Axial Flow Effects in Proximal Tubule

近端小管的轴流效应

• 批准号: 6850778
• 负责人: Tong Wang Wang
• 金额: $ 28.85万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2008-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6850778
• 关键词: adenosinetriphosphatase; angiotensin receptor; apical membrane; bicarbonates; brush border membrane; fluid flow; gene targeting; genetically modified animals; glomerular filtration; laboratory mouse; laboratory rat; mathematical model; mechanical pressure; membrane permeability; perfusion; renal tubular transport; saluresis; second messengers; sodium hydrogen exchanger; viscosity

DESCRIPTION (provided by applicant): Glomerulotubular balance (GTB) is a critical aspect of proximal tubule transport, that maintains nearly proportional change in reabsorption of Na+, HCO3-, C1-, and water with variation in glomerular filtration (GFR). GTB acts to prevent renal solute loss following a GFR increase, and also allows preservation of adequate distal isodium delivery in times of low GFR, thus limiting compromise of distal nephron acid and potassium excretion. The mechanisms by which GFR can modulate proximal reabsorption are uncertain, although it is well established that variation in axial flow of tubular fluid can, by itself, induce proportional changes in Na+ transport. We hypothesize that brush border microvilli are the sensors for transducing the signal of increased flow rate, and that the downstream ion exchanger on the apical membrane NHE3 is the key effector for increasing the reabsorption of Na+, HCO3- and fluid. A recent mathematical model of fluid flow within the proximal tubule brush border supports the idea that the microvilli configuration is ideally suited for them to serve as the mechanosensors of proximal tubule fluid flow. In the work proposed, both in vivo and in vitro microperfusion experiments will be conducted with the following three aims: 1) To test whether brush border microvilli act as mechanotransducers that sense axial flow in rat and mouse proximal tubules; 2) To examine whether the increment of proximal tubule transport attributed to enhanced flow rate is due to increasing transcellular transport via NHE3, rather than by changing the physical factors that alter the epithelial permeability and increase paracellular transport; and 3) utilize both knockout animals and inhibitors to define key cytosolic mediators of flow-dependent transport. The unique features of our proposed collaboration are: (1) the comparison of flow-dependent proximal tubule transport, both in vivo and in vitro microperfusion in mice and in knockout animals; (2) the representation of reabsorptive fluxes as a function of hydrodynamic forces and torques on microvilli; (3) the development of a model to explain the non-linear relationship between flow and reabsorption that takes account of changing tubule and microvilli geometry and (4) the assessment of transport and permeability data within a mathematical model of proximal tubule transport. These studies will provide new information on mechanisms of GTB and aspects of renal fluid and HCO3- transport in physiological and pathophysiological conditions.

描述（由申请人提供）：肾小球肾小管平衡（GTB）是近端肾小管转运的一个关键方面，随着肾小球滤过（GFR）的变化，Na+、HCO3-、C1-和水的重吸收几乎保持成比例的变化。 GTB 的作用是防止 GFR 增加后肾溶质丢失，并且还可以在 GFR 较低时保留足够的远端钠输送，从而限制远端肾单位酸和钾排泄的损害。 GFR 调节近端重吸收的机制尚不确定，但已明确肾小管液轴向流量的变化本身可引起 Na+ 转运的比例变化。我们假设刷状缘微绒毛是转导流速增加信号的传感器，顶膜 NHE3 上的下游离子交换器是增加 Na+、HCO3- 和液体重吸收的关键效应器。最近近端小管刷状边界内流体流动的数学模型支持这样的观点：微绒毛结构非常适合它们作为近端小管流体流动的机械传感器。在拟议的工作中，将进行体内和体外微灌注实验，以实现以下三个目的：1）测试刷状缘微绒毛是否充当感知大鼠和小鼠近曲小管中轴向流动的机械传感器； 2) 检查由于流速增加而导致的近曲小管转运的增加是否是由于通过NHE3增加跨细胞转运，而不是通过改变改变上皮通透性和增加旁细胞转运的物理因素； 3）利用基因敲除动物和抑制剂来定义流量依赖性运输的关键胞质介质。 我们提出的合作的独特之处在于：（1）比较小鼠和基因敲除动物体内和体外微灌注的流量依赖性近端小管运输； (2)重吸收通量作为微绒毛上的水动力和扭矩的函数的表示； （3）开发一个模型来解释流量和重吸收之间的非线性关系，考虑到肾小管和微绒毛几何形状的变化，以及（4）在近端肾小管运输的数学模型中评估运输和渗透性数据。这些研究将提供有关 GTB 机制以及生理和病理生理条件下肾液和 HCO3- 转运方面的新信息。