates Hypertension in an Experimental Model of Systemic Lupus Erythematosus

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease that predominantly affects women during their reproductive years, leading to speculation that estrogens factor in the pathogenesis of the disease. However, published data from our laboratory show a complex temporal relationship with estrogens likely serving a permissive role for SLE disease early in life, but acting to protect against cardiovascular risk factors like hypertension during adulthood. Hypertension, a major cardiovascular risk factor and independent predictor of mortality in women with SLE, is prevalent in these patients for reasons that remain unclear. Our laboratory showed that autoimmunity is an important factor driving the pathogenesis of hypertension and that immunosuppressive therapies can attenuate the development of hypertension in an experimental mouse model of SLE. Cyclophosphamide is a common immunosuppressive treatment for patients with SLE that works by inhibiting DNA synthesis via the alkylation of nucleic acids in rapidly dividing cells. While CYC‐based treatment regimens have significantly improved survival rates, they also contribute to an increased prevalence of premature ovarian failure among patients treated for advanced lupus nephritis that could ultimately impact estrogen status of these women. We hypothesized that the administration of CYC (25 mg/kg, once/week, IP injection) for four weeks would blunt the development of hypertension and renal disease in an established female mouse model of SLE with hypertension (adult NZBWF1 female mice at 30 weeks of age), and that the estrogen status of the mice would be impaired as a side effect of the treatment. Mean arterial pressure (MAP) was measured by indwelling carotid catheters at the conclusion of the study in conscious freely moving mice. Results suggest that MAP was lower in CYC treated SLE mice (n=4) compared to vehicle treated SLE mice (n=4) [119.7±2.0 vs 135.1±5.1 mmHg, p<0.05]. Preliminary data suggest that treatment with CYC attenuates renal injury assessed by urinary albumin excretion [0.0858±0.0657 (n=4) vs 0.4539±0.2565 (n=6) mg/day] and may have had an effect to reduce uterine weight [0.13±0.01 (n=5) vs 0.20±0.03 (n=6) % of body weight], a surrogate marker for estrogen status. CYC treatment also did not significantly affect body weight, with a decrease of 2.68±0.02% (n=5) in CYC treated SLE mice compared to a decrease of 2.88±0.01%(n=6) in vehicle treated SLE mice, suggesting that the change in MAP was not caused by the loss of body weight that sometimes accompanies cytotoxic drugs. Additional studies are required to determine the impact of CYC on hormonal status in mice with SLE and whether hormone therapy can be safely used in SLE patients using CYC that may be at risk of losing ovarian function.Support or Funding InformationVA Merit Award (BX002604‐01A2) NIH (PO1HL051971, P20GM104357, T32HL105324‐05)