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Axial flow modulates proximal tubule NHE3 and H-ATPase activities by changing microvillus bending moments

¹Department of Cellular and Molecular Physiology, Yale University, New Haven, Connecticut; ²Department of Biomedical Engineering, The City College of New York, City University of New York; and ³Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, New York

Submitted 20 June 2005 ; accepted in final form 24 August 2005

We have previously demonstrated that mouse proximal tubules in vitro respond to changes in luminal flow with proportional changes in Na⁺ absorption (Du Z, Duan Y, Yan Q, Weinstein AM, Weinbaum S, and Wang T. Proc Natl Acad Sci USA 101: 13068–13073, 2004). 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, 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 potential difference (PD). It is found that 1) an increase in 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 HCO₃^– 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 HCO₃^– 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 the proximal tubule is a direct effect of flow-induced torque on brush-border microvilli to regulate luminal cell membrane transporter activity.

kidney proximal tubule; glomerulotubular balance; flow-dependent transport; sodium-hydrogen exchange

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