The Role of T Lymphocytes in Hypertension During Chronic Inflammatory Disease

描述（由申请人提供）：促进高血压发展的机制继续被阐明，最近的证据表明免疫系统和炎症起着突出作用。系统性红斑狼疮（SLE）是一种慢性炎症性疾病，估计在美国影响近200万人，其中90%是年轻女性。虽然年轻健康女性患高血压的风险较低，但患有SLE的年轻女性高血压的患病率非常高。高血压是主要的心血管危险因素，是SLE患者死亡的主要原因，SLE患者血压升高的机制尚不清楚。我的实验室之前的工作表明，在一个已建立的SLE遗传小鼠模型中，肾脏炎症有助于高血压。此外，慢性压力尿钠关系与肾血管阻力和血管紧张素II （AngII）敏感性增加呈右平行变化，提示炎症通过肾血管机制促进SLE高血压。导致肾脏炎症和高血压的具体因素尚不清楚。我的初步数据表明，系统性和肾性T细胞耗竭都能降低SLE小鼠的血压，SLE小鼠的CD4+ T细胞（T辅助细胞）比对照T细胞分泌更多的炎症细胞因子[即白细胞介素(IL)-17]。IL-17受体在SLE小鼠的肾脏表达也增加。肾炎症与氧化应激有关，我最近表明氧化应激在机制上有助于SLE高血压。基于这些数据，我将验证T细胞通过增加IL-17产生导致SLE高血压的中心假设，IL-17促进氧化应激，导致肾血管对AngII的敏感性增加。AngII敏感性的增加损害了肾脏血流动力学（即肾血流和肾血管阻力），并导致导致高血压的压钠尿关系的降低。特异性目的1将验证T细胞通过损害肾脏血流动力学促进SLE高血压的假设，从而导致压力钠尿关系的改变。特异性目的2将验证T细胞介导的IL-17的产生促进肾脏氧化应激并增强肾血管对AngII的敏感性的假设。为了研究这些目标，我将在小鼠身上使用最先进的生理学、药理学、免疫学和生物分子方法。综上所述，这些研究的数据将为肾T淋巴细胞在SLE高血压中的机制作用提供证据。

DESCRIPTION (provided by applicant): Mechanisms contributing to the development of hypertension continue to be elucidated and recent evidence suggests a prominent role for the immune system and inflammation. Systemic lupus erythematosus (SLE) is a chronic inflammatory disorder estimated to affect nearly 2 million people in the United States, of which 90% are young women. While young healthy women have a low risk for developing hypertension, the prevalence of hypertension is very high in young women with SLE. Hypertension is a major cardiovascular risk factor, the predominant cause of mortality during SLE, and the mechanisms promoting elevated blood pressure during SLE are unknown. Previous work from my laboratory shows that renal inflammation contributes to hypertension in an established genetic mouse model of SLE. In addition, there is a rightward parallel shift in the chronic pressure natriuresis relationship and increased renal vascular resistance and renal vascular sensitivity to angiotensin II (AngII) suggesting that inflammation contributes to SLE hypertension though a renal vascular mechanism. The specific factors that contribute to the renal inflammation and hypertension are not clear. My preliminary data suggest that both systemic and renal T cell depletion reduces blood pressure in SLE mice and that CD4+ T cells (T helper) from SLE mice secrete more inflammatory cytokines [i.e., interleukin (IL)-17] than control T cells. Renal expression of the IL-17 receptor is also increased in SLE mice. Renal inflammation is associated with oxidative stress and I recently showed that oxidative stress mechanistically contributes to SLE hypertension. Based on this data, I will test the central hypothesis that T cells contribute to SLE hypertension through increased IL-17 production, which promotes oxidative stress leading to increased renal vascular sensitivity to AngII. The increased AngII sensitivity impairs renal hemodynamics (i.e., renal blood flow and renal vascular resistance) and leads to a decrease in the pressure natriuresis relationship that causes hypertension. Specific Aim 1 will test the hypothesis that T cells promote SLE hypertension through impairment of renal hemodynamics, leading to a shift in the pressure natriuresis relationship. Specific Aim 2 will test the hypothesis that T cell mediated production of IL-17 promotes renal oxidative stress and enhances renal vascular sensitivity to AngII. To investigate these aims, I will use state-of-the-art physiological, pharmacological, immunological, and biomolecular methods in mice. Taken together, data from the proposed studies will provide evidence of a mechanistic role of renal T lymphocytes in SLE hypertension.