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Secretin As a Neurohypophysial Factor Regulating Body Water Homeostasis

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Secretin As a Neurohypophysial Factor Regulating Body Water Homeostasis Secretin as a neurohypophysial factor regulating body water homeostasis Jessica Y. S. Chua, Leo T. O. Leea,C.H.Laib, H. Vaudryc, Y. S. Chanb, W. H. Yungd, and Billy K. C. Chowa,1 aSchool of Biological Sciences and bDepartment of Physiology and Research Centre of Heart, Brain, Hormone and Healthy Aging, University of Hong Kong, Hong Kong, China; cInstitut National de la Sante´et de la Recherche Me´dicale Unite´413, Laboratory of Cellular and Molecular Neuroendocrinology, University of Rouen, 76821 Mont-Saint-Aignan, France; and dDepartment of Physiology, Chinese University of Hong Kong, Hong Kong, China Edited by Roger Guillemin, The Salk Institute for Biological Studies, La Jolla, CA, and approved July 30, 2009 (received for review April 5, 2009) Hypothalamic magnocellular neurons express either one of the neu- ng/g of protein in the rat pituitary. Consistent with previous rohypophysial hormones, vasopressin or oxytocin, along with differ- findings that showed a high concentration of SCT in the neu- ent neuropeptides or neuromodulators. Axonal terminals of these rointermediate lobe of pituitary (7), the current study revealed neurons are generally accepted to release solely the two hormones intense IR signals for both SCT and its receptor (SCTR) almost but not others into the circulation. Here, we show that secretin, exclusively in the posterior lobe (Fig. 1A), where they were originally isolated from upper intestinal mucosal extract, is present distributed evenly throughout the neuronal fibers with SCT-IR throughout the hypothalamo–neurohypophysial axis and that it is enriched in Herring bodies and axonal terminals but not in released from the posterior pituitary under plasma hyperosmolality pituicytes. In the hypothalamus, abundant SCT and SCTR were conditions. In the hypothalamus, it stimulates vasopressin expression detected primarily in the PVN and SON by both in situ hybrid- and release. Considering these findings together with our previous ization and immunohistochemical staining (Fig. 1B). These findings that show a direct effect of secretin on renal water reab- findings are in agreement with previous studies showing distinct sorption, we propose here that secretin works at multiple levels in the localization of SCT-IR to the PVN and SON and intercalated hypothalamus, pituitary, and kidney to regulate water homeostasis. hypothalamic nuclei (8) and binding of 125I-SCT to hypothalamic Findings presented here challenge previous understanding regarding homogenate (9). Additionally, SCT-IR was found throughout the neurohypophysis and could provide new concepts in treating the hypothalamo–neurohypophysial tracts. Within SON, SCT disorders related to osmoregulation. and SCTR were found to be present in the magnocellular PHYSIOLOGY neurons (Ͼ20 ␮m) and in the varicose or beaded fibers located hypothalamic–pituitary axis ͉ osmoregulation ͉ vasopressin in the ventral position of the nucleus, whereas within the PVN high proportions of large (Ͼ20 ␮m) and small (Ͻ20 ␮m) neurons he pituitary is essential for life. It consists of adenohypoph- were shown to express SCT and SCTR. The latter findings Tysis and neurohypophysis and is responsible for the release indicated that SCT and SCTR are expressed in both parvocel- of hormones that regulate all major body functions, including lular and magnocellular subdivisions of the PVN. water homeostasis, blood pressure, growth, development, and To investigate the potential activity of SCT within the hypo- reproduction. Currently, only two nonapeptide hormones, va- thalamus, the expression of the immediate early Fos protein, sopressin (Vp) and oxytocin (Oxt), are widely accepted to be which is a well-established marker to identify activated neurons released from the neurohypophysis. The two peptides differ by in the autonomous and central nervous system after chemical, a single amino acid substitution and are synthesized within the mechanical, or sensory stimuli, was examined1hafterintrace- magnocellular neurosecretory cells in the paraventricular nu- rebroventricular (ICV) injection of SCT. Fig. 2A shows the cleus (PVN) and supraoptic nucleus (SON). Oxytocin is best effects of SCT on activating Fos-IR in the rat hypothalamus known for its role in parturition and lactation, whereas Vp is compared with that of the saline control. In control rats treated with isotonic saline, in agreement with Pirnik et al. (10), Chang critical to water conservation in the renal collecting ducts via et al. (11), and Kobelt et al. (12), no Fos signal was found in translocation and expression of aquaporin-2 (AQP2). In addition neither the PVN nor the SON. In SCT-injected rats, however, to Vp, many studies have indicated the presence of Vp- Fos-IR was detected over the whole areas of the PVN and SON. independent mechanisms in the kidney. In isolated collecting The Fos signals were found only in the nuclei of certain duct