THE ANGIOTENSIN-II AT(2) RECEPTOR INHIBITS PROLIFERATION AND PROMOTESDIFFERENTIATION IN PC12W CELLS

Angiotensin II (ANG II) has been implicated in cell growth and differe ntiation. We investigated the effect of AT(2) receptor stimulation on proliferation and morphological differentiation in cells of neuronal o rigin by using the pheochromocytoma derived cell line, PC12W. ANG II ( 10(-8)-10(-6) M) inhibited fetal calf serum (FCS)-induced cell prolife ration in a concentration dependent manner. In half of the experiments , the epidermal growth factor (EGF) exerted a mitogenic action which w as concentration-dependently inhibited by ANG II. In the other half of the experiments, EGF bad an antimitogenic effect which was further en hanced by ANG II (maximally at 10(-6) M). Treatment with nerve growth factor (NGF) induced an inhibition of [H-3]thymidine incorporation, wh ich was enhanced by ANG II, maximally 25% at the highest concentration . The effects of ANG II on [H-3]thymidine incorporation were reflected by those on cell number and were prevented by the AT(2) receptor anta gonist, PD123177, but not influenced by the AT(1) receptor antagonist, losartan. The ANG II-induced inhibition of cell proliferation was par alleled by morphological differentiation in response to daily treatmen t with ANG II. ANG II also enhanced low-dose NGF-induced neurite forma tion. Again, these effects of ANG II were abolished by the AT(2) recep tor antagonist, PD123177. Our data in PC12W cells show that the AT(2) receptor not only inhibits growth factor-induced proliferation and enh ances the NGF-mediated growth arrest but also induces morphological di fferentiation in cells of neuronal origin. These findings strongly sup port the hypothesis that the AT(2) receptor promotes differentiation i n neuronal cells.