Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that predominantly affects young women. Due to this partiality towards women, estrogen is commonly implicated in disease development. The potential for estrogens to promote SLE disease progression stems from data showing that removal of estrogens in young female mice with SLE (6-8 week old NZBWF1 mice) delays the development of renal injury and mortality. The primary cause of mortality in women with SLE is cardiovascular disease, and hypertension, a major cardiovascular risk factor, is highly prevalent in this patient population. Based on the presumed role of estrogen to promote SLE, we hypothesized that estrogen promotes hypertension during SLE. To test this, 30 week old SLE mice (NZBWF1) and control mice (NZW/LacJ) were subjected to either ovariectomy (OVX) or a sham operation and a subset of these mice were replete with 17β-estradiol (E2, 5μg/mouse, s.c., 2x/week). At 34 weeks of age, mean arterial pressure (MAP in mmHg) was measured by carotid catheter in conscious freely moving mice. MAP was higher in SLE sham mice compared to control shams (133±3, n=17 vs. 120±3, n=13, p<0.05). Contrary to our hypothesis, OVX at 30 weeks exacerbated the hypertension (154±3, n=9, p<0.05 vs. SLE sham) and prevalence of albuminuria in mice with SLE (83%, 10 of 12 vs 36%, 5 of 14 measured by dipstick > 100 mg/dL). OVX did not alter MAP (115±3, n=9) or albuminuria in control mice. The hypertensive response to OVX was prevented in OVX SLE mice replete with E2 (133±4, n=3) suggesting a protective role for E2 against SLE-associated hypertension. Because previous studies showed that estrogen removal in young mice delayed SLE disease progression, we tested whether OVX starting at 8 weeks of age delayed the development of hypertension. OVX in young SLE mice did not significantly alter the progression of SLE-associated hypertension (141±4, n=4 measured at 34 weeks of age). Consistent with previous work of others, OVX in young SLE mice reduced the prevalence of albuminuria (20%, 1 of 5 vs 33%, 1 of 3). These data suggest that estrogen has a complex temporal role in the pathogenesis of SLE with the potential to promote disease early in life, but protect against the progression of SLE associated hypertension later in the course of the disease.
AB0009 ASSOCIATION OF STAT4 RS7574865, RUNX1 RS9979383, IL6 RS1800795, IL6R RS2228145, IL6R RS4845618 WITH SYSTEMIC LUPUS ERYTHEMATOSUS SUSCEPTIBILITY AND SOME LUPUS MANIFESTATIONS IN BELARUSIAN POPULATION
