Blood Pressure, Renal Hemodynamics, and Inflammation

血压、肾脏血流动力学和炎症

• 批准号: 7449931
• 负责人: MICHAEL RYAN
• 金额: $ 7.79万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7449931
• 关键词: Affect; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Area; Atherosclerosis; Autoimmune Process; Blood Pressure; Blood Vessels; Cardiovascular Diseases; Central obesity; Chronic; Data; Development; Disease; Functional disorder; Funding; Gender; Human; Hypertension; Impairment; Incidence; Individual; Inflammation; Inflammatory; Interleukin-6; K-Series Research Career Programs; Kidney; Laboratories; Leptin; Lupus Erythematosus; Mediating; Mediator of activation protein; Modeling; Natriuresis; Nerve; Nuclear; Obesity; Oxidative Stress; PPAR gamma; Renal function; Research; Risk Factors; Role; Stress; Stroke; Systemic Lupus Erythematosus; Testing; Time; Tubular formation; United States; Vascular resistance; Vasculitis; Woman; career; child bearing; cytokine; hemodynamics; kidney vascular structure; man; mouse model; pressure; programs; transcription factor

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.

系统性狼疮女性高血压和血管功能障碍的发生率较高 红斑狼疮（SLE）。系统性红斑狼疮期间炎症细胞因子增加，越来越多的证据表明 细胞因子可以促进高血压。慢性炎症可能的一种可能机制 SLE 高血压的原因是氧化应激增加介导的肾功能损害 血管功能障碍。肾脏中 PPARgamma 表达减少可能会加剧这种情况。 PPARgamma 是一种核转录因子，具有抗炎和抗氧化作用。我们的 初步数据表明 SLE 小鼠模型中肾 PPARgamma 表达降低 （NZBWF1）；然而，其在 SLE 高血压中的作用尚不清楚。目前的中心假设 RO1 的资助是在 SLE 期间，炎症细胞因子 TNFα 和 IL-6 以及 PPARgamma 促进氧化应激，导致内皮功能障碍。这会导致肾 血管阻力和高血压。该假设正在以下具体目标中得到检验。 1) 至 测试 RVR 增加和肾压排钠关系受损是否会导致 SLE 高血压。 2) 测试TNFα和IL-6是否是肾血流动力学受损的介质， SLE 期间的肾小管功能和高血压。 3) 测试氧化应激是否会导致受损 SLE 期间的肾血流动力学和高血压。 4) 测试肾 PPARgamma 降低是否是一种 导致 SLE 高血压的重要潜在机制。我们实验室的最新数据还 显示该系统性红斑狼疮模型具有内脏肥胖和细胞因子瘦素循环水平升高。 有证据表明瘦素通过交感神经对肥胖期间血压升高很重要 神经激活，系统性红斑狼疮患者的瘦素循环水平增加。因此，在一个 新的目标，我们建议检验系统性红斑狼疮期间瘦素升高会增加交感神经的假设 活动作为 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 计划进入这个令人兴奋的新领域。