17β-Estradiol Protects Against the Progression of Hypertension During Adulthood in a Mouse Model of Systemic Lupus Erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease with a high prevalence of hypertension and cardiovascular disease. Because SLE predominantly affects women, estrogen is commonly implicated as a contributor to SLE disease progression. Utilizing an established mouse model of SLE (female NZBWF1) we tested whether estrogen has a causal role in the development of hypertension in adulthood. Thirty-week-old SLE and control mice (NZW/LacJ) underwent either a sham or ovariectomy (OVX) procedure. 17β-estradiol (E2; 5μg/mouse, twice/week, s.c.) was administered to a subset of OVX mice. Mean arterial pressure (in mmHg) was increased in SLE mice (134±4 versus 119±3 in controls). Contrary to our hypothesis, OVX exacerbated the hypertension in female SLE mice (153±3; p<0.05 vs. SLE sham), and repletion of E2 prevented the OVX induced increase in blood pressure (132±2). The prevalence of albuminuria was increased in SLE mice in comparison to controls (37% vs. 0%). OVX increased the prevalence in SLE mice (70% versus 37% in SLE shams). Repletion of E2 completely prevented albuminuria in OVX SLE mice. Renal cortical TNF-α was increased in SLE mice compared to controls and was further increased in OVX SLE. The OVX induced increase in renal TNF-α expression was prevented by repletion of E2. Treatment of OVX SLE mice with the TNF-α inhibitor, etanercept, blunted the OVX induced increase in blood pressure (140±2) and prevalence of albuminuria (22%). These data suggest that 17β-estradiol protects against the progression of hypertension during adulthood in SLE, in part, by reducing TNF-α.

Impact of early life ovariectomy on blood pressure and body composition in a female mouse model of systemic lupus erythematosus

“…We recently reported that OVX during adulthood (at 30 wk of age) exacerbates the hypertension associated with SLE (12). In the present study, we tested whether blood pressure in adulthood during SLE is impacted by OVX in young animals (8 wk of age).…”

“…When SLE and Ctrl mice were 8 wk old, an OVX was performed through a dorsal midline incision, as previously described (12). The OVX was performed at this age to mimic the early life removal of estrogens or its actions, as previously described by others (5,35,43).…”

“…Surprisingly, the contribution of estrogens to SLE disease progression in humans remains unclear, and understanding their role in the cardiovascular risk is complicated by the large body of literature pointing to cardioprotective actions of estrogens in women (22,47) as well as their relatively safe use in women with SLE (3,7,8,20,26,31,40). Using an established experimental model of SLE (female NZBWF1 mice), we (12) recently reported that loss of estradiol in adulthood exacerbates the hypertension and renal injury, which, when considering that loss of estrogens early in life delays disease onset, suggests that there are distinct temporal effects of estrogens on SLE disease progression and its consequences. The major goal of the present study was to extend the findings of our recent work (12) by testing whether early life removal of estrogens in female NZBWF1 mice delays the onset of SLE and attenuates the hypertension in adulthood.…”

“…Using an established experimental model of SLE (female NZBWF1 mice), we (12) recently reported that loss of estradiol in adulthood exacerbates the hypertension and renal injury, which, when considering that loss of estrogens early in life delays disease onset, suggests that there are distinct temporal effects of estrogens on SLE disease progression and its consequences. The major goal of the present study was to extend the findings of our recent work (12) by testing whether early life removal of estrogens in female NZBWF1 mice delays the onset of SLE and attenuates the hypertension in adulthood. Because loss of estrogens can have a profound impact on body composition, another cardiovascular risk factor, the second goal of the study was to assess the impact of early life ovariectomy (OVX) on body weight and body composition.…”

Autoimmunity in the Pathogenesis of Hypertension

“…52 The prohypertensive role of tumor necrosis factor-α-mediated inflammation has been shown in several studies that inhibited this cytokine with a tumor necrosis factor-α receptor fusion protein bound to the cristallisable fragment of IgG (etanercept). [53][54][55] Participation of the adaptive immunity in hypertension was also shown in the studies of Vinh et al 56 that examined the effects of suppressing the costimulation required for antigen-induced T cell activation and demonstrated that mice lacking B7 ligands or treated with CTLA4 (Abatacept) to block T cell costimulation showed inhibited cytokine production, reduced of vascular T cell accumulation and resistance to angiotensin-induced hypertension.…”