Abstract
Osmoregulation via maintenance of water and salt homeostasis is a vital process. In the brain, a functional secretin (SCT) and secretin receptor (SCTR) axis has recently been shown to mediate central actions of angiotensin II (ANGII), including initiation of water intake and stimulation of vasopressin (VP) expression and release. In this report, we provide evidence that estrogen-related receptor α (ERRα, NR3B1), a transcription factor mainly involved in metabolism, acts as an upstream activator of the SCT gene. In vitro studies using mouse hypothalamic cell line N-42 show that ERRα upregulates SCT promoter and gene expression. More importantly, knockdown of endogenous ERRα abolishes SCT promoter activation in response to hypertonic and ANGII stimulations. In mouse brain, ERRα coexpresses with SCT in various osmoregulatory brain regions, including the lamina terminalis and the paraventricular nucleus of the hypothalamus, and its expression is induced by hyperosmotic and ANGII treatments. Based on our data, we propose that both the upregulation of ERRα and/or the increased binding of ERRα to the mouse SCT promoter are two possible mechanisms for the elevated SCT expression upon hyperosmolality and central ANGII stimulation.
Highlights
Secretin (SCT) is a classical gastrointestinal hormone [1]
In view of a recent study revealing a potential function of estrogen-related receptor a (ERRa) in the renin-angiotensin system (RAS) for osmoregulation [9] and the presence of an estrogen response element (ERE)-half site in the proximal region of the mouse, rat and human SCT promoters (Fig. 1A), we initially investigated the in vitro function of ERRs to control the mouse SCT gene in a mouse hypothalamic N-42 cell-line
The promoter activities were increased with ERRa cotransfection in the mutants that not related to ERE-half site (M1 1.8 fold and M4 1.9 fold when compare to pKS+ control), whereas the mutation of ERE-half site can severely decrease ERRa-mediated activation effects
Summary
Secretin (SCT) is a classical gastrointestinal hormone [1]. Beyond its best known actions on the regulation of bicarbonate, electrolytes and volume secretion from the pancreatic ductular epithelial cells, there is a growing body of evidence showing SCT as a neuropeptide in the CNS [2,3,4,5] and as an anti-diuretic hormone, SCT stimulate the process of renal water reabsorption in kidney by a VP-independent mechanisms [6]. The roles of SCT in the brain in water regulation were reported, and SCT was found to have similar functions as the osmoregulatory peptide, angiotensin II (ANGII) [8]. In these studies, with the aid of the SCTR2/2 and SCT2/2 mice, it was found that the presence of a functional SCT/ SCTR axis is a prerequisite for some actions of ANGII, including the upregulation of VP expression in the hypothalamic PVN and the release of VP protein from posterior pituitary into the circulation. SCT itself was found as a dipsogenic hormone that controls water intake behavior as well as mediates the dipsogenic effects of ANGII [8]
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