Endothelin receptor antagonism improves glucose tolerance and adipose tissue inflammation in an experimental model of systemic lupus erythematosus

Endothelin-1 (ET-1) is elevated in patients with systemic lupus erythematosus (SLE), an autoimmune disease characterized by high rates of hypertension, renal injury, and cardiovascular disease. SLE is also associated with increased prevalence of obesity and insulin resistance compared to the general population. In the present study, we tested the hypothesis that elevated ET-1 in SLE is contributes to obesity and insulin resistance. For these studies, we used the NZBWF1 mouse model of SLE, which develops obesity and insulin resistance on a normal chow diet. To test this hypothesis, we treated control (NZW) and SLE (NZBWF1) mice with vehicle, atrasentan (ETA receptor antagonist, 10mg/kg/day), or bosentan (ETA/ETB receptor antagonist, 100mg/kg/day) for four weeks. Neither treatment impacted circulating immunoglobulin levels, but treatment with bosentan lowered anti-dsDNA IgG levels, a marker of SLE disease activity. Treatment with atrasentan and bosentan decreased glomerulosclerosis, and atrasentan lowered renal T cell infiltration. Body weight was lower in SLE mice treated with atrasentan or bosentan. Endothelin receptor antagonism also improved hyperinsulinemia, HOMA-IR, and glucose tolerance in SLE mice. Adipose tissue inflammation was also improved by endothelin receptor blockade. Taken together, these data suggest a potential therapeutic benefit for SLE patients with obesity and insulin resistance.