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Provided by Elsevier - Publisher Connector mini review http://www.kidney-international.org & 2011 International Society of Nephrology

Secretin and body fluid Jessica Y.S. Chu1, Carrie Y.Y. Cheng1, Vien H.Y. Lee1, YS Chan2 and Billy K.C. Chow1

1School of Biological Sciences, The University of Hong Kong, Hong Kong, China and 2Department of Physiology and Research Centre of , , and Healthy Aging, The University of Hong Kong, Hong Kong, China

Body fluid homeostasis is critical for the survival of living The progression of life forms from the paleozoic oceans to organisms and hence is tightly controlled. From initial studies rivers and to different terrestrial eco-niches required the on the effects of (SCT) on renal water in coevolution of osmoregulatory mechanisms that defend body the 1940s and recent investigations of its role in cardiovascular cells from the changes in the osmotic pressure imposed by and neuroendocrine functions, it has now become the surrounding fluids. In terrestrial , sophisticated increasingly clear that this is an integral component physiological, behavioral, and cardiovascular responses of the homeostatic processes that maintain body fluid evolved so as to ensure the constancy of milieu interieur. balance. This review, containing some of our recent findings The physiological approach comprises adjustments in the of centrally expressed SCT on water intake, focuses on renal handling of water and , which is primarily the actions of SCT in influencing the physiological, regulated by the hormone, (Vp). The neuroendocrine, and cardiovascular processes that behavioral approach consists of the regulation of water subserve body fluid homeostasis. and salt intake, which is mainly modulated by the dipsogen, International (2011) 79, 280–287; doi:10.1038/ki.2010.397; II (ANGII). The cardiovascular approach published online 13 October 2010 controls the volume and pressure of body fluid using KEYWORDS: ; secretin; vasopressin; water drinking behavior both the –ANG system and Vp. These osmoregulatory responses arose from stimuli that activated groups of specialized nerve cells which are capable of transducing changes in into electrical signals to maintain fluid and balance in our body. In recent years, it has become evident that secretin (SCT), the oldest known peptide hormone1 controlling pancreatic secretion of ion, is actually expressed in those osmoregulatory and could regulate multiple processes, including neuroendocrine, behavioral, and cardio- vascular responses, that underlie body fluid homeostasis. This review will center on the influence of SCT in these processes at various tissues.

SECRETIN SCT is a 27-residue with an amidated carboxyl terminus. The peptide was discovered by Bayliss and Starling in 19021 and has subsequently been isolated/cloned from porcine,2 chicken,3 cow,4 human,5 dog,6 rat,7 rabbit,8 guinea ,9 ovine,10 and mouse.11 The best known action of SCT is its stimulatory effects on the exocrine secretion of , whereas the physiology of this peptide is complex exerting pleiotropic activities in many tissues.12 When reviewing its function, SCT is depicted as a peptide that controls directional fluxes of water and electrolytes across the plasma membrane. It was found to exhibit nanomolar potency in stimulating channel-mediated Cl efflux in the Correspondence: Billy K.C. Chow, School of Biological Sciences, 13 The University of Hong Kong, Pokfulam, Hong Kong, China. lung, and evoke the translocation of aquaporin-1 (AQP1) E-mail: [email protected] from intracellular compartments to the apical membrane for Received 18 March 2010; revised 28 July 2010; accepted 4 August 2010; the transepithelial movement of water into the ductal 14 published online 13 October 2010 lumen.

280 Kidney International (2011) 79, 280–287 JYS Chu et al.: Secretin and water homeostasis mini review

RENAL EFFECTS OF SCT the conclusion that SCT is a peptide.15–17 These In the early 1930s, it became apparent that SCT could observations contrast with the findings by Charlton et al.,18 modulate renal functions.15 Unfortunately, these investigations who showed an anti-diuretic function of SCT, with an effective bunged up, in part, because of the conflicting reports showing dose 50 at about 0.70 nmol/kg. Therefore, it is until the recent diuretic and antidiuretic effects of SCT. A number of studies usage of the SCT (SCTR)-deficient mouse model19 monitoring the effects of SCT on renal water handling led to that a role of SCT in the kidney was finally confirmed.

