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Activation of the apical Na⁺/H⁺ exchanger NHE3 by formate: a basis of enhanced fluid and electrolyte reabsorption by formate in the kidney

¹Department of Medicine, University of Cincinnati, Cincinnati 45267; ²Veterans Affairs Medical Center, Cincinnati, Ohio 45220; and ³Department of Physiology, Weill Medical College of Cornell University, New York, New York 10021

Submitted 11 November 2003 ; accepted in final form 8 April 2004

ABSTRACT

Formate stimulates sodium chloride and fluid reabsorption in kidney proximal tubule; however, the exact cellular mechanism of this effect remains unknown. We hypothesized that the primary target of formate is the apical Na⁺/H⁺ exchanger. Here, we demonstrate that formate directly enhances the apical Na⁺/H⁺ exchanger (NHE3) activity in mouse kidney proximal tubule. In the absence of CO₂/HCO₃^–, addition of formate (500 µM) to the bath and lumen of microperfused mouse kidney proximal tubule caused significant intracellular alkalinization, with intracellular pH (pH_i) increasing from baseline levels 7.17 ± 0.01 to 7.55 ± 0.01 (P < 0.001, n = 14), with a pH of 0.38 ± 0.02. Removal of luminal chloride did not block cell pH alkalinization by formate (baseline pH of 7.26 ± 0.01 to 7.53 ± 0.01 with formate, P < 0.001, n = 10), indicating that the apical Cl^–/OH^– exchanger was not the primary mediator of the effect of formate on cell pH. However, removal of sodium from the lumen or addition of EIPA completely prevented cell pH alkalinization. Addition of formate to the lumen and bath in the outer medullary collecting duct, which does not express any apical Na⁺/H⁺ exchanger, did not cause any cell pH alkalinization. At lower concentrations (50 µM), formate caused significant pH_i alkalinization in proximal tubule cells, with pH_i increasing from baseline levels 7.15 ± 0.02 to 7.36 ± 0.02 (P < 0.02, n = 11). Acetate, at 50 µM, had no effect on pH_i. Formate’s effect was observed both in the absence and presence of CO₂/HCO₃^– in the media. We conclude that formate stimulates the apical Na⁺/H⁺ exchanger NHE3 in the kidney proximal tubule. We propose that formate stimulation of chloride reabsorption in the proximal tubule is indirect and is secondary to the activation of apical Na⁺/H⁺ exchanger NHE3, which then leads to the stimulation of the apical chloride/base exchanger.

SLC26A6; chloride absorption; sodium absorption; anion exchange

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