Angiotensin II type 2 receptor-mediated apoptosis of cultured neurons fromnewborn rat brain

Angiotensin II(Ang II) type 2 (AT(2)) receptors are highly expressed in neo nate brain and may have a role in developmental processes such as apoptosis . Concurrent activation of c-Jun N-terminal kinase (JNK) and inhibition of Erk mitogen-activated protein kinase activities is important for apoptosis in many cells, and we previously demonstrated that stimulation of AT(2) rec eptors causes decreased mitogen-activated protein kinase activity in neuron s cultured from newborn rat hypothalamus and brain stem. Using such culture s we have employed terminal deoxynucleotidyl transferase-mediated deoxy-UTP nick end labeling and internucleosomal DNA fragmentation to assess the rol e of AT(2) receptors in neuronal apoptosis. Ang II (100 nM; 4-72 h) alone p roduced no significant neuronal apoptosis, and AT, receptor activation did not stimulate JNK activity. However, exposure of cultures to UV radiation ( 6 J/m(2)/sec for 4 sec) to stimulate JNK elicited neuronal apoptosis that w as significantly enhanced by Ang II, an effect that was abolished by the AT (2) receptor antagonist PD 123,319 (1 mu M) or the serine/threonine phospha tase inhibitor okadaic acid (3 nM). Additionally, Ang II Enhanced the UV ra diation-induced decrease in the levels of the DNA repair enzyme poly-(ADP-r ibose) polymerase. These data indicate that Ang II, via AT(2) receptors and activation of a serine/threonine phosphatase, contributes to neuronal apop tosis.