Abstract
The synthesis of arginine vasopressin (AVP) in the supraoptic nucleus (SON) and paraventricular nucleus (PVN) of the hypothalamus is sensitive to increased plasma osmolality and a decreased blood volume, and thus is robustly increased by both dehydration (increased plasma osmolality and decreased blood volume) and salt loading (increased plasma osmolality). Both stimuli result in functional remodelling of the SON and PVN, a process referred to as functional‐related plasticity. Such plastic changes in the brain have recently been associated with altered patterns of DNA methylation at CpG (cytosine‐phosphate‐guanine) residues, a process considered to be important for the regulation of gene transcription. In this regard, the proximal Avp promoter contains a number of CpG sites and is recognised as one of four CpG islands for the Avp gene, suggesting that methylation may be regulating Avp transcription. In the present study, we show that, in an immortalised hypothalamic cell line 4B, the proximal Avp promoter is highly methylated, and treatment of these cells with the DNA methyltransferase inhibitor 5‐Aza‐2′‐deoxycytidine to demethylate DNA dramatically increases basal and stimulated Avp biosynthesis. We report no changes in the expression of DNA methyltransferases, Dnmt1 and Dnmt3a, whereas there is decreased expression of the demethylating enzyme ten‐eleven‐translocation 2, Tet2, in the SON by dehydration and salt loading. We found higher methylation of the SON Avp promoter in dehydrated but not salt‐loaded rats. By analysis of individual CpG sites, we observed hypomethylation, hypermethylation and no change in methylation of specific CpGs in the SON Avp promoter of the dehydrated rat. Using reporter gene assays, we show that mutation of individual CpGs can result in altered Avp promoter activity. We propose that methylation of the SON Avp promoter is necessary to co‐ordinate the duel inputs of increased plasma osmolality and decreased blood volume on Avp transcription in the chronically dehydrated rat.
Highlights
The neuropeptide hormone arginine vasopressin (AVP) is synthesised in magnocellular neurons of the supraoptic nucleus (SON) and paraventricular nucleus (PVN) of the hypothalamus
We found that dehydration induces hypermethylation of the proximal arginine vasopressin (Avp) promoter, whereas methylation status was not altered by salt loading
Demethylation of the Avp promoter dramatically increases Avp transcription We firstly looked at Avp promoter methylation in an immortalised rat hypothalamic cell line 4B
Summary
The neuropeptide hormone arginine vasopressin (AVP) is synthesised in magnocellular neurons of the supraoptic nucleus (SON) and paraventricular nucleus (PVN) of the hypothalamus. Increases in plasma osmolality are detected by osmosensitive neurons in circumventricular organs that provide direct excitatory inputs leading to increased Avp synthesis by magnocellular neurons of the SON and PVN and AVP secretion from the posterior pituitary [1]. A decrease in blood volume (hypovolemia) is detected by the cardiac right atrium, again resulting in increased AVP synthesis and secretion [8]. In this regard, changes in blood volumes greater than 8% are necessary to facilitate this response [3, 5, 9, 10]. A population of smaller AVP expressing parvocellular neurons is found in the PVN, which are important in co-ordinating responses to stress [11]
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