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

项目总结/摘要 肾脏是血压的重要调节器。它们通过控制 钠和水平衡，从而维持细胞外液体积的稳态。已充分证实 盐敏感性高血压的发病机制是由肾脏中钠处理受损引起的，但 导致肾钠潴留的关键因素仍未确定。T细胞的重要作用是 在过去的十年中已经提出了高血压。然而，没有相关的可行的治疗方案， 这是因为T细胞这种作用的机制尚未阐明。我们 最近发现肾脏浸润的CD 8 + T细胞（CD 8 Ts）在增强盐潴留中的新作用;肾 浸润的CD 8 T与远曲小管细胞（DCT）相互作用，刺激钠-氯化物共刺激。 DCTs中的NCC转运蛋白（NCC），导致血压升高。这些发现让我们假设 CD 8 Ts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 代表一种肾缺陷，其导致盐敏感性高血压的发病机制。拟议 在这项研究中，我们将研究肾脏中的关键分子决定因素，通过这些决定因素，CD 8 Ts与肾脏相互作用。 肾小管细胞，并确定这种CD 8 Ts的肾脏归巢机制如何导致过量的盐 保持，导致高血压。具体来说，目标1将测试我们的假设，细胞因子产生 从活化的CD 8 T引发DCT表达共信号分子，这引发了 DCTs和CD 8 Ts; Aim 2将鉴定介导假定免疫突触的粘附分子 这两种细胞类型之间的联系。目的3将确定钾通道Kir4.1在CD 8 T细胞中的关键作用。 诱导远端肾单位NCC和其他可能的钠转运蛋白上调，导致 过多的盐潴留和随之而来的血压升高。我们的初步研究发现 每个目标的关键分子。作为原理实验的证明，免疫中和或遗传 这些分子在小鼠肾脏中的缺失阻止了刺激诱导的NCC在小鼠肾脏中的上调。 肾，从而降低血压。补充的体内和体外研究设计于 这一建议，以实现我们的目标。我们将在动物中使用肾脏特异性敲除或击倒方法 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 关于T细胞归巢肾脏的重要分子机制，从而损害盐和容量 体内平衡和影响血压。我们认为，盐敏感性高血压是由，至少在 一部分是由于肾脏的免疫紊乱。此外，这项研究中确定的关键分子可能代表了 新的目标，为未来的免疫疗法对这一普遍的健康问题。

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.