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Characterization of Monocarboxylate Transport in Human Kidney HK-2 Cells

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Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Amherst, New York 14260, and Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York 14263
Cite this: Mol. Pharm. 2006, 3, 6, 675–685
Publication Date (Web):October 12, 2006
https://doi.org/10.1021/mp060037b
Copyright © 2006 American Chemical Society
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    Abstract

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    The objectives of this study were to characterize the expression and function of monocarboxylate transporters (MCTs) in human kidney HK-2 cells and to compare the expression of MCTs in HK-2 cells to that found in human kidney. mRNA and protein expression of MCTs were determined by RT-PCR and Western analyses, respectively, while immunofluorescence staining was used to determine the membrane localization of MCT1. The driving force, transport kinetics, and inhibition of two MCT substrates, d-lactate and butyrate, were characterized in HK-2 cells. mRNA of MCT1, -2, -3, -4 isoforms were present in HK-2 cells and in human kidney cortex. MCT1 was present predominantly on the basal membranes of HK-2 cells. The cellular uptake of d-lactate and butyrate exhibited pH- and concentration-dependence (d-lactate, Km of 26.5 ± 2.2 mM and Vmax of 72.0 ± 14.5 nmol mg-1 min-1; butyrate, Km of 0.8 ± 0.3 mM, Vmax of 29.3 ± 2.5 nmol mg-1 min-1, and a diffusional clearance of 2.1 μL mg-1 min-1). The uptake of d-lactate and butyrate by HK-2 cells was inhibited by MCT analogues and the classical MCT inhibitors α-cyano-4-hydroxycinnamate, pCMB, and phloretin. The uptake of d-lactate and butyrate by HK-2 cells significantly decreased after transfection with small-interference RNA for MCT1. In summary, MCTs were present in both HK-2 cells and human kidney cortex, and HK-2 cells exhibited polarized MCT expression and pH-dependent transport of d-lactate and butyrate. Our results also support the usefulness of HK-2 cells as an in vitro model for studying monocarboxylate transport in renal proximal tubule cells.

    Keywords: Monocarboxylate transporter (MCT); HK-2 cells; RNA interference; cellular transport

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    †

     State University of New York.

    ‡

     Present address:  Novartis Institutes for BioMedical Research, 250 Mass St., 3C-341-04, Cambridge, MA 02139.

    §

     Roswell Park Cancer Institute.

    ‖

     Present address:  Cognigen Corporation, 395 Youngs Road, Williamsville, NY 14221.

    *

     Author to whom correspondence should be addressed. Mailing address:  Department of Pharmaceutical Sciences, 517 Hochstetter Hall, University at Buffalo, State University of New York, Amherst, NY 14260-1200. Tel:  (716) 645-2842 ext 230. Fax:  (716) 645-3693. E-mail:  [email protected].

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