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在高血压和肾脏疾病的发展中很重要。本研究的初步数据表明，肾脏中的浸润性T细胞被激活，它们可以作为细胞因子和AngII升高的来源，并且从患病的Dahl SS大鼠肾脏中获取的活化浸润性细胞的过性转移可以介导供体动物的疾病。此外，为这一应用而开发的独特动物模型的初步数据表明，重组激活基因1 （Rag1）或CD247这两个免疫细胞信号传导的重要基因在Dahl SS遗传背景下发生了基因突变，这支持了肾脏浸润T细胞可以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很重要。该提案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。这些新数据证明了肾中浸润免疫细胞在盐敏感性高血压和肾损害发展中的重要性。然而，目前尚不清楚哪种免疫细胞类型在这种反应中起重要作用，或者什么因素介导高血压和肾损害。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）来发挥有害作用，从而夸大正在进行的疾病过程。本提案的实验将验证与人类高血压相关的基因CD247通过改变肾脏中T淋巴细胞的浸润和激活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来起作用。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将验证CD247介导T细胞向Dahl SS大鼠肾脏浸润的假设。Aim 2将验证在盐敏感性高血压和Dahl SS大鼠肾损伤过程中浸润T细胞在肾脏中产生促炎细胞因子（即IL-6）和AngII的假设。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害的假设。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，并利用专门为本提案开发的动物模型。

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.