UREA ACTIVATES RIBOSOMAL S6 KINASE (RSK) IN A MEK-DEPENDENT FASHION IN RENAL MIMCD3 CELLS

Urea activates a characteristic subset of signaling pathways in a tiss ue-specific fashion, including transcription of immediate early genes through activation of the mitogen-activated protein kinase (MAPK), ERK (extracellular signal-regulated kinase), and activation of its transc ription factor substrate, Elk-l. The ability of urea to activate the E RK effector and pivotal regulatory kinase, ribosomal S6 kinase (RSK), was investigated in mIMCD3 renal inner medullary collecting duct cells . Urea upregulated RSK activity in a time-dependent fashion in serum-d eprived mIMCD3 cells; the effect was maximal at 5 min. Activation by h ypertonic NaCl, in contrast, was negligible at 5 min and peaked at 15 min. Both stimuli induced the nuclear translocation of cytosolic RSK, as determined via immunofluorescence. Importantly, activation of RSK b y both solutes was MAPK/ERK kinase (MEK) dependent, as determined by t he ability of the specific MEK inhibitor, PD-98059, to abrogate the re sponse. Taken together, these data indicate that urea activates the ER K effector, RSK, in cells of the renal medulla in an ERK-dependent fas hion, further emphasizing the functional significance of urea signalin g through ERK activation in renal medullary cells.