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+稳态对于正常的心血管和神经肌肉功能至关重要，K+稳态的紊乱（例如，高钾血症）可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+稳态由肾和肾外机制维持。肾脏具有调节K+排泄以匹配K+摄入的显著能力。我们最近研究了通过各种途径（即，颈静脉、肝门静脉和胃）。结果表明，当K+与膳食一起进入胃时，血浆K+清除率显著增加，表明存在肠道因子，其在膳食K+摄入期间增加血浆K+清除率。此外，肾脏K+排泄效率明显增加，表明存在胃-肾K+轴。这些挑衅性的发现是有限的，因为血浆K+水平在不同的K+输注组中是不相同的，因此，在不同的血浆K+水平下评估了K+排泄的肾效率。此外，我们没有评估 肾外细胞K+摄取。我们开发了K+钳夹技术，用于定量测定肾脏K+ 在各种条件下，大鼠在匹配的K+水平下的排泄和细胞K+摄取。我们建议联合收割机的K+钳技术与K+输液实验，以跟进我们的新发现：我们将测试的假设，有一个肠道因素，并确定潜在的机制。目标1.检验以下假设：在膳食K+摄入过程中，存在增强肾和肾外K+处理的肠道因素。利用K+钳夹技术，我们将试图确定当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+排泄的影响是否由肾脏中的ROMK激活介导。目标2.检验假设，即肠道因子仅在膳食营养素存在时被激活，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被K+和葡萄糖同时输注到肠道中激活，以及其对肾脏K+排泄的影响是否由体液因子（已知或未知）或肾脏的传出神经通路介导。该项目将可能确定一个重要的、以前未知的因素的存在，即，肠因子，在维持K+稳态，这可能是确定和研究在细胞或分子水平的后续R 01补助金。公共卫生相关性本项目将潜在地确定存在一个重要的、以前未知的因素（即，肠因子），其在膳食K+摄入期间被激活用于K+稳态。如果一个新的肠道因子随后被确定，这将大大提高我们的K+稳态机制的理解。此外，有一个有趣的可能性，这样一个因素介导的一些有益的影响，增加饮食中的K+摄入量对高血压，中风，和/或心血管疾病。