Blood Pressure, Renal Hemodynamics, and Inflammation

描述（由申请人提供）：项目概述。女性系统性红斑狼疮（SLE）患者高血压和血管功能障碍的发生率较高。越来越多的证据表明，炎症细胞因子促进高血压的机制尚未阐明。一种可能的机制是慢性炎症促进氧化应激和内皮功能障碍，导致肾脏血流动力学改变和肾压尿减少。转录因子PPARgamma的激活可降低血压、细胞因子表达和氧化应激。我们的初步数据表明，在SLE小鼠模型（NZBWF1）中，肾脏pppargamma表达降低。这表明PPARgamma在SLE中的保护作用可能会减弱。虽然炎性细胞因子、氧化应激和PPARgamma在SLE中发生改变，但它们在引起高血压和肾微血管功能障碍中的作用尚不清楚。我们的中心假设是，在SLE期间，炎症细胞因子TNFalpha和IL-6以及PPARgamma表达的减少促进氧化应激导致内皮功能障碍。这导致肾血管阻力增加和高血压。我们实验室的初步数据表明，NZBWF1模型血压升高，内皮功能受损。中心假设将在以下具体目标中进行检验。(1) SLE引起肾血管阻力增加，肾压钠尿关系受损，导致血压升高。(2) TNFalpha和IL-6是SLE期间内皮功能障碍、肾压尿钠受损和血压升高的重要介质。(3) SLE期间活性氧水平升高是肾脏血流动力学和血压改变的重要介质。(4)肾PPARgamma的减少促进氧化应激和炎症，从而导致SLE期间肾血管功能障碍和高血压。相关性：系统性红斑狼疮（SLE）是一种主要影响女性的自身免疫性疾病。患有SLE的女性可能患有高血压和肾脏疾病。对SLE期间引起高血压的因素了解甚少。本提案将开始解决SLE期间导致高血压的一些机制。

DESCRIPTION (provided by applicant): 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.