ERK activation by urea in the renal inner medullary mIMCD3 cell line

Urea- and NaCl-inducible extracellular signal-regulated kinase (ERK) phosph orylation exhibited dissimilar kinetics. Among cell lines examined, the eff ect of urea was unique to mIMCD3 inner medullary collecting duct cells and MDCK cells. Urea-inducible ERK activation was similar to 10-fold less sensi tive to the MEK inhibitor, PD-98059, than was that of NaCl. This difference did not appear to be accounted for by differential activation of MEK isofo rms. Interestingly, the inhibitor of p38 activation, SB-203580, abrogated t he effect of both urea and NaCl upon both ERK and MEK activation; however, the former was much less sensitive to the inhibitor. Consistent with this o bservation, NaCl was much more effective than urea at inducing p38 phosphor ylation. The effect of hypertonic stress (e.g., sorbitol 100 mM) could be b locked by appropriate medium dilution such that isotonicity was maintained. In marked contrast, the effect of hyperosmotic urea could not be blocked i n this fashion, implying the absence of dependence upon cell volume. Togeth er, these data suggest that cells of the renal inner medulla are potentiall y uniquely responsive to urea and that urea and hypertonic stressors induce ERK activation through distinct mechanisms.