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Characterization of Signal Transduction Pathway in Neurotropic Action of Angiotensin II in Brain Neurons

Department of Physiology, College of Medicine, and McKnight Brain Institute, University of Florida, Gainesville, Florida 32610

Address all correspondence and requests for reprints to: Mohan K. Raizada, Ph.D., University of Florida College of Medicine, P.O. Box 100274, Gainesville, Florida 32610-0274. E-mail: mraizada{at}phys.med

Interaction of angiotensin II with the neuronal angiotensin type 1 receptor stimulates the PI3K signaling pathway. Our objective in this study was to investigate the hypothesis that the PI3K cascade regulates the neurotropic actions of angiotensin II in rat brain neurons. We followed growth associated protein-43 expression and neurite extension as markers of neurotropic activity. Angiotensin II, through its interaction with the angiotensin type 1 receptor, increased growth associated protein-43 expression and neurite extension. These effects were abolished by pretreatment of neurons with wortmannin and rapamycin, but not by PD 98059. Antisense oligonucleotides specific for p70^S6 kinase also inhibited angiotensin II-stimulated neurotropic activity. These data confirm the involvement of PI3K and p70^S6 kinase in angiotensin II-mediated neurotropic action. Further support for this was provided by the observation that angiotensin II caused a time-dependent stimulation of p70^S6 kinase by an angiotensin type 1 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) angiotensin II-stimulated neuronal plasminogen activator inhibitor-1 gene expression, 2) potent neurotropic action of exogenous plasminogen activator inhibitor-1, and 3) inhibitory neurotropic effect of angiotensin II by antisense oligonucleotide-mediated depletion of plasminogen activator inhibitor-1. Finally, we found that the neurotropic action of plasminogen activator inhibitor-1 is not blocked by either angiotensin type 1 receptor antagonist or inhibitors of PI3K or p70^S6 kinase, indicating that the plasminogen activator inhibitor-1 step is downstream from the p70^S6 kinase. These observations demonstrate that angiotensin II is a neurotropic hormone that engages a distinct PI3K-p70^S6 kinase-plasminogen activator inhibitor-1 signaling pathway for this action.

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