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Adenosine inhibits the transfected Na⁺-H⁺ exchanger NHE3 in Xenopus laevis renal epithelial cells (A6/C1)

Francesca Di Sole *², Valeria Casavola ¹, Luca Mastroberardino ², François Verrey ², Orson W. Moe ³, Gerhard Burckhardt *, Heini Murer ² and Corinna Helmle-Kolb *²

Adenosine influences the vectorial transport of Na⁺ and HCO₃^- across kidney epithelial cells. However, its action on effector proteins, such as the Na⁺-H⁺ exchanger NHE3, an epithelial brush border isoform of the Na⁺-H⁺ exchanger (NHE) gene family, is not yet defined.

The present study was conducted in Xenopus laevis distal nephron A6 epithelia which express both an apical adenosine receptor of the A₁ type (coupled to protein kinase C (PKC)) and a basolateral receptor of the A₂ type (coupled to protein kinase A (PKA)). The untransfected A6 cell line expresses a single NHE type (XNHE) which is restricted to the basolateral membrane and which is activated by PKA.

A6 cell lines were generated which express exogenous rat NHE3. Measurements of side-specific pH_i recovery from acid loads in the presence of HOE694 (an inhibitor with differential potency towards individual NHE isoforms) detected an apical resistant Na⁺-H⁺ exchange only in transfected cell lines. The sensitivity of the basolateral NHE to HOE694 was unchanged, suggesting that exogenous NHE3 was restricted to the apical membrane.

Stimulation of the apical A₁ receptor with N ⁶-cyclopentyladenosine (CPA) inhibited both apical NHE3 and basolateral XNHE. These effects were mimicked by the addition of the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) and partially prevented by the PKC inhibitor calphostin C which also blocked the effect of PMA.

Stimulation of the basolateral A₂ receptor with CPA inhibited apical NHE3 and stimulated basolateral XNHE. These effects were mimicked by 8-bromo-cAMP and partially prevented by the PKA inhibitor H89 which entirely blocked the effect of 8-bromo-cAMP.

In conclusion, CPA inhibits rat NHE3 expressed apically in A6 epithelia via both the apical PKC-coupled A₁ and the basolateral PKA-coupled A₂ adenosine receptors.

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