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 disorder 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. Using 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; 5 μg/mouse, twice/week, subcutaneously) was administered to a subset of OVX mice. Mean arterial pressure (in mm Hg) 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 versus 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 compared with controls (37% versus 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 tumor necrosis factor α was increased in SLE mice compared with controls and was further increased in OVX SLE. The OVX-induced increase in renal tumor necrosis factor α expression was prevented by repletion of E2. Treatment of OVX SLE mice with the tumor necrosis factor 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 tumor necrosis factor α.

Keywords: estrogens; lupus erythematosus, systemic; pressure.

Figure 1

Effect of ovariectomy (OVX), estradiol (E2) repletion, and etanercept (Etan) on MAP in control mice (A) and SLE mice (B). A, Neither OVX, E2 repletion, nor etanercept altered MAP in comparison to control Sham mice (n≥5). B, MAP was significantly higher in OVX SLE mice (n=11) compared with Sham (n=16). Repletion of E2 prevented the OVX induced increase in MAP in SLE mice (n=6). Treatment with etanercept blunted the exaggerated increase in MAP in OVX SLE mice (n=6). * p<0.05 vs. SLE sham

Figure 2

Effect of estradiol on renal cortical TNF-α protein expression in control and SLE mice. TNF-α protein expression was significantly increased in the renal cortex of SLE mice compared with controls. OVX increased TNF-α expression in SLE mice, and repletion of estradiol blunted this increase. * p<0.05 vs. Ctrl

Figure 3

Effect of OVX and estradiol (E2) repletion on uterine weight in control mice (A) and SLE mice (B). OVX significantly reduced uterine weight in both control and SLE mice. Repletion of E2 following OVX significantly increased uterine weight in comparison to respective shams. * p<0.05 vs. Sham and OVX+E2. # p<0.05 vs. Sham, OVX, and OVX+Etan.

Figure 4

A, Weekly percentage of SLE mice with positive urinary albumin as measured by dipstick assay (n≥8/group). No control mice developed albuminuria. B, Urine albumin in control mice at 34 weeks of age as measured by ELISA (n≥6). Urine albumin was similar between groups. C, Urine albumin in SLE mice at 34 weeks of age as measured by ELISA (n≥8). Urine albumin was increased after ovariectomy (OVX) in comparison to shams. Repletion of estradiol (E2) prevented the OVX induced increase in urine albumin. Treatment with etanercept blunted the increase in urine albumin in OVX SLE mice. * p<0.05 vs. OVX+E2

Figure 5

Effect of OVX, estradiol (E2) repletion, and etanercept (Etan) on plasma anti-dsDNA antibodies in control mice (A) and SLE mice (B). A, Plasma anti-dsDNA antibodies were similar between control mice at 34 weeks of age. B, Plasma anti-dsDNA antibodies were increased at 34 weeks of age in SLE mice compared to controls. OVX and repletion of E2 did not significantly alter these levels in comparison to SLE shams. Treatment with etanercept in OVX mice increased antibody levels in comparison to OVX mice. * p<0.05 vs. OVX