The angiotensin II AT(2) receptor inhibits proliferation and promotes differentiation in PC12W cells

Angiotensin II (ANG II) has been implicated in cell growth and differentiation. We investigated the effect of AT(2) receptor stimulation on proliferation and morphological differentiation in cells of neuronal origin by using the pheochromocytoma derived cell line, PC12W. ANG II (10(-8)-10(-6) M) inhibited fetal calf serum (FCS)-induced cell proliferation in a concentration dependent manner. In half of the experiments, the epidermal growth factor (EGF) exerted a mitogenic action which was concentration-dependently inhibited by ANG II. In the other half of the experiments, EGF bad an antimitogenic effect which was further enhanced by ANG II (maximally at 10(-6) M). Treatment with nerve growth factor (NGF) induced an inhibition of [H-3]thymidine incorporation, which 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 antagonist, PD123177, but not influenced by the AT(1) receptor antagonist, losartan. The ANG II-induced inhibition of cell proliferation was paralleled by morphological differentiation in response to daily treatment with ANG II. ANG II also enhanced low-dose NGF-induced neurite formation. Again, these effects of ANG II were abolished by the AT(2) receptor antagonist, PD123177. Our data in PC12W cells show that the AT(2) receptor not only inhibits growth factor-induced proliferation and enhances the NGF-mediated growth arrest but also induces morphological differentiation in cells of neuronal origin. These findings strongly support the hypothesis that the AT(2) receptor promotes differentiation in neuronal cells.