a Collecting tubules Bowman’s capsule

Thick ascending limb of

PT

Proximal tubules (PT) Loop of Henle

GTP-Gas Basolateral b SCTR H2O AC AQP4 AQP3

cAMP ? PKA CREB P Transcription CRE TATA 3′ IV AQP2 promoter

AQP2 Nucleus

H2O

Apical AQP2 Principal cell Figure 1 | SCT and its receptor in the kidney. (a) Bright-field photomicrograph of mouse kidney sections labeled with rabbit anti-mouse SCTR antibody raised in our laboratory (1:250). The specificity of this antibody was tested using sections obtained from SCTR/ mice.19 SCTR was shown to localize in almost every segment of the . (b) Diagrammatic illustration of the functions of SCT in the renal collecting duct tubules. SCT might be capable of inducing water reabsorption in renal collecting duct principal cells by binding to SCTR, which is localized on the basolateral membranes of the cells.19 On binding to its receptor, SCT activates an AC-cAMP–PKA cascade, which could then lead to an increase in AQP2 expression, probably via the subsequent phosphorylation of CREB and the docking of this factor onto the CRE site of the AQP2 gene promoter. In addition, SCT also induces the trafficking of AQP2 from the IV to the apical membrane of the collecting duct. This could allow water influx into the principal cells via AQP2 and water outflux from the cells via AQP3 and AQP4, which are constitutively expressed on the basolateral membrane. It is therefore possible that SCT could enhance water reabsorption from the collecting tubules. AC, ; AQP, aquaporin; cAMP, cyclic monophosphate; CRE, cAMP responsive element; CREB, cAMP responsive element binding protein; GTP, guanosine triphosphate; IV, intracellular vesicles; PKA, ; SCT, secretin; SCTR, SCT receptor.

Kidney International (2011) 79, 280–287 281 mini review JYS Chu et al.: Secretin and water homeostasis

SCTR is expressed throughout the kidney (Figure 1a). Its a serum concentration was found to increase significantly in hemodialysis patients20 and in patients with chronic 21 renal failure in comparison with controls, indicating SON that the peptide might be associated with clinical-patholo- gical status of the kidney. Morphologically, SCTR-deficient Rb-anti-SCT Ab Goat-anti-Vp Ab Overlay image mice showed no growth abnormality, but their kidney/body SCT weight ratio was significantly higher than their normal littermates.19 Besides, histological examination showed that the kidneys of SCTR/ mice were abnormal, char- acterized by increased mesangial area, enlarged urinary space, PVN and frequent tubular dilation and hypertrophy in the collecting tubules of the medullary region.19 This suggested that SCTR/ might have altered water absorption and filtration processes. Consistent to this notion, apart from the effects of SCT in increasing the renal blood flow,22 single-nephron glomerular filtration rate, and glomerular SON plasma flow,23 the peptide could probably induce renal water reabsorption in kidney tubules. In medullary tubules isolated þ / þ Rb-anti-SCTR Ab Goat-anti-Vp Ab Overlay image from the SCTR mice and normal Wistar rat, SCT was SCTR found to induce a dose-dependent increase in AQP2 expression on the plasma membrane and a dose-dependent decrease in AQP2 expression in the intracellular vesicles.19,24 This induced translocation of AQP2 was found to be PVN mediated via a cyclic /protein kinase A-dependent pathway,24 and was found to be absent in / 19 the medullary tubules isolated from SCTR mice, hence b SCT SCTR indicating that SCT induces the movement of AQP2 on binding with its receptor (Figure 1b). This latest finding is in agreement with an early report from Charlton et al.,18 who showed a reduction of output via the stimulation of adenylate cyclase in the outer medulla of the kidney when SCT was injected intravenously. Apart from in vitro treatment of SCT to medullary tubules, the movement and the expression of AQP2 were also examined in vivo in dehydrated mice. It was found that SCTR/ mice showed less movement of AQP2 to the plasma membrane than the SCTR þ / þ mice,19 suggesting that there was an altered AQP2 response during hyperosmolality. c As SCTR/ mice showed normal transcript levels of Vp receptor in their kidney, and slightly higher serum Vp levels Figure 2 | Cellular distribution of SCT and SCTR in the central as well as hypothalamic Vp transcript levels (1.54-fold±0.19- osmoregulatory regions. (a) SCT and its receptor were colocalized with Vp in the hypothalamic SON and PVN. The fold; Po0.05; n ¼ 20) when compared with their wild-type antibodies employed were rabbit anti-SCT (1:250 dilution; Phoenix 19 littermates, these data collectively suggested that SCT has a Pharmaceuticals, Burlingame, CA), rabbit anti-SCTR (1:200 dilution; Vp-independent role in the expression and movement of Chu et al.19), goat anti-Vp (1:400 dilution; Santa Cruz AQP2s in the kidney, and hence were consistent with the Biotechnology, Santa Cruz, CA), Alexa Fluor 594 donkey anti-goat 18 IgG (1:500 dilution; Molecular Probes, Invitrogen, Carlsbad, CA), finding by Charlton et al., who reported that the and Alexa Fluor 488 chicken anti-rabbit IgG (1:500 dilution; antidiuretic effect of SCT was as potent as Vp in homozygous Molecular Probes. (b) Photographs of SFO section stained with Vp-deficient Brattleboro rats. Taken together, these data antiserum against SCT and SCTR. Both SCT and its receptor were provided a plausible explanation for the underlying causes of shown to be highly expressed within the SFO. Controls (c) were / performed by liquid-phase preabsorption of the antiserum with and phenotypes observed in SCTR either 0.1 mM rat secretin or synthetic mouse mice. Besides, these data could also be of great interest to peptide (R-A-E-C-L-R-E-L-S-E-E-K-K, which is present in the mouse the nephrogenic diabetic insipidus community as it shows a secretin receptor) for 3 h at room temperature before incubating with the sections. Bar ¼ 6 mm. Ab, antibody; IgG, immunoglobulin direction of study for developing therapies to treat nephro- G; PVN, paraventricular; Rb, rabbit; paraventricular; SCT, secretin; genic diabetic insipidus that are independent of the Vp SCTR, SCT receptor; SFO, subfornical organ; SON, supraoptic; Vp, pathway. vasopressin.

