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

被引:84
作者
Shenoy, UV
Richards, EM
Huang, XC
Sumners, C
机构
[1] Univ Florida, Dept Physiol, Coll Med, Gainesville, FL 32610 USA
[2] Univ Florida, Inst Brain, Gainesville, FL 32610 USA
关键词
D O I
10.1210/en.140.1.500
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Angiotensin II(Ang II) type 2 (AT(2)) receptors are highly expressed in neonate 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) receptors causes decreased mitogen-activated protein kinase activity in neurons cultured from newborn rat hypothalamus and brain stem. Using such cultures we have employed terminal deoxynucleotidyl transferase-mediated deoxy-UTP nick end labeling and internucleosomal DNA fragmentation to assess the role of AT(2) receptors in neuronal apoptosis. Ang II (100 nM; 4-72 h) alone produced 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 was 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 phosphatase inhibitor okadaic acid (3 nM). Additionally, Ang II Enhanced the UV radiation-induced decrease in the levels of the DNA repair enzyme poly-(ADP-ribose) polymerase. These data indicate that Ang II, via AT(2) receptors and activation of a serine/threonine phosphatase, contributes to neuronal apoptosis.
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页码:500 / 509
页数:10
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