LYSOPHOSPHATIDIC ACID AND BRADYKININ HAVE OPPOSITE EFFECTS ON PHENOTYPIC TRANSFORMATION OF NORMAL RAT-KIDNEY CELLS

The bioactive lipid lysophosphatidic acid is besides a strong mitogen for quiescent fibroblasts, a potent inducer of phenotypic transformation of normal rat kidney cells. The lysophosphatidic acid induced loss of density-arrest is strongly inhibited by bradykinin. Although their effects on normal rat kidney cell proliferation are opposite, bradykinin mimics many of the intracellular effects induced upon lysophosphatidic acid receptor activation, including phosphoinositide turnover, Ca2+-mobilization and arachidonic acid release. Bradykinin does not counteract the lysophosphatidic acid induced reduction of cAMP levels in normal rat kidney cells. However, bradykinin inhibits the lysophosphatidic acid and other growth factor induced phenotypic transformation through the induction of a so far uncharacterized prostaglandin G/H synthase product. The growth inhibitory effect of bradykinin is limited to density-arrested cells, while upon prolonged treatment bradykinin itself is capable to induce the loss of density-dependent growth control. It is concluded that bradykinin is a bifunctional regulator of normal rat kidney cell proliferation and that its inhibitory effects are mediated via the induction of a prostaglandin derivative. (C) 1994 Wiley-Liss, Inc.