282 Kidney International (2011) 79, 280–287 JYS Chu et al.: Secretin and water homeostasis mini review

NEUROENDOCRINE EFFECTS OF SECRETIN monophosphate/protein kinase A-dependent insertion of Magnocellular neurons of the hypothalamic supraoptic AQP2 onto the apical membrane of the collecting duct and paraventricular nuclei are integral component of the principal cells, wherein it functions as a hydrophilic pore to hypothalamic–neurohypophysial system that is crucially allow initial water movement from lumen to cytoplasm, and involved in the regulation of body fluid and electrolyte then subsequently via AQP3 and AQP4 located on the homeostasis. Vp released from the basolateral membrane to plasma. Evidence from both in vitro regulates renal water reabsorption and thereby controlling and in vivo studies, however, have indicated the presence of the rate of water loss from our body. In the kidney, the Vp-independent mechanisms regulating this renal water capability of Vp in maintaining body fluids depends on its reabsorption process. The first piece of evidence came from action on a water channel, AQP2, which is largely responsible using Vp-deficient Brattleboro rats. Li et al.25 showed that for renal water reabsorption and hence the urine concentrat- hyperosmolality in these animals could increase AQP2 ing ability. This is achieved by the cyclic adenosine expression and trafficking, as well as urinary osmolality,

a ICV-PBS ICV-SCT

b A 2 1.8 ** 1.6 ** * 1.4 * 1.2 1 0.8 0.6 Fold difference 0.4 0.2

(relative to PBS-injected animals) 0 Water intake Urine output ICV-PBS 1.00 ±0.09 1.00±0.10

30 µM SCT 1.41±0.15 1.19 ±0.20

50 µM SCT 1.45±0.14 1.56 ±0.16

B

3.5 Water intake 3 Fold difference in urine output

Urine output (relative to PBS-pumped rat)

3 ** IV-ANGII ** 2.5 2.5 2 2 1.5 1.5 1 1 IV-PBS * * ** 0.5 0.5 ** IV-SCT ** (relative to PBS-pumped rat) Fold difference in water intake 0 0 Day 1DDay 2DDay 3Day 1 ay 2 ay 3

Figure 3 | Centrally expressed SCT is a dipsogenic agent. (a) ICV-SCT (30 mM) into the lateral ventricular induced Fos-immunoreactivities in the SFO when compared with ICV injection of isotonic saline (ICV-PBS). (b) Centrally expressed SCT, but not circulating SCT, induces drinking behavior. (A) Centrally injected SCT dose-dependently increase water intake and urine output. Data points are the mean fold±s.e.m. of values obtained in 15–20 rats per group. *Po0.05 and **Po0.01 versus PBS-treatment group. (B) Peripheral injection of SCT through osmotic minipump was not capable of increasing water intake in rats compared with those injected with isotonic saline (IV-PBS). ANGII, a dipsogenic agent when intravenously injected into the rat, was used as an internal control. ANGII, angiotensin II; ICV, intracerebroventricular; IV, intracellular vesicles; PBS, phosphate-buffered saline; SCT, secretin.