segments, Jeon et al. (1) found that the highest plasma magnocellular neurons in the PVN and SON, thereby suggesting concentration of Vp (10 pM) under severe dehydration could a regulated and differential response to SCT among individual increase osmotic water permeability to only 44% of the maximal magnocellular cells. value. Our group has shown recently that secretin (SCT), a hormone that modulates water and electrolyte transport in SCT Induces Vp Gene Expression and Its Secretion from the Hypo- pancreatic ductal cells (2), liver cholangiocytes (3, 4), and thalamo–Pituitary Axis. To identify the downstream mechanism of epididymal epithelial cells (5), is part of the Vp-independent SCT, double-immunofluorescent labeling of Fos with either Vp mechanisms in regulating renal water reabsorption (6). Because or Oxt was performed (Fig. 2B). Up-regulation of Fos was we observed changes in plasma SCT levels during chronic observed in the cytoplasm of both Vp- and Oxt-expressing hyperosmolality and the presence of intense SCT-immunoreac- neurons, whereas Fos protein was detected only within the nuclei tivity (IR) signals in the posterior pituitary, the present study of vasopressinergic neurons but not in the nuclei of oxytocinergic intended to investigate a putative role of SCT as a pituitary neurons. Expression of this immediate early gene in magnocel- hormone in the hypothalamo–neurohypophysial system, a cen- lular cells has been shown already to link various physiological tral integrative structure that regulates coordinated responses to perturbations in water balance and osmotic stability. Author contributions: J.Y.S.C., L.T.O.L., H.V., Y.S.C., W.H.Y., and B.K.C.C. designed research; Results and Discussion J.Y.S.C. performed research; L.T.O.L., C.H.L., Y.S.C., W.H.Y., and B.K.C.C. contributed new Secretin Induces Expression of the Immediate Early Gene c-fos in the reagents/analytic tools; J.Y.S.C. analyzed data; and J.Y.S.C. and B.K.C.C. wrote the paper. Vasopressinergic Neurons of the Hypothalamic PVN and SON. The The authors declare no conflict of interest. concentrations of SCT and Vp were 122 Ϯ 6 and 142 Ϯ 35 ng/g This article is a PNAS Direct Submission. of protein in the rat hypothalamus and 799 Ϯ 87 and 4,684 Ϯ 426 1To whom correspondence should be addressed. E-mail: [email protected]. www.pnas.org͞cgi͞doi͞10.1073͞pnas.0903695106 PNAS Early Edition ͉ 1of6 Downloaded by guest on October 1, 2021 Fig. 1. Cellular distribution of secretin (SCT) and SCT receptor (SCTR) in the hypothalamus and pituitary. (Ai) SCT and SCTR immunoreactivity (IR) in a panoramic view of the pituitary. Both SCT and SCTR were shown to localize almost exclusively in the pars nervosa but not in the pars distalis and pars intermedia of the adenohypophysis. Negative controls (SCT-1 and SCT-2) were performed using primary SCT antiserum preabsorbed with 0.1 mM SCT and pituitary andenylate cyclase-activating polypeptide (PACAP), respectively. SCTR-1, primary SCTR antiserum preabsorbed with 0.1 mM immunizing peptide; SCTR-2, prebleed rabbit serum as primary antiserum; PN, pars nervosa; PI, pars intermedia; PD, pars distalis. (Aii) Bright-field photomicrograph of a rat pituitary section labeled with anti-SCT antiserum. SCT-IR is shown in brown against a blue background of hematoxylin staining. Note that intensely stained structures of various sizes (arrows) are present in the neurohypophysis, representing dilations of the axon formally known as Herring bodies. Negative controls as in A1 were not shown. (B1 and B2) Localization of SCT and SCTR in the paraventricular nucleus (PVN) and supraoptic nucleus (SON). (Bi) SCTR-IR was observed in the soma of magnocellular neurons, whereas SCT-IR was found in both the soma and the axonal projections (arrow) of the parvocellular and magnocellular neurons. (Bii) In situ hybridization showing the presence of SCT and SCTR transcripts within the PVN and SON. The riboprobes for SCT and SCTR were made reverse and complementary to sequences corresponding to base pairs 34–488 of the rat SCT (GenBank accession no. NM࿝022670) and 211–639 that encode the N-terminal extracellular region of the rat SCTR (GenBank accession no. NM࿝031115) cDNAs, respectively. (Biii) Localization of SCT in the hypothalamo–neurohypophysial tracts. The SCT-containing axons were shown to project laterally from the PVN and run inferiorly above and below the fornix toward the SON. Processes from the SON then cross ventrally to these axonal tracts from the PVN and continue medially along the basal of hypothalamus to the median eminence. stimulations to Vp gene expression (13–15). Thus, we hypothe- right jugular vein (Fig. 2Dii). The plasma Vp levels in SCT- sized that SCT could stimulate Vp expression via the cAMP/ treated rats reached 3.78-fold within 30 min compared with protein kinase A (PKA)/Fos pathway. To test this hypothesis, those at time 0 or before peptide injection. Note also that Vp ICV injection of SCT coupled to laser capture microdissection levels of control animals remained relatively constant through- and real-time PCR (Fig. 2C) was performed.
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