Project Summary. The incidence of hypertension and vascular dysfunction is high in women with systemic lupus erythematosus (SLE). Growing evidence suggests that inflammatory cytokines promote hypertension by mechanisms yet to be elucidated. One possible mechanism is that chronic inflammation promotes oxidative stress and endothelial dysfunction leading to altered renal hemodynamics and reduced renal pressure natriuresis. Activation of the transcription factor PPARgamma reduces blood pressure, cytokine expression, and oxidative stress. Our preliminary data indicates that renal PPARgamma expression is reduced in a mouse model of SLE (NZBWF1). This suggests that protective effects of PPARgamma may be reduced in SLE. Although inflammatory cytokines, oxidative stress, and PPARgamma are altered in SLE, their role in causing hypertension and renal microvascular dysfunction is not clear. Our central hypothesis is that during SLE, inflammatory cytokines TNFalpha and IL-6, and reduced expression of PPARgamma promote oxidative stress leading to endothelial dysfunction. This leads to increased renal vascular resistance and hypertension. Preliminary data from our laboratory indicates that blood pressure is elevated and endothelial function is impaired in the NZBWF1 model. The central hypothesis will be tested in the following specific aims. (1) SLE causes increased renal vascular resistance and an impaired renal pressure natriuresis relationship which contributes to increased blood pressure. (2) TNFalpha and IL-6 are important mediators of endothelial dysfunction, impaired renal-pressure natriuresis, and increased blood pressure during SLE. (3) Elevated levels of reactive oxygen species are important mediators of altered renal hemodynamics and blood pressure during SLE. (4) Reductions in renal PPARgamma promote oxidative stress and inflammation which contribute to the renal vascular dysfunction and hypertension during SLE. Relevance: Systemic lupus erythematosus (SLE) is an autoimmune disorder that predominantly affects women. Women with SLE are likely to have high blood pressure and kidney disease. Very little is understood about the factors that cause high blood pressure during SLE. This proposal will begin to address some of the mechanisms that contribute to hypertension during SLE.