Kidney International (2011) 79, 280–287 283 mini review JYS Chu et al.: Secretin and water homeostasis

indicating the presence of mechanisms independent of Vp in axonal terminals into the systemic circulation.31 All these stimulating AQP2 expression and translocation. Another observations implicate a functional role of SCT as one of piece of evidence came from the observation that 10 pM Vp, the fluid regulating in our bodies. which is the highest plasma concentration of Vp found in severe dehydration, could only increase osmotic water EFFECTS OF SCT ON DRINKING BEHAVIOR permeability to 44% of its maximal.26 Other factors, The function of SCT in changing behaviors associated therefore, could boost osmotic water permeability to levels with fluid balance is suggested by the presence of SCT and higher than those by Vp alone. Consistent with this notion, SCTR in the subfornical organ (SFO; Figure 2b), a Bauman27 observed a reduction in the osmotic gradient circumventricular region that is known to be important along the length of the papilla in hypophysectomized rats, in ANGII-induced water intake. Intracerebroventricular and this reduction could not be restored back to normal SCT could induce Fos-immunoreactivities in this region upon exogenous Vp treatment. This indicates the limited (Figure 3a), showing that SFO is responsive to SCT. effectiveness of Vp in the absence of other pituitary Moreover, intracerebroventricular SCT-injected rats were hormone(s) which is/are likely required for developing the found to drink more water and hence produce more urine osmotic gradient. than rats injected with the saline control (Figure 3A); SCT is SCT has recently been identified to potentially regulate therefore a putative dipsogenic agent. Peripherally injected renal water reabsorption, and interestingly, this peptide SCT, however, was incapable of inducing the water drinking hormone has a much higher expression in the pituitary behavior (Figure 3B). Our data therefore shows that only when compared with the brain.28 O’Donohue et al.29 centrally injected SCT, but not circulating SCT, could detected B17 times higher amount of SCT in the than that in the cerebral cortex, whereas Charlton 30 et al. revealed that within the pituitary, concentration of a 2.50 SCT in the neurointermediate lobe was about 45-fold higher ** than that observed in the anterior lobe. Consistent with 2.00 this, a recent study demonstrated abundant levels of SCT 1.50 immunoreactivities in the of the posterior pituitary,31 indicating the potential of SCT as a neuro- 1.00 expression secretory hormone. This is supported by peptide release 0.50 studies, in which exposure of pituitary explants to a depolari- þ (relative to PBS infusion) zing stimulation of 80 mM K evoked SCT release in a 0.00 Fold difference in central SCT IV ICV tetrodotoxin-dependent manner.31 Besides, an increase in the PBS 1.00 ± 0.21 1.00 ± 0.09 plasma SCT level was also found during water deprivation in 5 µg ANG 1.39 ± 0.07 1.90 ± 0.18 normal rats but not hypophysectomized rats.31 These support the idea that SCT is a neurosecretory factor being release b 4.50 from the posterior pituitary into the circulation during 4.00 ** hyperosmolality. It then functions in the kidney in a similar 3.50 ** ** manner as Vp to stimulate the translocation of AQP2, and 3.00 * * * hence a possible role on renal water reabsorption. 2.50 Apart from releasing into the systemic circulation, SCT 2.00 can also be released locally within the central nervous SCT level 1.50 32,33 system, indicating its role as a . Within the 1.50 brain, SCTRs were localized in areas including the circum- Fold difference in plasma 0.50 ventricular organs and the Vpergic neurons within paraven- 0.00 tricular and supraoptic (Figure 2).31 These nuclei are the –5 min 0 min 5 min 10 min 15 min 20 min 25 min 30 min primary brain sites that are engaged in the defense of fluid PBS 1.26 0.74 0.76 0.62 0.81 0.67 0.43 0.70 perturbation, thus providing anatomical evidence to support ANG 0.89 0.97 3.37 2.84 2.86 2.26 2.57 2.35 the functional role of SCT in modulating neuroendocrine Figure 4 | Secretin is possibly a mediator of ANGII action. responses to osmotic stimuli. Consistent to this notion, we (a) Centrally, but not peripherally, injected ANGII induced central had previously shown that (1) transcript levels of SCT SCT expression. Results are presented in mean fold and SCTR were both increased in the during changes±s.e.m. (n ¼ 5). *Po0.05 versus PBS-treatment group. 31 (b) Centrally injected ANG triggers SCT release into peripheral water deprivation, and (2) SCT could be released from the circulation. Blood samples (150 ml) were collected every 5 min from 32 hypothalamic explants under depolarizing stimulation. In the jugular vein from 5 min before to 30 min (5-min interval) after addition, intracerebroventricular injection of SCT was able to ICV infusion of 5 mg ANG. The results are presented in mean fold ± induce c-fos expression in Vp-expressing magnocellular changes s.e.m. relative to PBS-infused basal level of SCT in the plasma (0.099±0.005 ng/ml). *Po0.05 and **Po0.01. neurons in paraventricular and supraoptic, in which it ANG; angiotensin; ICV, intracerebroventricular; IV, intracellular specifically augments Vp expression and secretion from the vesicles; PBS, phosphate-buffered saline; SCT, secretin.

