REGULATION OF RENAL K+ EXCRETION BY GUT FACTOR

肠道因子对肾 K 排泄的调节

• 批准号: 7528744
• 负责人: JANG H. YOUN
• 金额: $ 24.45万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7528744
• 关键词: Acute; Aldosterone; Beds; Buffers; Cardiovascular Diseases; Cardiovascular system; Condition; Event; Excretory function; Extracellular Fluid; Glucose; Grant; Hepatic; Homeostasis; Hypertension; Infusion procedures; Insulin; Intake; KCNJ1 gene; Kidney; Lead; Life; Liver; Maintenance; Mediating; Molecular; Neural Pathways; Nutrient; Plasma; Portal vein structure; Public Health; Rattus; Reflex action; Regulation; Route; Skeletal Muscle; Stomach; Stroke; Structure of jugular vein; Techniques; Testing; Tissues; collecting tubule structure; extracellular; follow-up; hyperkalemia; neuromuscular function; neuroregulation; novel; proctolin; research study; sensor; uptake

DESCRIPTION (provided by applicant): K+ homeostasis is critical for normal cardiovascular and neuromuscular function, and disturbances in K+ homeostasis (e.g., hyperkalemia) can lead to life-threatening cardiovascular events. Our long-term objective is to fully understand K+ homeostatic mechanisms. Extracellular K+ homeostasis is maintained by renal and extrarenal mechanisms. The kidneys have a remarkable capacity to regulate K+ excretion to match K+ intake. We recently studied the sensing of K+ intake by infusing K+ into rats via various routes (i.e., jugular vein, hepatic portal vein, and stomach). The results demonstrated that, when K+ enters the stomach together with a meal, there was a marked increase in plasma K+ clearance, suggesting the existence of a gut factor that increases plasma K+ clearance during dietary K+ intake. Additionally, there was an apparent increase in renal efficiency of K+ excretion, suggesting that there is a gastric-renal K+ axis. These provocative findings are limited in that plasma K+ level was not the same in the different K+ infusion groups, and, thus, renal efficiency of K+ excretion was assessed at different plasma K+ levels. In addition, we did not assess extrarenal cellular K+ uptake. We developed the K+ clamp technique for quantification of both renal K+ excretion and cellular K+ uptake at matched K+ levels under various conditions in rats. We propose to combine the K+ clamp technique with the K+ infusion experiments to follow up on our novel findings: we will test the hypothesis that there is a gut factor and identify the underlying mechanisms. Aim 1. Test the hypothesis that there is a gut factor that enhances both renal and extrarenal K+ handling during dietary K+ intake. Using the K+ clamp technique, we will attempt to establish that a gut factor is activated when K+ enters the stomach together with a meal and that it stimulates not only renal K+ excretion but also extrarenal cellular K+ uptake. We will also test whether the effect on renal K+ excretion is mediated by ROMK activation in the kidney. Aim 2. Test the hypothesis that the gut factor is activated only in the presence of meal nutrients, involving secretion of humoral factors, but not neural regulation. We will test whether the gut factor is activated by concurrent infusion of K+ and glucose into the gut and whether its effect on renal K+ excretion is mediated by a humoral factor (known or unknown) or an efferent neural pathway to the kidneys. This project will potentially establish the existence of an important, previously unknown factor, i.e., gut factor, in the maintenance of K+ homeostasis, which could be identified and studied at cellular or molecular levels by a subsequent R01 grant. PUBLIC HEALTH RELEVANCE This project will potentially establish the existence of an important, previously unknown factor (i.e., gut factor) that is activated for K+ homeostasis during dietary K+ intake. If a novel gut factor is subsequently identified, it would greatly enhance our understanding of K+ homeostatic mechanisms. In addition, there is an intriguing possibility that such a factor mediates some of the beneficial effects of increased dietary K+ intake on hypertension, stroke, and/or cardiovascular disease.

描述（由申请人提供）：K+稳态对于正常心血管和神经肌肉功能至关重要，K+稳态紊乱（例如高钾血症）可能导致危及生命的心血管事件。我们的长期目标是充分了解 K+ 稳态机制。细胞外 K+ 稳态由肾脏和肾外机制维持。肾脏具有调节 K+ 排泄以匹配 K+ 摄入量的卓越能力。我们最近通过不同途径（即颈静脉、肝门静脉和胃）将 K+ 注入大鼠体内，研究了 K+ 摄入量的感知。结果表明，当 K+ 与膳食一起进入胃时，血浆 K+ 清除率显着增加，这表明在膳食 K+ 摄入过程中存在增加血浆 K+ 清除率的肠道因子。此外，肾脏 K+ 排泄效率明显增加，表明存在胃-肾 K+ 轴。这些令人兴奋的发现是有限的，因为不同K+输注组中的血浆K+水平并不相同，因此，在不同血浆K+水平下评估K+排泄的肾效率。另外，我们没有评估 肾外细胞 K+ 摄取。我们开发了 K+ 钳夹技术，用于定量肾 K+ 大鼠在不同条件下匹配 K+ 水平的排泄和细胞 K+ 吸收。我们建议将 K+ 钳技术与 K+ 输注实验相结合，以跟进我们的新发现：我们将检验存在肠道因子的假设并确定潜在机制。目标 1. 检验以下假设：在膳食 K+ 摄入过程中，存在一种肠道因子可以增强肾脏和肾外 K+ 的处理能力。使用 K+ 钳技术，我们将尝试确定当 K+ 与膳食一起进入胃时，肠道因子被激活，并且它不仅刺激肾脏 K+ 排泄，而且刺激肾外细胞 K+ 摄取。我们还将测试对肾脏 K+ 排泄的影响是否是由肾脏中 ROMK 激活介导的。目标 2. 检验以下假设：肠道因子仅在膳食营养素存在的情况下才会被激活，涉及体液因子的分泌，但不涉及神经调节。我们将测试肠道因子是否通过同时向肠道输注 K+ 和葡萄糖而被激活，以及其对肾脏 K+ 排泄的影响是否由体液因子（已知或未知）或通往肾脏的传出神经通路介导。该项目将有可能确定一种重要的、以前未知的因素（即肠道因素）在维持 K+ 稳态中的存在，可以通过随后的 R01 资助在细胞或分子水平上进行识别和研究。公共健康相关性 该项目将有可能确定一种重要的、以前未知的因子（即肠道因子）的存在，该因子在膳食 K+ 摄入期间被激活以实现 K+ 稳态。如果随后发现一种新的肠道因子，将极大地增强我们对 K+ 稳态机制的理解。此外，还有一种有趣的可能性是，这种因素可能会介导增加膳食 K+ 摄入量对高血压、中风和/或心血管疾病的一些有益影响。