Axial Flow Effects in Proximal Tubule

近端小管的轴流效应

• 批准号: 6709361
• 负责人: Tong Wang Wang
• 金额: $ 28.91万
• 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/6709361
• 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（由申请方提供）：肾小球肾小管平衡（GTB）是近端小管转运的一个关键方面，其维持Na+、HCO 3-、Cl-和水的重吸收几乎成比例变化，并伴随肾小球滤过（GFR）的变化。 GTB用于防止GFR增加后的肾溶质损失，并且还允许在低GFR时保留足够的远端碘递送，从而限制远端肾单位酸和钾排泄的损害。GFR可调节近端重吸收的机制尚不确定，尽管已经确定肾小管液轴向流的变化本身可诱导Na+转运的成比例变化。我们推测刷状缘微绒毛是传导流速增加信号的传感器，而顶膜上的下游离子交换剂NHE 3是增加Na+、HCO 3-和液体重吸收的关键效应器。最近的近端小管刷状缘内的流体流动的数学模型支持这样的想法，即微绒毛配置非常适合于它们作为近端小管流体流动的机械传感器。本论文的主要工作包括：1）在大鼠和小鼠近端小管中，检测刷状缘微绒毛是否作为机械传感器感知轴向血流; 2）为了检查流速增加引起的近端小管转运的增加是否是由于通过NHE 3增加的跨细胞转运，而不是通过改变改变上皮通透性和增加细胞旁转运的物理因素;和3）利用敲除动物和抑制剂来定义流动依赖性转运的关键胞质介质。 本研究的独特之处在于：（1）在小鼠和基因敲除动物体内和体外微灌注中比较了近端小管的流量依赖性转运;（2）将重吸收通量表示为微绒毛上的流体动力学力和扭矩的函数;（3）开发一个模型来解释流动和重吸收之间的非线性关系，该模型考虑了小管和微绒毛几何形状的变化;（4）在近端小管转运的数学模型中评估转运和渗透性数据。这些研究将提供新的信息GTB的机制和方面的肾液和HCO 3-运输的生理和病理生理条件。