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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

基本信息

批准号：
10608091
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
项目类别：
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/10608091
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 infiltration T-Cell Activation T-Lymphocyte Testing Time Tubular formation Up-Regulation Water Withdrawal adaptive immunity 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 new therapeutic target novel overexpression pressure prevent programmed cell death ligand 1 public health relevance salt sensitive hypertension therapeutic target therapeutically effective thiazide

项目摘要

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