Control of Polyamine Biosynthesis by Antizyme Inhibitor 1 is Important for Transcriptional Regulation of Arginine Vasopressin in the Male Rat Hypothalamus

The polyamines spermidine and spermine are small cations present in all living cells. In the brain, these cations are particularly abundant in the neurons of the paraventricular (PVN) and supraoptic nuclei (SON) of the hypothalamus, which synthesise the neuropeptide hormones arginine vasopressin (AVP) and oxytocin (OT). We recently reported increased mRNA expression of antizyme inhibitor 1 (Azin1), an important regulator of polyamine synthesis, in rat SON and PVN as a consequence of 3 days of dehydration (DH). Here, we show that Azin1 protein is highly expressed in both AVP and OT positive magnocellular neurons of the SON and PVN, together with antizyme 1 (AZ1), ornithine decarboxylase (ODC) and polyamines. Azin1 mRNA expression increased in the SON and PVN as a consequence of DH, salt loading (SL) and by acute hypertonic stress. In organotypic hypothalamic cultures, addition of the irreversible ODC inhibitor DL-2-(Difluoromethyl)-ornithine hydrochloride (DFMO) significantly increased the abundance of heteronuclear AVP (hnAVP), but not hnOT. To identify the function of Azin1 in vivo, lentiviral vectors that either over-express or knockdown Azin1 were stereotaxically delivered into the SON and/or PVN. Azin1 shRNA delivery resulted in decreased plasma osmolality and had a significant effect on food intake. The expression of AVP mRNA was also significantly increased in the SON by Azin1 shRNA. In contrast, Azin1 overexpression in the SON decreased AVP mRNA expression. We have therefore identified Azin1, and hence by inference polyamines, as novel regulators of the expression of the AVP gene.