284 Kidney International (2011) 79, 280–287 JYS Chu et al.: Secretin and water homeostasis mini review

significantly change water intake and urinary output over sent via the IXth and Xth cranial nerves primarily to the a 24-h period. nucleus tractus solitarius (NTS), which is a region essential The forebrain SFO is an upstream component of the for the regulation of cardiovascular function. The notion that central ANGII pathway leading to water intake and Vp SCT can directly influence central processing of information secretion from the neurohypophyseal system.34 SCT induc- related to via NTS is supported by the fact tion of Fos immunoreactivities in SFO therefore raises the that (i) 125I-SCT binding sites were detected in NTS35; possibility of the interaction between ANGII and SCT at SFO. (ii) intravenous injection of SCT was found to stimulate c-fos In fact, centrally injected ANGII was able to increase plasma expression in NTS36; and (iii) SCT was found to directly SCT level as well as its expression in central (Figure 4). It is activate NTS neurons via the stimulation of a nonselective therefore possible that SCT mediates the central effects of cationic conductance.35 Consistently, there are findings ANGII on water ingestion as well as Vp secretion from the showing that intravenous injection of SCT causes a posterior pituitary. significant fall of arterial blood pressure,2 and that the heart membranes of Lyon strain of hypertensive rats have a 30–35% CARDIOVASCULAR EFFECTS OF SECRETIN decrease of SCT-stimulated adenylate cyclase activity Changes in the extracellular volume () and when compared with Lyon normotensive rats and Lyon pressure are detected by baroreceptors, and information are low-blood-pressure rats.37 These suggested a possible role of

Drinking

Secretin

Secretin

GTP-Gas

GTP-Gas AC cAMP AC PKA SCTR cAMP CREB Fos ? PKA SCTR CREB P Transcription Transcription + P 5′ CRE TATA 3′ Fos ? CRE TATA 3′ c-fos gene promoter Jun c-fos gene promoter P P Transcription Nucleus 5′ CRE-AP-1 3′ AAA AAA Vp gene promoter AAA Nucleus

Magnocellular Subfornical organ soma Vasopressin

Hypothalamus

Figure 5 | Diagrammatic illustration of the functions of SCT in SFO and hypothalamus. In the SFO, SCT-stimulated c-fos expression is believed to function via the binding of SCT onto its receptor, hence triggering the activation of AC that increases the intracellular cAMP level. Activated PKA could then induce the phosphorylation of CRE binding protein (CREB), and hence the transcription of c-fos immediate early gene. SCT also functions as a dipsogenic peptide, probably through its action on the renin–angiotensin system within this region. In the hypothalamic magnocellular neurons, SCT-induced increases in cAMP might lead, via the activation of PKA, CREB, and/or activating transcription factor proteins, to the stimulation of Fos/Jun family of transcription factors. Subsequent dimerization of the product Fos with Jun protein could allow their interaction with the CRE sequences in Vp promoter, hence upregulating the Vp . As cAMP was demonstrated to upregulate the Vp gene transcriptionally via CRE and post-transcriptionally via enhancing the polyadenylation of its mRNA, SCT-induced cAMP could probably function directly to stimulate the Vp gene expression through CREB phosphorylation as well as to enhance the stability of vasopressin mRNA in the cytoplasm by increasing the polyadenylate tail length. In the hypothalamo–pituitary axis, SCT induces the secretion of Vp within the hypothalamic nuclei as well as from the posterior pituitary into the circulation. SCT itself could also be liberated into the fenestrated capillaries within the pars nervosa, exerting its action in the kidney. AC, adenylyl cyclase; cAMP, cyclic adenosine monophosphate; CRE, cAMP responsive element; CREB, cAMP responsive element binding protein; PKA, protein kinase A; SCT, secretin; SCTR, SCT receptor; SFO, subfornical organ; SON, supraoptic; Vp, vasopressin.

