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1 Experimental Oncology, Cross Cancer Institute, Edmonton, Canada; Oncology, University of Alberta, Edmonton, Canada
2 Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada
3 Institute of Membrane and Systems Biology, University of Leeds, United Kingdom
4 Physiology, University of Alberta, Edmonton, Canada
5 Medical Oncology, Cross Cancer Institute, Edmonton, Canada; Oncology, University of Alberta, Edmonton, Canada
6 Biochemistry, University of Alberta, Edmonton, Canada; Oncology, University of Alberta, Edmonton, Canada; Experimental Oncology, Cross Cancer Institute, Edmonton, Canada
* To whom correspondence should be addressed. E-mail: carol.cass{at}cancerboard.ab.ca.
Nucleoside transporters in kidney mediate renal re-absorption and secretion of nucleosides. Using RT-PCR, we demonstrated mRNAs encoding hENT1, hENT2, hCNT1, hCNT2 and hCNT3 in both cortex and medulla. Immunoblotting with crude membrane preparations revealed abundant hENT1 and hCNT3 in both cortex and medulla, and little, if any, hENT2, hCNT1 or hCNT2, indicating that the latter were either absent or below limits of detection of immunoassays. hENT1 immunostaining was observed on apical surfaces of proximal tubules and on both apical and basal surfaces of thick ascending loops of Henle and collecting ducts. Prominent hCNT3 immunostaining was observed on apical surfaces of proximal tubules, and thick ascending loops of Henle in addition to some cytoplasmic staining. Equilibrium binding of [3H]-nitrobenzylmercaptopurine ribonucleoside (NBMPR), a high-affinity inhibitor of hENT1, to brush border membrane vesicles from cortex confirmed the presence of hENT1 on apical surfaces of proximal tubules. Uptake of [3H]uridine by polarized renal proximal tubule cells exhibited a sodium-dependent component that was inhibited by thymidine and inosine as well as a sodium-independent component that was partially inhibited by NBMPR and completely inhibited by dilazep, indicating high levels of hENT1 and hCNT3 and low levels of hENT2 activities. The presence of (i) transcripts for hENT1/2 and hCNT1/2/3 and the hENT1 and hCNT3 proteins in human kidneys and (ii) hENT1, hENT2 and hCNT3 activities in cultured proximal tubule cells suggest involvement of hENT1, hCNT3 and possibly also hENT2 in renal handling of nucleosides and nucleoside drugs.
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