T cell homing to the kidney contributes to salt retention and blood pressure regulation

项目摘要/摘要 肾脏是血压的重要调节器。它们通过控制血流量来调节循环量 钠和水平衡，从而维持细胞外液容量的动态平衡。众所周知， 盐敏感型高血压的发病机制是由肾脏对钠的处理受损引起的，但 导致肾钠滞留的关键因素仍未确定。T细胞在人类免疫系统中的重要作用 高血压是在过去的十年中被提出的。然而，没有相关的可行的治疗方案 被提出，因为T细胞这种作用的潜在机制还没有被阐明。我们 最近发现了肾脏浸润性CD8+T细胞(CD8+T细胞)在增强盐滞留方面的新作用；肾脏 浸润性CD8T细胞与远端曲小管细胞(DCT)相互作用，刺激 DCT中的转运体(NCC)，导致血压升高。这些发现让我们提出了假设 CD8T和肾小管细胞之间的相互作用介导T细胞归巢到肾脏，这可能是 代表肾脏缺陷，导致盐敏感型高血压的发病机制。在建议的 在这项研究中，我们将研究肾脏中CD8T与肾脏相互作用的关键分子决定因素 并确定CD8T的这种肾归巢机制是如何导致过量盐的 滞留，导致高血压。具体地说，目标1将测试我们的假设，即细胞因子产生 活化的CD8T激活DCT表达共信号分子，从而启动DCT与CD8T之间的相互作用 DCT和CD8T；AIM 2将识别介导假定的免疫突触的黏附分子 在这两种细胞类型之间。AIM 3将确定钾通道Kir4.1在CD8T中的关键作用 诱导NCC和可能的其他钠转运体在远端肾单位上调，导致 盐分滞留过多，导致血压升高。我们的初步研究已经确定 每个目标的关键分子。作为原则性实验的证明，免疫中和或基因 小鼠肾脏中这些分子的缺失可阻止刺激诱导的NCC在小鼠肾脏中的上调 肾脏，从而降低血压。体内和体外互补研究设计于 这项建议是为了实现我们的目标。我们将在动物身上使用肾脏特异性基因敲除或基因敲除方法 以确定关键分子在这项研究中的确切作用。实现我们的目标将阐明 T细胞归巢到肾脏的重要分子机制，从而损害盐分和体积 动态平衡，并影响血压。我们认为盐敏感型高血压至少是由 部分原因是肾脏的免疫功能紊乱。此外，这项研究中确定的关键分子可能代表 针对这一普遍的健康问题，未来免疫治疗的新靶点。

PROJECT SUMMARY / ABSTRACT The kidneys are important regulators of blood pressure. They regulate circulatory volume by controlling sodium and water balance, thus maintaining extracellular fluid volume homeostasis. It is well established that the pathogenesis of salt-sensitive hypertension is caused by impaired sodium handling in the kidneys, but the critical factors leading to renal sodium retention remain unidentified. An important role for T cells in hypertension has been proposed in the past decade. However, no related feasible treatment options have been proposed, because the mechanisms underlying this role for T cells have not been elucidated. We recently identified a novel role for kidney-infiltrated CD8+ T cells (CD8Ts) in enhancing salt retention; renal infiltrated CD8Ts interact with distal convoluted tubule cells (DCTs), stimulating the sodium-chloride co- transporter (NCC) in the DCTs, resulting in elevation of blood pressure. These findings led us to hypothesize that the interaction between CD8Ts and renal tubular cells mediates T cell-homing to the kidney, which may represent a kidney defect that contributes to the pathogenesis of salt sensitive hypertension. In the proposed study, we will investigate the critical molecular determinants in the kidney, by which CD8Ts interact with renal tubular cells and determine how this kidney-homing mechanism of CD8Ts contributes to excessive salt retention, leading to high blood pressure. Specifically, Aim 1 will test our hypothesis that cytokines produced from activated CD8Ts prime DCTs to express co-signaling molecule, which initiates the interaction between DCTs and CD8Ts; Aim 2 will identify the adhesion molecules that mediate a putative immunological synapse between these two cell types. Aim 3 will determine the critical role of potassium channel Kir4.1 in CD8T- induced upregulation of NCC and possibly other sodium transporters in the distal nephron, leading to excessive salt retention and consequent elevation of blood pressure. Our preliminary studies have identified key molecules for each Aim. As proof of principle experiments, immunological neutralization or genetic deletion of these molecules in the kidneys of mice prevented stimuli-induced upregulation of NCC in the kidney and consequently lowered blood pressure. Complementary in vivo and in vitro studies are designed in this proposal to accomplish our aims. We will use kidney-specific knockout or knockdown methods in animals to determine the precise roles of key molecules in this study. Accomplishing our aims will elucidate the important molecular mechanisms regarding T cell homing to the kidney, thus impairing salt and volume homeostasis, and affecting blood pressure. We propose that salt-sensitive hypertension is caused, at least in part, by immune disorders in the kidney. Moreover, the key molecules identified in this study may represent novel targets for future immunotherapy against this prevalent health problem.