PROTEIN-KINASE-C IN CYCLIC STRETCH-INDUCED NERVE GROWTH-FACTOR PRODUCTION BY URINARY-TRACT SMOOTH-MUSCLE CELLS

Cyclic stretch of cultured urinary tract smooth muscle cells has been used to mimic some of the events that occur with bladder obstruction. The stretch stimulus induces production of nerve growth factor (NGF), which has been implicated in changes in bladder innervation. Stretch-induced NGF production was blocked by actinomycin. Involvement of protein kinase C (PKC) in the stretch-induced NGF production is strongly suggested by the following observations. Phorbol ester activators of PKC mimicked the stretch response as did platelet-derived growth factor (PDGF), which acts, in part, through generation of endogenous diacylglycerols. Both stretch- and PDGF-induced NGF production were blocked by prolonged incubation with phorbol ester to downregulate PKC. Western blot analysis confirmed partial downregulation of the Ca2+-dependent PKC-alpha and PKC-beta 1 and near complete downregulation of the Ca2+-independent PKC isozymes delta, epsilon, and zeta. The involvement of PKC in transducing a physical stimulus (stretch) into a biochemical response (NGF production) has implications for novel types of therapeutic intervention in ailments such as bladder obstruction.