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，免疫细胞浸润到肾脏中在高血压和肾脏疾病的发展中是重要的。该提案中的初步数据表明，肾脏中的浸润性T细胞被激活，它们可以作为升高的细胞因子和AngII的来源，并且从患病Dahl SS大鼠的肾脏收获的活化的浸润性细胞的过继转移可以介导供体动物的疾病。此外，来自为此应用开发的独特动物模型的初步数据支持肾脏中的浸润性T细胞可以介导高血压和肾脏疾病的概念，其中重组激活基因1（Rag 1）或CD 247（免疫细胞信号传导中的两个重要基因）在Dahl SS遗传背景中发生遗传突变。特别值得注意的是，遗传关联研究表明，CD 247在人类高血压和肾脏疾病中很重要。该提案的这一独特的翻译方面强调了该提案中在动物身上进行的实验观察与人类疾病之间的重要联系。这些新的数据证明了肾脏中浸润的免疫细胞在盐敏感性高血压和肾损伤的发展中的重要性。然而，尚不清楚哪些免疫细胞类型在应答中是重要的，或者哪些因素介导高血压和肾损伤。我们认为浸润细胞，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AngII）来加重正在进行的疾病过程，从而发挥有害作用。本提案中的实验将检验与人类高血压相关的基因CD 247通过改变肾脏中的T淋巴细胞浸润和活化来影响高血压和肾脏疾病的一般假设。作为这一假设的推论，我们提出浸润性免疫细胞通过增加影响肾功能的肾内细胞因子和AngII起作用。这一假设将在三个基于机械的具体目标中进行检验。目的1将检验CD 247介导Dahl SS大鼠中T细胞浸润到肾脏中的假设。目的2将测试的假设，浸润T细胞产生促炎细胞因子（即IL-6）和血管紧张素II在肾脏中的盐敏感性高血压和肾脏损害的Dahl SS大鼠。目的3将验证肾内IL-6和AngII通过改变肾功能参与Dahl SS大鼠盐敏感性高血压和肾损伤的发展的假设。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设，并利用专门为此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危险因素。实验和人体数据表明，免疫细胞浸润到肾脏中在高血压和肾损伤的发展中是重要的。然而，尚不清楚哪些浸润性免疫细胞在疾病反应中是重要的，或者从这些细胞释放的哪些因子介导了肾脏中的有害作用。拟议的研究将通过利用独特的动物模型，新的实验工具和综合方法来证明特定的免疫细胞类型和从这些细胞释放的因子，从而推动科学领域的发展，这些细胞导致钠敏感性高血压的放大和肾损伤的发展。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.