Axial Flow Effects in Proximal Tubule

近端小管的轴流效应

• 批准号: 7025074
• 负责人: Tong Wang Wang
• 金额: $ 28.23万
• 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/7025074
• 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-小管平衡（GTB）是近端小管运输的一个关键方面，它维持Na+、HCO3-、C1-和水的重吸收与肾小球滤过（GFR）的变化几乎成比例的变化。GTB的作用是防止GFR增加后的肾溶质损失，并在GFR低时保留足够的远端钠输送，从而限制远端肾元酸和钾排泄的损害。GFR调节近端重吸收的机制尚不确定，尽管已经确定管状流体轴向流动的变化本身可以诱导Na+转运的比例变化。我们假设刷状边缘微绒毛是传导流速增加信号的传感器，而顶端膜上的下游离子交换器NHE3是增加Na+、HCO3-和流体重吸收的关键效应因子。最近的一个近端小管刷状边界内流体流动的数学模型支持了微绒毛结构非常适合作为近端小管流体流动的机械传感器的观点。本研究拟开展体内和体外微灌注实验，目的有三个：1)测试刷状边缘微绒毛是否作为大鼠和小鼠近端小管轴向流感知的机械换能器；2)研究流速增加引起的近端小管运输的增加是否是由于通过NHE3的跨细胞运输增加，而不是由于改变了改变上皮通透性和增加细胞旁运输的物理因素；3)利用敲除动物和抑制剂来确定流动依赖转运的关键细胞质介质。