Identification of the multivalent PDZ protein PDZK1 as a binding partner of sodium-coupled monocarboxylate transporter SMCT1 (SLC5A8) and SMCT2 (SLC5A12).

Sodium-coupled monocarboxylate transporters SMCT1 (SLC5A8) and SMCT2 (SLC5A12) mediate the high- and low-affinity transport of lactate in the kidney, but their regulatory mechanism is still unknown. Since these two transporters have the PDZ-motif at their C-terminus, the function of SMCTs may be modulated by a protein-protein interaction. To investigate the binding partner(s) of SMCTs in the kidney, we performed yeast two-hybrid (Y2H) screenings of a human kidney cDNA library with the C-terminus of SMCT1 (SMCT1-CT) and SMCT2 (SMCT2-CT) as bait. PDZK1 was identified as a partner for SMCTs. PDZK1 coexpression in SMCT1-expressing HEK293 cells enhanced their nicotinate transport activity. PDZK1, SMCT1, and URAT1 in vitro assembled into a single tri-molecular complex and their colocalization was confirmed in the renal proximal tubule in vivo by immunohistochemistry. These results indicate that the SMCT1-PDZK1 interaction thus plays an important role in both lactate handling as well as urate reabsorption in the human kidney.

Plasma urate level is directly regulated by a voltage-driven urate efflux transporter URATv1 (SLC2A9) in humans.

Hyperuricemia is a significant factor in a variety of diseases, including gout and cardiovascular diseases. Although renal excretion largely determines plasma urate concentration, the molecular mechanism of renal urate handling remains elusive. Previously, we identified a major urate reabsorptive transporter, URAT1 (SLC22A12), on the apical side of the renal proximal tubular cells. However, it is not known how urate taken up by URAT1 exits from the tubular cell to the systemic circulation. Here, we report that a sugar transport facilitator family member protein GLUT9 (SLC2A9) functions as an efflux transporter of urate from the tubular cell. GLUT9-expressed Xenopus oocytes mediated saturable urate transport (K(m): 365+/-42 microm). The transport was Na(+)-independent and enhanced at high concentrations of extracellular potassium favoring negative to positive potential direction. Substrate specificity and pyrazinoate sensitivity of GLUT9 was distinct from those of URAT1. The in vivo role of GLUT9 is supported by the fact that a renal hypouricemia patient without any mutations in SLC22A12 was found to have a missense mutation in SLC2A9, which reduced urate transport activity in vitro. Based on these data, we propose a novel model of transcellular urate transport in the kidney; urate [corrected] is taken up via apically located URAT1 and exits the cell via basolaterally located GLUT9, which we suggest be renamed URATv1 (voltage-driven urate transporter 1).

Mouse organic anion transporter 2 (mOat2) mediates the transport of short chain fatty acid propionate.

In this study, we have elucidated that propionate, one of the short chain fatty acids (SCFAs), is the transport substrate for murine organic anion transporter 2 (mOat2), which is expressed in the kidneys and the liver. When expressed in Xenopus oocytes, mOat2-mediated [(3)H]PGE(2) transport was inhibited by three- to five-carbon SCFAs (C3 to C5). Among the SCFAs tested, propionate (3-carbon SCFA) was transported by mOat2 in a time-dependent manner. Since propionate is a potent glucogenic compound, Oat2 may be involved in the regulation of cellular metabolism through the transport of these metabolites in the kidneys and the liver.