Control of polyamine biosynthesis by antizyme inhibitor 1 is important for transcriptional regulation of arginine vasopressin in the male rat hypothalamus

Abstract

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 synthesize the neuropeptide hormones arginine vasopressin (AVP) and oxytocin. 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. Here we show that AZIN1 protein is highly expressed in both AVP- and oxytocin-positive magnocellular neurons of the SON and PVN together with antizyme 1 (AZ1), ornithine decarboxylase, and polyamines. Azin1 mRNA expression increased in the SON and PVN as a consequence of dehydration, salt loading, and acute hypertonic stress. In organotypic hypothalamic cultures, addition of the irreversible ornithine decarboxylase inhibitor DL-2-(difluoromethyl)-ornithine hydrochloride significantly increased the abundance of heteronuclear AVP but not heteronuclear oxytocin. To identify the function of Azin1 in vivo, lentiviral vectors that either overexpress or knockdownAzin1 were stereotaxically delivered intotheSONand/orPVN.Azin1shorthairpinRNAdelivery resulted indecreasedplasmaosmolalityandhad asignificant effectonfoodintake.Theexpression ofAVPmRNAwasalso significantly increased in theSON by Azin1 short hairpinRNA.In contrast, Azin1 overexpression in theSONdecreasedAVPmRNAexpression. We have therefore identified AZIN1, and hence by inference, polyamines as novel regulators of the expression of the AVP gene.