Characterization of signal transduction pathway in neurotropic action of angiotensin II in brain neurons

Interaction of angiotensin II with the neuronal angiotensin type 1 receptor stimulates the P13K signaling pathway. Our objective in this study was to investigate the hypothesis that the P13K cascade regulates the neurotropic actions of angiotensin II in rat brain neurons. We followed growth associat ed protein-43 expression and neurite extension as markers of neurotropic ac tivity. Angiotensin II, through its interaction with the angiotensin type 1 receptor, increased growth associated protein-43 expression and neurite ex tension. These effects were abolished by pretreatment of neurons with wortm annin and rapamycin, but not by PD 98059. Antisense oligonucleotides specif ic for p7(S6) kinase also inhibited angiotensin II-stimulated neurotropic a ctivity. These data confirm the involvement of P13K and p70(S6) kinase in a ngiotensin II-mediated neurotropic action. Further support for this was pro vided by the observation that angiotensin II caused a time-dependent stimul ation of p70(S6) kinase by an angiotensin type I receptor-mediated process. We also found that the neurotropic actions of angiotensin II are mediated by plasminogen activator inhibitor-1. Evidence for this includes 1) angiote nsin II-stimulated neuronal plasminogen activator inhibitor-1 gene expressi on, 2) potent neurotropic action of exogenous plasminogen activator inhibit or-1, and 3) inhibitory neurotropic effect of angiotensin II by antisense o ligonucleotide-mediated depletion of plasminogen activator inhibitor-1. Fin ally, we found that the neurotropic action of plasminogen activator inhibit or-1 is not blocked by either angiotensin type I receptor antagonist or inh ibitors of P13K or p70(S6) kinase, indicating that the plasminogen activato r inhibitor-1 step is downstream from the p70(S6) kinase. These observation s demonstrate that angiotensin II is a neurotropic hormone that engages a d istinct P13K-p70(S6) kinase-plasminogen activator inhibitor-1 signaling pat hway for this action.