Abstract
The molecular identity of the luminal element of renal organic cation (OC) secretion is suspected to include two novel homologous transport proteins, Multidrug And Toxin Extruders 1 & 2K (MATE1 and MATE2K); they share anticipated characteristics of luminal OC transport, including expression in the apical membrane of human renal proximal tubule (RPT) cells and support of OC/H+ exchange. Here we investigated aspects of the multispecificity of human MATE1 (hMATE1) and MATE2K (hMATE2K). Stable transfection in Chinese Hamster Ovary cells resulted in Kt values for transport of 1‐methyl‐4‐phenylpyridinium (MPP) of 7.6 μM (MATE1) 5.2 μM (MATE2K). Inhibition by tetraethylammonium produced IC50 values of 52 μM and 26 μM for hMATE1 and hMATE2K, respectively. Preliminary data shows that cimetidine is a potent inhibitor of MPP, with IC50s of 1 μM (MATE1) and 3μM (MATE2K). Increasing extracellular H+ concentration cis inhibited hMATE1‐mediated MPP transport with an IC50 value of 15.4 nM (pH of 7.8). Immunohistochemical analysis of paraffin embedded human kidney cortex samples confirmed that hMATE1 and hMATE2K are located in the apical membrane of RPT cells and initial evidence suggests a heterogeneous distribution of both transporters in the cortical RPTs. In conclusion, the selectivities and distribution of MATE1 and MATE2K support the contention that they play a key role in OC secretion in human RPT. (F31DK084769)
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