Our mathematical model and experimental data indicated that luminal flow also affects peritubular transporters, as the flow produces only minor changes in cell volume. By using our theory which takes into account the changes of tubular diameter with flow, we were able to resolve the long-standing mystery as to why the GTB demonstrated in vivo did not appear to be present in single-perfused rabbit proximal tubule (vide infra). Our experimental data proved the hypothesis that brush border microvilli serve as the mechanosensors of axial flow along the proximal tubule. We were able to demonstrate that flow-induced changes in Na + and HCO 3 − absorption are torque dependent (bending moment at the apical membrane due to fluid flow). We also developed a theory and an equation that enable us to calculate the changes of torque at the base of the brush border microvilli due to fluid drag forces on their tips. Changes in tight junction permeabilities do not play a role in flow-activated sodium and bicarbonate transport. This perfusion-absorption balance is independent of neuronal and systemic hormonal regulation and requires the intact actin cytoskeleton to transmit the signal of altered axial flow sensed by brush border micro-villi. Flow-stimulated NHE3 and H-ATPase activities both contribute to the increased HCO 3 − absorption by higher flow. In that work, we demonstrated that flow-modulated Na/H-exchanger isoform 3 (NHE3) activity is the basis for flow-dependent proximal tubule Na + reabsorption. We undertook examination of the flow effect on Na and HCO 3 − absorption by isolated tubule perfusion of mouse proximal tubules as the first study. Although many investigators examined the flow effect on the proximal tubule transport, the mechanism and regulation of GTB remained uncertain.
However, it is relatively clear that flow-stimulated K secretion in the collecting tubule, by the mechanism of flow-stimulated MaxiK channel activity, and flow-stimulated Ca 2+ influx play a critical role for the regulation in the collecting tubule. in vivo could not also be demonstrated in vitro in single-perfused rabbit tubules by Burg and Orloff. Historically, one point of difficulty was to determine whether axial flow directly or indirectly regulates tubule transport, specifically, why the GTB convincingly demonstrated by Schnermann et al. This perfusion-absorption balance in the proximal tubule has been termed glomerulotubular balance (GTB). In this review, we summarize our findings of the regulatory mechanism of flow-mediated Na + and HCO 3 − transport in the proximal tubule and review available information about flow sensing and regulatory mechanism of glomerulotubular balance.įlow-modulated salt and water transport in proximal tubules has been recognized for more than four decades. IP3 receptor-mediated intracellular Ca 2+ signaling is critical to transduction of microvillus drag. Dopamine blunts the responsiveness of proximal tubule transporters to changes in luminal flow velocity, while a DA1 antagonist increases flow sensitivity of solute reabsorption.
Secondary messengers that regulate the flow-mediated tubule function have also been delineated. Beyond that, there is evidence that transporter activity within the peritubular membrane is also modulated by luminal flow.
We have demonstrated that alterations in fluid drag impact tubule function by modulating ion transporter availability within the brush border membrane of the proximal tubule. The signal to NHE3 depends upon the integrity of the actin cytoskeleton the signal to the H +-ATPase depends upon microtubules. In the proximal tubule, brush border microvilli are the major flow sensors, which experience changes in hydrodynamic drag and bending moment as luminal flow velocity changes and which transmit the force of altered flow to cytoskeletal structures within the cell. Increased fluid flow stimulates Na + and HCO 3 − absorption in the proximal tubule via stimulation of Na/H-exchanger isoform 3 (NHE3) and H +-ATPase. Since the earliest micropuncture studies of mammalian proximal tubule, it has been recognized that tubular flow is an important regulator of sodium, potassium, and acid-base transport in the kidney. The purpose of this review is to summarize our knowledge and understanding of the physiological importance and the mechanisms underlying flow-activated proximal tubule transport.
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