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An apical K⁺-dependent HCO₃^– transport pathway opposes transepithelial HCO₃^– absorption in rat medullary thick ascending limb

Departments of Medicine and Physiology and Biophysics, University of Texas Medical Branch, Galveston, Texas 77555

Submitted 7 November 2003 ; accepted in final form 8 March 2004

Absorption of HCO₃^– in the medullary thick ascending limb (MTAL) is mediated by apical membrane Na⁺/H⁺ exchange. The identity and function of other apical acid-base transporters in this segment have not been defined. The present study was designed to examine apical membrane HCO₃^–/OH^–/H⁺ transport pathways in the rat MTAL and to determine their role in transepithelial HCO₃^– absorption. MTALs were perfused in vitro in Na⁺- and Cl^–-free solutions containing 25 mM HCO₃^–, 5% CO₂. Lumen addition of either 120 mM Cl^– or 50 mM Na⁺ (50 µM EIPA present) had no effect on intracellular pH (pH_i). Lumen Cl^– addition also had no effect on pH_i in the presence of 145 mM Na⁺ or in the nominal absence of HCO₃^–/CO₂. Thus there was no evidence for apical Cl^–/HCO₃^– (OH^–) exchange, Na⁺-dependent Cl^–/HCO₃^– exchange, or Na⁺-HCO₃^– cotransport. In contrast, in tubules studied in Na⁺- and Cl^–-free solutions containing 25 mM HCO₃^–, 5% CO₂ and 120 mM K⁺, removal of luminal K⁺ induced a rapid and pronounced decrease in pH_i (pH_i = 0.56 ± 0.06 pH U). pH_i recovered following lumen K⁺ readdition. The initial rate of net base efflux induced by lumen K⁺ removal was decreased 85% at the same pH_i in the nominal absence of HCO₃^–/CO₂, indicating a dependence on HCO₃^–/CO₂ and arguing against apical K⁺/H⁺ exchange. A combination of the apical K⁺ channel blockers quinidine (0.1 mM) and glybenclamide (0.25 mM) had no effect on the lumen K⁺-induced pH_i changes, arguing against electrically coupled K⁺ and HCO₃^– conductances. The effect of lumen K⁺ on pH_i was inhibited by 1 mM H₂DIDS. In addition, lumen addition of DIDS increased transepithelial HCO₃^– absorption from 10.7 ± 0.7 to 14.9 ± 0.7 pmol·min^–1·mm^–1 (P < 0.001) and increased pH_i slightly in MTAL studied in physiological solutions (25 mM HCO₃^– and 4 mM K⁺). Lumen DIDS stimulated HCO₃^– absorption in the absence and presence of furosemide. These results are consistent with an apical membrane K⁺-dependent HCO₃^– transport pathway that mediates coupled transfer of K⁺ and HCO₃^– from cell to lumen in the MTAL. This mechanism, possibly an apical K⁺-HCO₃^– cotransporter, functions in parallel with apical Na⁺/H⁺ exchange and opposes transepithelial HCO₃^– absorption.

K⁺-HCO₃^– cotransport; Na⁺/H⁺ exchange; Cl^–/HCO₃^– exchange; acid-base transport; KCC

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