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

• Published in: Endocrinology (Philadelphia) Vol. 156; no. 8; pp. 2905 - 2917
• Main Authors: Greenwood, Michael P, Greenwood, Mingkwan, Paton, Julian F. R, Murphy, David
• Format: Journal Article
• Language: English
• Published: United States Endocrine Society 01.08.2015
• Subjects: Animals; Arginine Vasopressin - genetics; Arginine Vasopressin - metabolism; Carrier Proteins - physiology; Cells, Cultured; Female; Gene Expression Profiling; Gene Expression Regulation; Hypothalamus - metabolism; Male; Original Research; Ornithine Decarboxylase - genetics; Ornithine Decarboxylase - metabolism; Polyamines - metabolism; Rats; Rats, Sprague-Dawley; Transcription, Genetic
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2015-1074

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 knock down Azin1 were stereotaxically delivered into the SON and/or PVN. Azin1 short hairpin RNA 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 short hairpin RNA. 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.