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）：肾小球平衡（GTB）是近端小管转运的关键方面，它在Na+，HCO3-，C1-，C1-，C1-和水的重新吸收和肾小球过滤（GFR）变化时保持了几乎比例的变化。 GTB的作用是防止GFR增加后肾脏溶质损失，并且还可以在低GFR时保存足够的远端异端递送，从而限制了远端肾脏酸和排泄钾的损害。 GFR可以调节近端重吸附的机制尚不确定，尽管已经很好地确定，管状流体的轴向流动的变化本身可以引起Na+转运的比例变化。我们假设刷子边界微绒毛是传输流量增加信号的传感器，并且顶部膜NHE3上的下游离子交换器是增加Na+，HCO3-和流体重新吸收的关键效应。近端小管刷边框中流体流动流的最新数学模型支持了这样的观念：微绒毛构型非常适合它们作为近端小管流体流动的机械传感器。在提出的工作中，将使用以下三个目的进行体内和体外微灌注实验：1）测试刷子微绒毛是否充当机械转换器，这些机械转换器是否会在大鼠和小鼠近端小管中感知轴向流动； 2）检查近端小管转运的增量是否归因于流量增强，这是由于通过NHE3增加了跨细胞运输，而不是通过改变改变上皮渗透性和增加副细胞运输的物理因素； 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。 我们提出的合作的独特特征是：（1）在小鼠和敲除动物中的体内和体外微灌注的流动依赖性近端小管转运的比较； （2）在微绒毛上的流动力和扭矩的函数的函数； （3）模型的开发解释了流动与重吸收之间的非线性关系，该模型考虑了改变小管和微绒毛几何形状，以及（4）评估近端小管传输数学模型中的传输和渗透率数据。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脏液和HCO3-转运方面的新信息。