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Isolation of Primary Human Proximal Tubule Epithelial Cells and Their Use in Creating a Microphysiological Model of the Renal Proximal Tubule
Published on: May 9, 2025
725
Flow-activated proximal tubule function underlies glomerulotubular balance
Zhaopeng Du1, Yi Duan1,2, QingShang Yan1
1Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT.
The Kitasato Medical Journal
|May 21, 2019
Summary
Fluid flow in kidney proximal tubules directly impacts salt and water absorption. Higher flow rates stimulate transporters like NHE3, with microvilli acting as crucial flow sensors. This process is independent of hormonal control.
Area of Science:
- Nephrology
- Renal Physiology
- Cellular Biology
Background:
- Flow-modulated salt and water transport in proximal tubules is a long-standing observation.
- Previous understanding lacked detailed cellular mechanisms for flow-dependent transport.
- Neuronal and systemic hormonal regulation were considered primary control factors.
Purpose of the Study:
- To elucidate the cellular mechanisms underlying flow-modulated transport in mouse proximal tubules.
- To investigate the role of fluid shear stress and microvilli in regulating tubule absorption.
- To determine the signaling pathways involved in flow-induced transport changes.
Main Methods:
- Isolated perfused mouse proximal tubule preparation.
- Measurement of sodium (Na+) and bicarbonate (HCO3-) absorption rates.
- Analysis of Na+/H+-exchanger isoform 3 (NHE3) trafficking and exocytosis.
- Experimental manipulation of fluid shear stress and microvillar torque.
- Investigation of intracellular calcium (Ca2+) signaling pathways.
- Modeling calculations to assess transporter density and cell volume changes.
Main Results:
- Perfusion-absorption balance in isolated tubules is independent of systemic control.
- Increased axial flow rates stimulate Na+ and HCO3- absorption via enhanced transporter activity (Na+/H+-transporter, H-ATPase, NHE3).
- Fluid shear stress promotes NHE3 exocytosis and apical membrane trafficking.
- Proximal tubule microvilli act as flow sensors, with absorption changes linked to microvillar torque.
- An intact actin cytoskeleton is essential for signal transduction from microvilli.
- Dopamine blockers enhance tubule sensitivity to torque; IP3 receptor-mediated Ca2+ signaling is critical.
- Flow-dependent transport occurs without significant changes in tubule cell volume.
Conclusions:
- Proximal tubule transport is directly modulated by luminal flow, independent of systemic regulation.
- Microvillar structure and function, coupled with intracellular signaling, are key to sensing and responding to flow.
- The findings reveal novel cellular mechanisms for regulating renal salt and water reabsorption.
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