The renal transport protein OATP4C1 mediates uptake of the uremic toxin asymmetric dimethylarginine (ADMA) and efflux of cardioprotective L-homoarginine

Elevated plasma concentrations of the uremic toxin asymmetrical dimethylarginine (ADMA) and low plasma concentrations of L-homoarginine are independently associated with cardiovascular events and total mortality. Enzymes degrading ADMA [dimethylaminohydrolase 1 (DDAH1)] and synthesizing L-homoarginine [L-arginine:glycine amidinotransferase (AGAT)] are expressed in human proximal tubule cells. So far, it is not known which transport protein in the basolateral membrane of proximal tubule cells is mediating the uptake of ADMA into the cells for subsequent degradation or the export of intracellularly synthesized L-homoarginine. One study suggested that the uptake transporter OATP4C1 (gene symbol SLCO4C1) may be involved in the transport of ADMA and other uremic toxins. OATP4C1 is a member of the SLCO/SLC21 family of solute carriers, localized in the basolateral membrane of human proximal tubule cells. By using stably-transfected HEK cells overexpressing human OATP4C1, we demonstrate that ADMA and L-homoarginine are substrates of OATP4C1 with Km values of 232.1 μM and 49.9 μM, respectively. ADMA and the structurally related uremic toxin SDMA (100 μM) inhibited OATP4C1-mediated L-homoarginine uptake (P