Blood Pressure, Renal Hemodynamics, and Inflammation

血压、肾脏血流动力学和炎症

• 批准号: 7800439
• 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/7800439
• 关键词: Affect; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Area; Atherosclerosis; Autoimmune Process; Blood Pressure; Blood Vessels; Cardiovascular Diseases; Central obesity; Chronic; Data; Disease; Functional disorder; Funding; Gender; Human; Hypertension; Impairment; Incidence; Individual; Inflammation; Inflammatory; Interleukin-6; K-Series Research Career Programs; Kidney; Laboratories; Leptin; 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 development; 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.

系统性红斑狼疮女性中高血压和血管功能障碍的发生率很高 红斑狼疮(SLE)。炎性细胞因子在SLE期间增加，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机制 导致系统性红斑狼疮高血压的原因是氧化应激增加和肾功能损害 血管功能障碍。肾脏中PPAR-Gamma的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 初步数据显示，在系统性红斑狼疮小鼠模型中，肾脏PPARGamma表达减少 NZBWF1)；然而，它在SLE高血压中的作用尚不清楚。当前的中心假说 资金来源的RO1是在SLE过程中，炎性细胞因子TNFα和IL-6的表达减少。 PPARGamma促进氧化应激，导致内皮功能障碍。这会导致肾脏增加。 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)至 检测RVR增加和肾压钠尿关系受损是否与SLE有关 高血压。2)检测肿瘤坏死因子α和白介素6是否是肾血流动力学受损的介质， 肾小管功能和系统性红斑狼疮时的高血压。3)测试氧化应激是否有助于 系统性红斑狼疮肾血流动力学与高血压的关系。4)测试降低的肾脏PPAR伽马是否是 系统性红斑狼疮高血压的重要潜在机制。我们实验室的最新数据也 说明这种SLE模型存在内脏肥胖，循环中细胞因子瘦素水平升高。 有证据表明，瘦素通过交感神经对肥胖期间血压升高起重要作用 神经激活，而且SLE患者循环中的瘦素水平升高。因此，在一个 新的目标是，我们建议检验SLE期间瘦素升高增加交感神经的假设 活动是导致系统性红斑狼疮高血压的另一个机制。这个职业发展奖将 在我职业发展的关键时刻提供额外的时间，这将使我能够扩大我的研究 计划进入这一令人兴奋的新领域。