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1 Department of Cellular and Molecular Physiology, Yale University, New Haven, CT, USA
2 Department of Biomedical Engineering, City College of New York, New York, NY, USA
3 Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, NY, USA
* To whom correspondence should be addressed. E-mail: tong.wang{at}yale.edu.
We have previously demonstrated that mouse proximal tubules in vitro respond to changes in luminal flow with proportional changes in Na+ absorption (11). It was hypothesized that brush border microvilli function as a sensor to detect and amplify luminal hydrodynamic forces and transmit them to the actin cytoskeleton. In the present study we examine whether 1) flow-dependent HCO3- transport is proportional to flow-dependent variations in microvillous torque (bending moment); 2) both luminal membrane Na+/H+-exchange (NHE3), and H+-ATPase activity are modulated by axial flow, and 3) paracellular permeabilities contribute to the flux perturbations. HCO3- absorption is examined by microperfusion of mouse S2 proximal tubules in vitro, with varying perfusion rates, and in the presence of the Na/H-exchange inhibitor, EIPA (ethylisopropylamiloride), the H-ATPase inhibitor, bafilomycin, and the actin cytoskeleton inhibitor, Cytochalasin D. Paracellular permeability changes are assessed with measurements of epithelial HCO3- permeability and transepithelial PD. It is found that 1) increase of perfusion rate enhances HCO3- absorption and microvillous torque, and the fractional changes of each are nearly identical; 2) inhibition of NHE3 by EIPA, or H-ATPase by bafilomycin, produced only partial inhibition of flow-stimulated bicarbonate transport; 3) disruption of the actin cytoskeleton by cytochalasin D blocked the increment of bicarbonate absorption by high flow; and 4) HCO3- permeability, and transepithelial PD are not modulated by flow. We conclude that flow-dependent modulation of proximal tubule bicarbonate reabsorption is due to changes in both NHE3 and H-ATPase activity within the luminal cell membrane and this requires an intact actin cytoskeleton. Paracellular permeability changes do not contribute to this flow-dependence. Perfusion-absorption balance in proximal tubule is a direct effect of flow-induced torque on brush border microvilli to regulate luminal cell membrane transporter activity.
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