MECHANISMS OF PRESSURE NATRIURESIS IN PROXIMAL TUBULES

近端肾小管压力尿钠机制

• 批准号: 6141037
• 负责人: Kay-Pong Daniel Yip
• 金额: $ 18.42万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2001-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6141037
• 关键词: acidity /alkalinity; adenosinetriphosphatase; apical membrane; blood pressure; brush border membrane; confocal scanning microscopy; fluorescence microscopy; fluorescent dye /probe; hypertension; immunocytochemistry; intracellular transport; kidney imaging /visualization; membrane transport proteins; optics; protein transport; renal tubular transport; saluresis; spontaneous hypertensive rat; western blottings

The long-term goal of this proposed study is to identify the mechanisms of pressure natriuresis in proximal tubules and its relationship with hypertension. Pressure natriuresis is an increase of Na+ excretion caused by an increase in arterial pressure in the absence of changes in renal blood flow and glomerular filtration rate, which enables the kidney to use arterial pressure as an input signal to regulate the extracellular fluid volume. However, pressure natriuresis is set to higher blood pressure levels in all form of hypertension. An acute blood pressure increase inhibits fluid and NaC1 reabsorption in rate proximal tubules, and this response is associated with a rapid internalization of apical Na+/H+ exchangers from the brush border into subapical intracellular stores. This response probably contributes a large fraction of the natriuresis and diuresis that occurs when blood pressure rises. The objective of this proposal is to test whether trafficking of apical Na+/H+ exchangers induced by acute hypertension inhibits apical Na+/H+ exchangers activity and fluid reabsorption in proximal tubules in vivo, to delineate the mechanisms of this protein-trafficking process, and to probe the possible changers in hypertension. The rate of change in intracellular pH (dpHi/dt) upon luminal removal of Na+ in perfused proximal tubules in situ is used as a index of the activities of Na+/H+ exchangers. The intracellular pH is monitored with a dual pulse-lasers system designed to measure intracellular pH with minimum bleaching of BCECF, a pH sensitive fluorescence dye commonly-used to measure intracellular pH. Proximal fluid reabsorption is measured continuously with a non-obstructing optical technique developed in this laboratory. Confocal fluorescent microscopy and immunohistochemistry are employed to investigate the protein trafficking process triggered by acute hypertension. Spontaneously hypertensive rates (SHR) are used as an animal model of chronic hypertension. This proposed study will provide new information to understand the cellular mechanism of pressure natriuresis in proximal tubules, and the altered relationship between renal perfusion pressure and urinary Na+ excretion in hypertension. These may lead to a better understanding of the role of the kidney in hypertension, and possibly to new treatment principles.

这项研究的长期目标是确定 近曲小管压力尿钠的机制及其 与高血压的关系。 压力尿钠增加 动脉压升高导致 Na+ 排泄 肾血流量和肾小球滤过没有变化 率，使肾脏能够使用动脉压作为输入 调节细胞外液体积的信号。 然而，压力 尿钠排泄会导致各种形式的血压升高 高血压。 急性血压升高会抑制液体和 近端小管中的 NaC1 重吸收率，这种反应是 与顶端 Na+/H+ 交换器的快速内化相关 从刷状缘进入根尖下细胞内商店。 这 反应可能贡献了尿钠排泄的很大一部分 血压升高时发生利尿。 的目标 该提案是为了测试顶端Na+/H+是否被贩运 急性高血压诱导的交换器抑制心尖Na+/H+ 近曲小管的交换活性和液体重吸收 体内，描绘这种蛋白质运输的机制 过程，并探讨高血压可能的变化因素。 这 管腔去除后细胞内 pH 值的变化率 (dpHi/dt) 原位灌注近端小管中的 Na+ 用作 Na+/H+交换剂的活性。 监测细胞内 pH 值 配备双脉冲激光系统，旨在测量细胞内 pH 值 对 pH 敏感荧光染料 BCECF 的漂白作用最小化 常用于测量细胞内的pH值。 近端液体 使用无阻碍光学装置连续测量重吸收 该实验室开发的技术。 共焦荧光 显微镜和免疫组织化学用于研究 急性高血压引发的蛋白质运输过程。 自发性高血压率（SHR）被用作以下疾病的动物模型： 慢性高血压。 这项拟议的研究将提供新的 了解压力的细胞机制的信息 近曲小管的尿钠排泄，以及之间关系的改变 高血压患者的肾灌注压和尿Na+排泄。 这些可能有助于更好地了解肾脏在疾病中的作用。 高血压，并可能需要新的治疗原则。