Abstract Body: Lupus is a chronic autoimmune disease characterized by IgG deposition, Toll-like receptor 7 (TLR7) overactivation, and autoantibody production resulting in end organ inflammation. SLE disproportionally affects women, SLE disproportionally affects women to men (9:1 ratio), with a high prevalence in African American women. Highly vascularized organs are severely impacted by lupus, specifically the kidneys and brain. Recent literature has shown that cardiovascular disease (CVD) has significant detrimental impacts on organ crosstalk. Endothelin-1 (ET-1), a potent vasoconstricting peptide, has been shown elevated in patients with CVD and in patients with lupus independent of disease severity. However, the extent to which ET-1 promotes lupus-associated CVD and end organ cross talk remains to be elucidated. Therefore, we hypothesized that TLR7 overactivation in a murine model of SLE-associated CVD would lead to a sex-dependent regulation of the renal and cerebral ET systems. Female and male lupus-prone B6.Nba2 mice were subjected to bi-weekly treatment with the Resiquimod (R848; TLR7/8 agonist; 100ug/30ul) or vehicle control (Acetone) for one month and subsequently studied for 12 weeks. At 16 weeks, the kidneys and brains were collected for histology and ET system (ET-1, ET_A, and ET_B) analysis. Exploration of specific end organ damage demonstrates a profound increase in renal and cerebral IgG complex deposition as well as renal macrophages and T cells in both females and males receiving R848. Renal ET-1 levels displayed no time nor treatment-dependent effects in females, while males exhibited a significant time-dependent increase in expression at the 4 and 16-week timepoints. Interestingly, at the receptor level, neither sex demonstrated differences in ET_A nor ET_B levels in the kidney. While renal ET-1 level did not change, females demonstrated a significant increase in cerebral ET-1 at the 16-week timepoint, while males trended for increased cerebral ET-1. At the receptor level, females had a trend for increased cerebral ET_A expression, while there was no change in males, and neither sex displayed a change in ET_B receptor expression. These findings suggest a potential shift towards a pro-inflammatory state via the cerebral ET-1/ET_A signaling axis in the R848-treated females. These findings warrant further exploration into the end-organ specific pathophysiological role ET-1/ET_A signaling in multiorgan crosstalk in lupus-associated CVD.