Du Zhaopeng, Duan Yi, Yan QingShang, Weinstein Alan M, Weinbaum Sheldon, Wang Tong
Department of Cellular and Molecular Physiology, Yale University, New Haven, CT 06520-8026, USA.
Proc Natl Acad Sci U S A. 2004 Aug 31;101(35):13068-73. doi: 10.1073/pnas.0405179101. Epub 2004 Aug 19.
Normal variations in glomerular filtration induce proportional changes in proximal tubule Na+ reabsorption. This "glomerulotubular balance" derives from flow dependence of Na+ uptake across luminal cell membranes; however, the underlying physical mechanism is unknown. Our hypothesis is that flow-dependent reabsorption is an autoregulatory mechanism that is independent of neural and hormonal systems. It is signaled by the hydrodynamic torque (bending moment) on epithelial microvilli. Such signals need to be transmitted to the terminal web to modulate Na+-H+-exchange activity. To investigate this hypothesis, we examined Na+ transport and tubular diameter in response to different flow rates during the microperfusion of isolated S2 proximal tubules from mouse kidneys. The data were analyzed by using a mathematical model to estimate the microvillous torque as function of flow. In this model, increases in luminal diameter have the effect of blunting the impact of flow velocity on microvillous shear stress and, thus, microvillous torque. We found that variations in microvillous torque produce nearly identical fractional changes in Na+ reabsorption. Furthermore, the flow-dependent Na+ transport is increased by increasing luminal fluid viscosity, diminished in Na+-H+ exchanger isoform 3 knockout mice, and abolished by nontoxic disruption of the actin cytoskeleton. These data support our hypothesis that the "brush-border" microvilli serve a mechanosensory function in which fluid dynamic torque is transmitted to the actin cytoskeleton and modulates Na+ absorption in kidney proximal tubules.
肾小球滤过的正常变化会引起近端小管钠重吸收的相应变化。这种“球管平衡”源于跨管腔细胞膜钠摄取的流量依赖性；然而，其潜在的物理机制尚不清楚。我们的假设是，流量依赖性重吸收是一种独立于神经和激素系统的自身调节机制。它由上皮微绒毛上的流体动力扭矩（弯矩）发出信号。此类信号需要传递至终末网以调节钠氢交换活性。为了验证这一假设，我们在对分离的小鼠肾脏S2近端小管进行微量灌注期间，检测了不同流速下的钠转运和管径。通过使用数学模型分析数据，以估计作为流量函数的微绒毛扭矩。在该模型中，管腔直径增加会减弱流速对微绒毛剪切应力以及微绒毛扭矩的影响。我们发现，微绒毛扭矩的变化会使钠重吸收产生几乎相同的分数变化。此外，增加管腔液粘度可增强流量依赖性钠转运，钠氢交换体同工型3基因敲除小鼠中的该转运则减弱，而肌动蛋白细胞骨架的无毒破坏可消除该转运。这些数据支持了我们的假设，即“刷状缘”微绒毛具有机械感觉功能，其中流体动力扭矩传递至肌动蛋白细胞骨架并调节肾近端小管中的钠吸收。
