Increased L-arginine transport via system b^0,+ in human proximal tubular cells exposed to albumin

Albumin has complex effects on PTECs (proximal tubular epithelial cells) and is able to stimulate growth or injury depending on its bound moieties. Albumin itself is a mitogen, inducing proliferation through a number of pathways. In PTEC exposed to purified albumin, polyamines are required for entry into the cell cycle and are critical for proliferation. Polyamines are synthesized from L-ornithine (itself derived by the action of arginase on L-arginine), and the transport and availability of L-arginine may thus be important for subsequent polyamine-dependent proliferation. In the present study we investigated radiolabelled cationic amino-acid transport in cultured PTEC exposed to 20 mg/ml ultrapure recombinant human albumin, describing the specific kinetic characteristics of transport and the expression of transporters. L-[³H]Arginine transport capacity in human PTEC is increased after exposure for 24 h to human albumin, mediated by the broad-scope high-affinity system b^0,+ and, to a lesser extent, system y⁺L (but not system y⁺) transport. Increased transport is associated with increased b^0,+-associated transporter expression. Inhibition of phosphoinositide 3-kinase, a key regulator of albumin endocytosis and signalling, inhibited proliferation, but had no effect on the observed increase in transport. PTEC proliferated in response to albumin. L-Lysine, a competitive inhibitor of L-arginine transport, had no effect on albumin-induced proliferation; however, arginine deprivation effectively reversed the albumin-induced proliferation observed. In conclusion, in PTEC exposed to albumin, increased L-arginine transport is mediated by increased transcription and activity of the apical b^0,+ transport system. This may make L-arginine available as a substrate for the downstream synthesis of polyamines, but is not critical for cell proliferation.