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

T 细胞归巢至肾脏有助于盐潴留和血压调节

• 批准号: 10394209
• 负责人: Shengyu Mu
• 金额: $ 38万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10394209
• 关键词: Adhesions; Adoptive Transfer; Affect; Animals; Antigens; Attention; Blood Pressure; CD8 Antigens; CD8-Positive T-Lymphocytes; Cardiovascular Diseases; Cell Adhesion Molecules; Cell Communication; Cells; DOCA; Defect; Development; Distal; Distal convoluted renal tubule structure; Equilibrium; Event; Excess Dietary Salt; Extracellular Fluid; Future; Genetic; Goals; Health; Homeostasis; Homing; Hypertension; Immune System Diseases; Immunologics; Immunotherapy; Impairment; In Vitro; Infiltration; Interferon Type II; Interruption; Kidney; Knock-out; Knockout Mice; Mediating; Methods; Modeling; Molecular; Mus; Myocardial Infarction; Nephrons; Organ failure; Pathogenesis; Pathway interactions; Perfusion; Play; Potassium Channel; Process; Production; Public Health; Regulation; Renal Hypertension; Renal tubule structure; Reporting; Research; Role; SLC12A3 gene; Signal Transduction; Signaling Molecule; Sodium; Sodium Chloride; Stimulus; Stroke; Surface; T-Cell Activation; T-Lymphocyte; Testing; Time; Tubular formation; Up-Regulation; Water; Withdrawal; adaptive immunity; base; blood pressure elevation; blood pressure reduction; blood pressure regulation; cell type; cytokine; design; epithelial Na+ channel; experimental study; hypertensive; immunological synapse; in vivo; kidney cell; knock-down; nephrogenesis; new therapeutic target; novel; overexpression; pressure; prevent; programmed cell death ligand 1; public health relevance; salt sensitive hypertension; symporter; therapeutic target; therapeutically effective; thiazide

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.

项目摘要 /摘要 肾脏是血压的重要调节剂。他们通过控制来调节循环量 钠和水平衡，从而保持细胞外液体体积稳态。已经确定了 盐敏感高血压的发病机理是由肾脏中的钠处理受损引起的，但是 导致肾钠保留率的关键因素仍然不明。 T细胞中T细胞的重要作用 在过去的十年中，已经提出了高血压。但是，没有相关可行的治疗选择有 已经提出了，因为尚未阐明这种T细胞作用的机制。我们 最近确定了肾脏浸润的CD8+ T细胞（CD8T）在增强盐保留率中的新作用。肾脏 浸润的CD8T与远端曲折小管细胞（DCT）相互作用，刺激氯化钠共同存在 DCT中的转运蛋白（NCC），导致血压升高。这些发现使我们假设 CD8T和肾小管细胞之间的相互作用将T细胞介导的肾脏中介导T细胞，这可能 代表肾脏缺陷，有助于盐敏感高血压的发病机理。在提议中 研究，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 管状细胞并确定CD8T的这种肾脏驯化机制如何有助于过多的盐 保留，导致高血压。具体而言，AIM 1将检验我们产生的细胞因子的假设 从激活的CD8TS Prime DCT到表达共同信号分子，从而启动了之间的相互作用 DCT和CD8T； AIM 2将识别介导推定免疫突触的粘附分子 在这两种细胞类型之间。 AIM 3将确定钾通道Kir4.1在CD8T-的关键作用 诱导的NCC和可能在远端肾脏中的其他钠转运蛋白的上调，导致 过度盐分保留率，随之而来的血压升高。我们的初步研究已经确定 每个目标的关键分子。作为主要实验的证明，免疫学中和或遗传 这些分子在小鼠肾脏中的缺失阻止了刺激诱导的NCC上调 肾脏，因此降低了血压。互补的体内和体外研究是在设计中的 这项提出了实现我们目标的建议。我们将在动物中使用特定于肾脏的敲除或敲除方法 确定这项研究中关键分子的确切作用。实现我们的目标将阐明 关于肾脏T细胞的重要分子机制，从而损害了盐和体积 稳态，影响血压。我们建议至少在 部分，通过肾脏中的免疫疾病。此外，本研究中确定的关键分子可能代表 对这种普遍的健康问题的未来免疫疗法的新颖目标。