Abstract 128: Leptin Accelerates Autoimmune Disease Progression and the Development of Hypertension in an Experimental Model of Systemic Lupus Erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that predominately affects women and is associated with high rates of hypertension and cardiovascular disease. SLE is characterized by B and T lymphocyte dysfunction and altered cytokine production, including elevated levels of the adipocytokine leptin. Leptin promotes the expansion of proinflammatory T helper (T H ) 1 and T H 17 cells and inhibits the differentiation of regulatory T cells (T REG ). Because T cells are mechanistically linked to the development of hypertension in SLE, we hypothesized that administration of leptin would alter T H subsets and accelerate the development of hypertension in a female mouse model of SLE. To test this hypothesis, 30 week old female SLE (NZBWF1, n=21) and control (NZW, n=25) mice were implanted with minipumps to continuously deliver recombinant mouse leptin (0.5 mg/kg/day) or vehicle for four weeks. At the conclusion of the study, splenic CD4 + T H subsets were analyzed by flow cytometric analyses and no significant alterations in T H 1, T H 2, T H 17, or T REG cells were detected; however, circulating T REG in SLE mice were lower after leptin administration (1.1±0.2% SLE-vehicle vs. 0.52±0.1% SLE-leptin, p<0.05). Circulating IgG isotypes were also analyzed to correlate with T H subset activities and circulating levels of IgG2a were higher in SLE mice administered leptin (0.79±0.2 mg/mL SLE-vehicle vs. 1.2±0.05 mg/mL SLE-leptin, p<0.05), indicating increased T H 1 activity. In further support of inflammatory T cell activity, circulating levels of TNF-α and IL-17 were elevated in SLE mice administered leptin (TNF-α: 18.6±8.4 pg/mL SLE-vehicle vs. 80.5±15.9 pg/mL SLE-leptin, p<0.01) (IL-17: 0.46±0.1 pg/mL SLE-vehicle vs. 1.68±0.5 pg/mL, p<0.01). Mean arterial pressure (MAP; mmHg), measured in conscious mice by carotid catheter, was higher in SLE mice than in control mice (113±3 Control-vehicle vs. 128±3, p=0.06), and leptin further increased blood pressure in SLE mice (SLE-leptin: 134±3; p<0.01 vs. Control-vehicle and Control-leptin). In conclusion, these data suggest that leptin plays a pathogenic role in the development of hypertension in autoimmunity, in part by altering the balance of T H 1, T H 17, and T REG activity.