17β‐estradiol attenuates renal TNFα and the progression of hypertension in mice with systemic lupus erythematosus

Abstract

The autoimmune disorder systemic lupus erythematosus (SLE) primarily affects young women suggesting a pathogenic role for estrogen. Cardiovascular and renal disease are the major causes of mortality in women with SLE, and hypertension, a major cardio‐renal risk factor, is prevalent in these women. This led to the hypothesis that estrogen promotes hypertension and renal injury during SLE. To test this, 30 week old female SLE (NZBWF1) and control (NZW/LacJ) mice underwent either an ovariectomy (OVX) or sham operation. A subset of OVX mice were supplemented with 17β‐estradiol (E2). At 34 weeks of age, mean arterial pressure (MAP in mmHg) was higher in SLE sham mice (133±3) than controls (120±3, p<0.05) as was the prevalence of albuminuria (33% vs 0%). OVX did not alter MAP (115±3) or albuminuria in controls; however, contrary to our hypothesis, OVX in SLE mice exacerbated the hypertension (154±3, p<0.05 vs SLE sham) and prevalence of albuminuria (75% vs 33%). This was associated with increased renal TNFα protein expression (3.2±0.8 SLE OVX vs 1.8±0.5 SLE sham), an inflammatory cytokine that contributes to SLE hypertension. E2 repletion prevented the increase in pressure caused by OVX in SLE mice (132±2) and reduced albuminuria and renal TNFα (2.3±0.3). These data suggest that estrogen protects against SLE hypertension via reduction of renal inflammatory cytokines. (HL085907, HL051971, AHA12050150, UMC‐IRSP).