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First published online on April 5, 2007.
 Copyright © 2007 by The Physiological Society
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jphysiol.2007.130138v1
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Ekaitz Errasti-Murugarren
Marçal Pastor-Anglada
Fco Javier Casado
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Received February 8, 2007
Revised March 26, 2007
Accepted after revision April 2, 2007

ROLE OF CNT3 IN THE TRANSEPITHELIAL FLUX OF NUCLEOSIDES AND NUCLEOSIDE-DERIVED DRUGS

Ekaitz Errasti-Murugarren1, Marçal Pastor-Anglada2, and Fco Javier Casado2*

1 University of Barcelona
2 Universitat de Barcelona

* To whom correspondence should be addressed. E-mail: fcasado{at}ub.edu.

We examined the role of the concentrative nucleoside transporter CNT3 in the establishment of a transepithelial flux of natural nucleosides and their pharmacologically active derivatives in renal epithelial cell lines. Murine PCT cells grown on a transwell dish showed endogenous CNT3 activity at their apical membrane that was responsible for the sodium-dependent transepithelial flux of both purine and pyrimidine nucleosides. hCNT3 was also identified in human kidney and its role in the transport of nucleosides was tested. To this end, MDCK cells, lacking endogenous CNT3 activity, were genetically engineered to express the human ortholog of CNT3 (hCNT3-MDCK cells). In these cells, hCNT3 was inserted into the apical membrane, thus generating, as for PCT cells, a transepithelial flux of both nucleosides and nucleoside-derived drugs. Apical-to- basolateral transepithelial flux was present in all cells expressing a functional CNT3 transporter and was significantly higher than that found either in PCT cells in absence of sodium or in mock-transfected MDCK cells. Nevertheless in all cases a significant amount of the transported nucleoside was retained and transformed inside cells. However release to the opposite compartment was CNT3-dependent, not only in terms of absolute flux (much higher when an apical CNT3 transporter was active) but also regarding metabolic transformations of the apically absorbed nucleosides. These results underline a critical role of CNT3 in the renal reabsorption of nucleosides and their derivatives as well as in their intracellular metabolism.


Key words: Adenosine • Epithelial cell • Membrane transport




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