Renal mechanisms of hypertension in autoimmune disease

 描述(由申请人提供)： 在患有系统性红斑狼疮(SLE)的妇女中，高血压的患病率明显增加，原因尚不清楚。高血压是死亡率的独立预测因子，也是该患者群体的主要心血管危险因素。肾脏损伤和炎症在SLE患者中是常见的，由于肾脏在长期血压控制中的中心作用，这对高血压的风险具有重要意义。越来越多的证据表明，自身免疫可能是人类和实验性高血压的基础。因此，自身免疫性肾炎可能促进了女性SLE患者高血压的发生。为了支持这一点，初步数据显示，在患有SLE的高血压小鼠模型中，肾脏血流动力学功能受损。此外，我们的数据显示，雌性SLE小鼠的高血压部分是由适应性免疫系统的B和T细胞介导的。例如，高血压与自身抗体的产生有关，B细胞的耗尽可以防止高血压和肾脏损伤。系统性红斑狼疮小鼠肾脏和循环中T细胞相关细胞因子(肿瘤坏死因子、白介素17)水平也升高。IL-17广泛参与自身免疫介导的组织损伤，肾脏肿瘤坏死因子促进系统性红斑狼疮相关性高血压。当系统性红斑狼疮小鼠的T细胞被耗尽时，自身抗体就会减少，高血压的进展就会减弱。T细胞耗竭的SLE小鼠血压降低与肾脏微血管结构的保存有关。这项建议的主要焦点将是确定不同免疫细胞亚群在SLE期间的相对贡献及其对肾血流动力学功能的影响。总体假设是Th2细胞介导的B细胞产生与SLE相关的自身抗体会损害肾血流动力学功能。此外，Th1和Th17细胞通过分泌细胞因子(TNF-IL-17)直接损害肾皮质或髓质的血管血流，从而导致高血压。这些变化的结果是改变了慢性压力性钠尿关系的设定点，导致高血压的发生。这一具体目标将考验(1) Th2/B细胞的相互作用和自身抗体的产生促进了SLE高血压的发生。(2)Th1、Th17细胞参与了SLE患者高血压和肾脏炎症的发病过程。(3)适应性免疫系统激活损害了肾血流动力学功能，导致SLE时压力-钠尿关系的高血压改变。拟议的研究对高血压仍然是一个重要的健康问题的退伍军人具有重要的临床意义。此外，100多年来，风湿病及其并发症一直是美国军队及其家人的主要健康问题。因此，了解促进SLE或其后遗症的机制将提高患有高血压或SLE的退伍军人的临床护理质量。

 DESCRIPTION (provided by applicant): The prevalence of hypertension is markedly increased in women with systemic lupus erythematosus (SLE) for reasons that are not clear. Hypertension is an independent predictor of mortality and a major cardiovascular risk factor for this patient population. Renal injury and inflammation is common in patients with SLE which is significant to the risk of hypertension because of the kidney's central role in the long term blood pressure control. Growing evidence suggests that autoimmunity may underlie both human and experimental hypertension. Therefore, autoimmune induced renal inflammation may promote the development of hypertension in women with SLE. In support of this, preliminary data show that renal hemodynamic function is impaired in a hypertensive mouse model with SLE. In addition, our data show that hypertension in female SLE mice is mediated in part by B and T cells of the adaptive immune system. For example, the hypertension associates with autoantibody production and B cell depletion prevents the hypertension and renal injury. Renal and circulating levels of T cell associated cytokines (TNF-, IL-17) are increased in mice with SLE, as well. IL- 17 is widely implicated in autoimmune mediated tissue injury and renal TNF- promotes SLE associated hypertension. When T cells are depleted in SLE mice, autoantibodies are reduced and the progression of hypertension is attenuated. The lower blood pressure in T cell depleted SLE mice is associated with preservation of renal microvascular structure. The major focus of this proposal will be to determine the relative contribution of different immune cell subsets and their impact on renal hemodynamic function during SLE. The overall hypothesis is that the Th2 cell mediated B cell production of autoantibodies associated with SLE impairs renal hemodynamic function. In addition, Th1 and Th17 cells contribute to the hypertension by secreting cytokines (TNF- IL-17) that directly impair renal cortical or medullary vascular flow. The result of these changes is to shift the set point of the chronic pressure natriuresis relationship resulting in the development of hypertension. This specific aims will test whether (1) Th2/B cell interaction and the production of autoantibodies promotes the development of hypertension during SLE. (2) Th1 and Th17 cells contribute to the pathogenesis of hypertension and renal inflammation during SLE. (3) Adaptive immune system activation impairs renal hemodynamic function causing a hypertensive shift in the pressure natriuresis relationship during SLE. The proposed studies have significant clinical implications for veterans for whom hypertension remains a significant health concern. In addition, rheumatic diseases and their complications have been a major health concern for the U.S. military and their families for over 100 years. Therefore understanding mechanisms that promote SLE or its sequelae will improve the quality of clinical care for veterans with hypertension or SLE.