Role of CD247 in Salt-Sensitive Hypertension and Renal Disease

描述(由申请人提供)：实验和人体数据表明，免疫细胞对肾脏的渗透在高血压和肾脏疾病的发展中是重要的。这项研究的初步数据表明，肾脏中浸润性T细胞被激活，它们可以作为升高的细胞因子和血管紧张素Ⅱ的来源，过继转移从患病的Dahl SS大鼠的肾脏中获得的活化的浸润性细胞可能会在供体动物中介导疾病。此外，在Dahl SS的遗传背景下，重组激活基因1(Rag1)或CD247是免疫细胞信号转导中的两个重要基因，为这一应用开发的独特动物模型的初步数据支持了肾脏中T细胞渗入可介导高血压和肾脏疾病的概念。特别值得注意的是，遗传关联研究表明，CD247在人类高血压和肾脏疾病中起着重要作用。该提案的这一独特的翻译方面强调了该提案中对动物进行的实验观察与人类疾病之间的重要联系。这些新的数据表明，肾脏中免疫细胞的渗透在盐敏感型高血压和肾脏损害的发展中的重要性。然而，目前尚不清楚什么免疫细胞类型(S)在这一反应中起重要作用，也不知道什么因素介导了高血压和肾脏损害。我们认为，浸润性细胞，特别是T淋巴细胞，通过在肾脏中释放血管活性因子(细胞因子和/或血管紧张素Ⅱ)来发挥有害作用，从而夸大正在进行的疾病过程。这项提议中的实验将检验与人类高血压相关的基因CD247通过改变肾脏中T淋巴细胞的渗透和激活来影响高血压和肾脏疾病的普遍假设。作为这一假说的推论，我们认为浸润性免疫细胞通过增加肾内细胞因子和血管紧张素转换酶来影响肾功能。这一假设将在三个以机械为基础的具体目标中得到检验。目的1验证CD247介导T细胞进入Dahl SS大鼠肾脏的假说。目的2验证Dahl SS大鼠盐敏感型高血压和肾损害过程中，肾脏中T细胞分泌促炎细胞因子(即IL-6)和血管紧张素转换酶(AngII)的假说。目的验证肾内IL-6和AngII通过改变肾功能参与Dahl SS大鼠盐敏感型高血压和肾损害的假说。这些综合目标将使用从细胞和分子机制到整个动物生理学和病理生理学的综合方法来解决这一假说，并利用专门为这一提议开发的动物模型。 公共卫生相关性：在美国，高血压是心血管和肾脏疾病的主要风险因素。实验和人体数据表明，免疫细胞向肾脏的渗透在高血压和肾脏损害的发生发展中起着重要作用。然而，目前尚不清楚哪些渗透的免疫细胞在疾病反应中起重要作用，或者这些细胞释放的哪些因素介导了肾脏的有害影响。拟议的研究将通过利用独特的动物模型、新颖的实验工具和一种综合的方法来展示特定的免疫细胞类型以及这些细胞释放的导致钠敏感型高血压放大和肾脏损害发展的因素，从而推动科学领域的发展。这项工作的结果将导致高血压和肾脏疾病的新疗法。

DESCRIPTION (provided by applicant): Experimental and human data indicate that infiltration of immune cells into the kidney is important in the development of hypertension and kidney disease. Preliminary data in this proposal indicate that infiltrating T cells in the kidney are activated, that they can serve as a source of elevated cytokines and AngII, and that adoptive transfer of the activated, infiltrating cells harvested from the kidney of diseased Dahl SS rats ca mediate disease in donor animals. Moreover, preliminary data from unique animal models developed for this application in which recombination activating gene 1 (Rag1) or CD247, two important genes in immune cell signaling have been genetically mutated in the Dahl SS genetic background, supports the concept that infiltrating T cells in the kidney can mediate hypertension and renal disease. Of particular note, genetic association studies indicate that CD247 is important in hypertension and kidney disease in humans. This unique translational aspect of the proposal emphasizes the important link between the experimental observations made in animals in this proposal and human disease. These novel data demonstrate the importance of infiltrating immune cells in the kidney in the development of salt-sensitive hypertension and renal damage. It is not known, however, what immune cell type(s) is/are important in the response or what factors mediate the hypertension and renal damage. We propose that the infiltrating cells, specifically T lymphocytes, exert deleterious actions by releasing vasoactive factors (cytokines and/or AngII) in the kidney to exaggerate the ongoing disease process. Experiments in this proposal will test the general hypothesis that CD247, a gene associated with human hypertension, affects hypertension and renal disease by altering T lymphocyte infiltration and activation in the kidney. As a corollary to this hypothesis, we propose that the infiltrating immune cells act by increasing intrarenal cytokines and AngII which affect kidney function. This hypothesis will be tested in three mechanistically-based, Specific Aims. Aim 1 will test the hypothesis that CD247 mediates infiltration of T cells into the kidney in Dahl SS rats. Aim 2 will test the hypothesis that infiltrating T cells produce proinflammatory cytokines (i.e. IL-6) and AngII in the kidney during salt-sensitive hypertension and kidney damage in Dahl SS rats. Aim 3 will test the hypothesis that intrarenal IL-6 and AngII participate in the development of salt-sensitive hypertension and renal damage in the Dahl SS rat by altering renal function. These integrative aims will address this hypothesis using a comprehensive approach ranging from cellular and molecular mechanisms to whole animal physiology and pathophysiology and utilize animal models specifically developed for this proposal. PUBLIC HEALTH RELEVANCE: Hypertension is a leading risk factor for cardiovascular and kidney disease in the US. Experimental and human data indicate that infiltration of immune cells into the kidney is important in the development of hypertension and kidney damage. It is not known, however, what infiltrating immune cells are important in the disease response or what factors released from these cells mediate the deleterious effects in the kidney. The proposed studies will advance the scientific field by utilizing unique animal models, novel experimental tools, and an integrative approach to demonstrate the specific immune cell types and the factors released from these cells that lead to the amplification of sodium-sensitive hypertension and the development of kidney damage. Results of this work should result in novel therapy for hypertension and kidney disease.