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Role of CNT3 in the transepithelial flux of nucleosides and nucleoside‐derived drugs
Author(s) -
ErrastiMurugarren Ekaitz,
PastorAnglada Marçal,
Casado F. Javier
Publication year - 2007
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2007.130138
Subject(s) - nucleoside , apical membrane , transporter , flux (metallurgy) , biochemistry , chemistry , intracellular , endogeny , nucleoside transporter , symporter , cell culture , microbiology and biotechnology , epithelial polarity , membrane transport , cell , biology , membrane , genetics , organic chemistry , gene
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 orthologue 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.