Blood Pressure, Renal Hemodynamics, and Inflammation

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The incidence of hypertension and vascular dysfunction is high in women with systemic lupus erythematosus (SLE). Inflammatory cytokines are increased during SLE and growing evidence suggests that cytokines can promote hypertension. One possible mechanism by which chronic inflammation may cause SLE hypertension is through impairment of renal function mediated by increased oxidative stress and vascular dysfunction. This may be exacerbated by a reduced expression of PPARgamma in the kidney. PPARgamma is a nuclear transcription factor that has anti-inflammatory and antioxidant affects. Our preliminary data indicates that renal PPARgamma expression is reduced in a mouse model of SLE (NZBWF1); however, its role in SLE hypertension is not clear. The central hypothesis of the currently funded RO1 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. This hypothesis is being tested in the following specific aims. 1) To test whether increased RVR and an impaired renal pressure natriuresis relationship contributes to SLE hypertension. 2) To test whether TNFalpha and IL-6 are mediators of impaired renal hemodynamics, tubular function, and hypertension during SLE. 3) To test whether oxidative stress contributes to impaired renal hemodynamics and hypertension during SLE. 4) To test whether reduced renal PPARgamma is an important underlying mechanism contributing to SLE hypertension. Recent data from our laboratory also shows that this model of SLE has visceral obesity and increased circulating levels of the cytokine leptin. Evidence suggests that leptin is important for increased blood pressure during obesity through sympathetic nerve activation, and that individuals with SLE have increased circulating levels of leptin. Therefore, in a new aim, we propose to test the hypothesis that elevated leptin during SLE increases sympathetic nerve activity as another contributing mechanism to SLE hypertension. This career development award will provide additional time at a critical point in my career development that will allow me to expand my research program into this new and exciting area.