Role of mitogen-activated protein (MAP) kinases in osmotic stimulation of endothelin (ET) synthesis in renal inner-medullary collecting duct (IMCD) cells

Previously, we have shown in porcine IMCD cells that ET in an autocrine-par acrine fashion suppresses arginine-vasopressin-(AVP) induced synthesis of c yclic adenosine monophosphate (cAMP) generation and that hyperosmolality st imulates ET-1 synthesis in these cells. Since hyperosmolality was also show n to activate MAP kinases in renal medullary tissue, we speculated that the y mediate the rise in ET-1 production in IMCD cells in response to hyperosm olality induced by various osmolytes. We, therefore, studied in porcine IMC D cells the effects of extracellular hypertonicity (similar to 600 mosmol/k g H2O), induced by supplementation of the incubation medium (DMEM) with ino rganic (NaCl) and organic osmolytes (betaine, myoinositol, sorbit, taurine, urea), on MAP kinases ERK, SAPK/JNK and p38 kinase as well as on ET-1 synt hesis in the absence and presence of specific inhibitors of ERK (U0126) and of p38 kinase activity (SB203580). Each of the osmolytes in the hypertonic medium differentially activated MAP kinases and increased ET-1 synthesis. More detailed studies on the time-dependent effects of betaine and urea sho wed that betaine, besides its ERK activation, most strongly activated p38 k inase and ET-1 synthesis. Inhibition of p38 kinase by SB203580 significantl y suppressed betaine-induced ET-1 synthesis. Urea had only a moderate effec t on ERK activity and on ET-1 synthesis which was not significantly affecte d by U0126. These data point to a functional relationship between activatio n of various MAP kinases and ET-1 synthesis by IMCD cells in response to ex tracellular hyperosmotic stress.