An indispensable role of secretin in mediating the osmoregulatory functions of angiotensin II

Abstract

Fluid balance is critical to life and hence is tightly controlled in the body. Angiotensin II (ANGII), one of the most important components of this regulatory system, is recognized as a dipsogenic hormone that stimulates vasopressin (VP) expression and release. However, detailed mechanisms regarding how ANGII brings about these changes are not fully understood. In the present study, we show initially that the osmoregu‐latory functions of secretin (SCT) in the brain are similar to those of ANGII in mice and, more important, we discovered the role of SCT as the link between ANGII and its downstream effects. This was substantiated by the use of two knockout mice, SCTR–/– and SCT–/–, in which we show the absence of an intact SCT/secretin receptor (SCTR) axis resulted in an abolishment or much reduced ANGII osmoregulatory functions. By immunohistochemical staining and in situ hybridization, the proteins and transcripts of SCT and its receptor are found in the paraventricular nucleus (PVN) and lamina terminalis. We propose that SCT produced in the circumventricular organs is transported and released in the PVN to stimulate vasopres‐sin expression and release. In summary, our findings identify SCT and SCTR as novel elements of the ANGII osmoregulatory pathway in maintaining fluid balance in the body.—Lee, V. H. Y., Lee, L. T. O., Chu, J. Y. S., Lam, I. P. Y., Siu, F. K Y, Vaudry, H., Chow, B. K C. An indispensable role of secretin in mediating the osmoregulatory functions of angiotensin II. FASEB J. 24, 5024–5032 (2010). http://www.fasebj.org

Secretin, at the hub of water-salt homeostasis

“…In the brain, SCT and AT1R co-localizes to PVN (76). Using extracellular recordings, SCT was found to increase the firing rate in more than half of the of the Wistar rats' PVN (21).…”

“…Thus associating SCT with the physiological role of the neuron presents in the PVN. Interestingly, the expression of SCT and SCTR in the PVN's magnocellular cells were increased following intracerebroventricular (ICV) injection of ANGII and exposure to chronic feeding of saline (①, Figure 1) (76). The circulatory level of SCT was also elevated (76).…”

“…SCT/SCTR was initially found to stimulate exocrine secretion of water, salt and bicarbonate from pancreatic ductal epithelial, and to inhibit gastric acid secretion and emptying (23). Using SCT and SCTR knockout mice other physiological roles of the ligand and its receptor have also been reported (30,76). In terms of energy homeostasis, the administration of peripheral and central SCT elicited anorectic effects in mice (22,29).…”

“…Perhaps more pertinent to this review is the finding that SCT increases c-FOS, an ANGII sensitive-transcription factor, expression in the central amygdala (53). Furthermore, there is also an increasing body of evidence indicating that SCT may play a role in body fluid homeostasis, by regulating water-drinking behavior (76) and potentially as a neurohypophyseal factor to regulate the water reabsorption independent of AVP in the kidney (Figure 1) (30,31).…”

“…Earlier work from several groups confirmed the expression of SCT in the CNS. Using high performance liquid chromatography (HLPC), the peptide was detected in the pituitary gland, pineal gland, hypothalamus, thalamus, olfactory lobe and cerebellum (20,41,76,110,131). The detection of the receptor transcript (131) and the binding of radioactive labelled SCT to the CVO, hypothalamus, hippocampus, cerebellum and central amygdala further suggested presence of the receptor in the brain (1,24,130).…”