Angiotensin II attenuates NMDA receptor-mediated neuronal cell death and prevents the associated reduction in Bcl-2 expression

作者：Schelman WR; Andres R; Ferguson P; Orr B; Kang E; Weyhenmeyer JA^*

来源：Molecular Brain Research, 2004, 128(1): 20-29.

DOI：10.1016/j.molbrainres.2004.06.001

• NMDA
• angiotensin II (Ang II)
• AT(1)
• receptor
• AT(2) receptor
• excitotoxicity
• Bcl-2
• N1E-115 cells
• NG108-15 cells
• neuron

While angiotensin 11 (Ang 11) plays a major role in the regulation of blood pressure, fluid homeostasis and neuroendocrine function, recent studies have also implicated the peptide hormone in cell growth, differentiation and apoptosis. In support of this, we have previously demonstrated that Ang 11 attenuates N-methyl-D-aspartate (NMDA) receptor signaling [Molec. Brain Res. 48 (1997) 197]. To further examine the modulatory role of Ang 11 on NMDA receptor function, we investigated the effect of angiotensin receptor (AT) activation on NMDA-mediated cell death and the accompanying decrease in Bcl-2 expression. The viability of differentiated NIE-115 and NG108-15 neuronal cell lines was reduced following exposure to NMDA in a dose-dependent manner. MTT analysis (mitochondrial integrity) revealed a decrease in cell survival of 49.4 +/- 12.3% in NG108 cells and 79.9 +/- 6.8% in N1E cells following treatment with 10 mM NMDA for 20 h. Cytotoxicity in N1E cells was inhibited by the noncompetitive NMDA receptor antagonist, MK-801. Further, NMDA receptor-mediated cell death in NG108 cells was attenuated by treatment with Ang II. The Ang 11 effect was inhibited by both AT(1) and AT(2) receptor antagonists, losartan and PD123319, respectively, suggesting that both receptor subtypes may play a role in the survival effect of Ang II. Since it has been shown that activation of NMDA receptors alters the expression of Bcl-2 family proteins, Western blot analysis was performed in N1E cells to determine whether Ang 11 alters the NMDA-induced changes in Bcl-2 expression. A concentration-dependent decrease of intracellular Bcl-2 protein levels was observed following treatment with NMDA, and this reduction was inhibited by MK801. Addition of Ang 11 suppressed the NMDA receptor-mediated reduction in Bcl-2. The Ang 11 effect on NMDA-mediated changes in Bcl-2 levels was blocked by PD123319, but was not significantly changed by losartan, suggesting AT2 receptor specificity. Taken together, these results suggest that Ang 11 attenuates NMDA receptor-mediated neurotoxicity and that this effect may be due, in part, to an alteration in Bcl-2 expression.

• 出版日期2004-9-10