Blood Pressure, Renal Hemodynamics, and Inflammation

女性系统性狼疮患者高血压和血管功能障碍的发生率高 红斑性狼疮（SLE）。SLE期间炎性细胞因子增加，越来越多的证据表明 细胞因子可以促进高血压。慢性炎症可能通过一种可能的机制 引起SLE高血压的原因是通过氧化应激增加介导的肾功能损害， 血管功能障碍这可能因肾脏中PPARgamma表达减少而加剧。 PPARgamma是一种具有抗炎和抗氧化作用的核转录因子。我们 初步数据表明，在SLE小鼠模型中， （NZBWF 1）;然而，其在SLE高血压中的作用尚不清楚。目前的核心假设是 在SLE期间，炎性细胞因子TNF α和IL-6， PPARgamma促进氧化应激，导致内皮功能障碍。这导致肾功能增加 血管阻力和高血压。这一假设正在以下具体目标中得到检验。1)到 检测RVR增加和肾压尿钠排泄关系受损是否有助于SLE 高血压2)为了测试TNF α和IL-6是否是肾血流动力学受损的介质， 肾小管功能和高血压。3)为了测试氧化应激是否有助于受损的 SLE时肾血流动力学和高血压的关系。4)为了测试肾脏PPARgamma减少是否是一种 导致SLE高血压的重要潜在机制。我们实验室的最新数据也 显示该SLE模型具有内脏肥胖和增加的细胞因子瘦素循环水平。 有证据表明，瘦素是重要的血压升高肥胖期间通过交感神经 神经激活，SLE患者的瘦素循环水平增加。因此，在A 新的目标，我们建议测试的假设，在SLE瘦素升高增加交感神经 活动是SLE高血压的另一个促成机制。该职业发展奖将 在我职业发展的关键时刻提供额外的时间，使我能够扩展我的研究 进入这个令人兴奋的新领域。

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.