Kidney International (2011) 79, 280–287 285 mini review JYS Chu et al.: Secretin and water homeostasis

SCT as a vasodilator. One interesting point to note is, during reported. Therefore, further understanding of the roles of SCT-induced mesenteric vasodilation, a significant redistribu- SCT in body fluid balance should provide direction for future tion of blood was observed,38 that is, SCT may affect blood programs aimed at developing SCT/SCT /SCTR flow distribution in certain peripheral organs. In fact, SCT has antagonists for the prevention and/or therapeutic interven- previously been found to cause a preponderance of flow of tion of disorders in homeostasis. A widespread cardiac output to the renal circulation among renal, carotid, use in disease treatment, however, requires well-designed femoral, and the superior mesenteric arteries39 In dogs with studies that lead us to a more detail understanding regarding an acute left ventricular failure, although, SCT injection their safety for repeated administration, as well as their restores blood flow to a level similar as in healthy subjects by dosage and side effects. directing cardiac output to all the investigated arteries.40 As injection of pharmacological doses of SCT in patients with DISCLOSURE reduced cardiac function could augment left ventricular All the authors declared no competing interests. performance by arteriolar dilation and its positive inotropic 41 ACKNOWLEDGMENTS effect, SCT may therefore regulate blood flow distribution. This work was supported by the HK government RGC grant Taken together, as precise control of body fluid homeostasis HKU7501/05 M and HKU7384/04 M to BKCC. requires mechanisms that maintain overall water and balance as well as appropriate regional and compartmental REFERENCES distributions of these substances, that is, consistency in blood 1. Bayliss WM, Starling EH. The mechanism of pancreatic secretion. volume and pressure, SCT might also be involved in the J Physiol 1902; 28: 325–353. 2. Mellanby J. The isolation of secretin-its chemical and physiological toning of cardiovascular response when there are changes in properties. J Physiol 1928; 66: 1–18. body fluid and volume. However, further studies are needed 3. Nilsson A, Carlquist M, Jornvall H et al. Isolation and characterization to confirm a role of the peptide in this aspect. of chicken secretin. Eur J Biochem 1980; 112: 383–388. 4. Carlquist M, Jornvall H, Mutt V. Isolation and sequence of bovine secretin. FEBS Lett 1981; 127: 71–74. CONCLUSION AND FUTURE PRESPECTIVE 5. Carlquist M, Joernvall H, Forssmann WG et al. Human secretin is not identical to the porcine/bovine hormone. IRCS J Med Sci 1985; 13: The objective of this review is to summarize findings and to 217–218. provide an overview on how SCT influences particular 6. Shinomura Y, Eng J, Yalow RS. Dog secretin: sequence and biologic compensatory responses during body fluid challenges. In the activity. Life Sci 1987; 41: 1243–1248. 7. Gossen D, Vandermeers A, Vandermeers-Piret MC et al. Isolation and central nervous system, the peptide stimulates drinking primary structure of rat secretin. Biochem Biophys Res Commun 1989; 160: behavior and the release of Vp into the circulation (Figure 5), 862–867. whereas in the renal system, it activates AQP2 expression and 8. Gossen D, Buscail L, Cauvin A et al. Amino acid sequence of VIP, PHI and secretin from the rabbit . 1990; 11: 123–128. trafficking in the collecting tubules, hence suggesting its 9. Buscail L, Cauvin A, Gourlet P et al. Purification and amino acid sequence potential role on renal water retention. Clearly, our under- of vasoactive intestinal peptide, peptide isoleucinamide (1–27) standing on the detail pathways and mechanisms involved in and secretin from the small intestine of guinea pig. Biochim Biophys Acta 1990; 1038: 355–359. SCT-regulated body fluid balance, the neuronal regions 10. Bounjoua Y, Vandermeers A, Robberecht P et al. Purification and amino participated in SCT-induced responses, and the cardiovas- acid sequence of vasoactive intestinal peptide, peptide histidine isoleucinamide and secretin from the ovine small intestine. Regul Pept cular role of this peptide during changes in body fluid are not 1991; 32: 169–179. completely understood. Nevertheless, with the generation 11. Lan MS, Kajiyama W, Donadel G et al. cDNA sequence and genomic and functional characterization of transgenic mouse models, organization of mouse secretin. Biochem Biophys Res Commun 1994; 200: 1066–1071. we could have experimentally accessible system for re- 12. Chu JY, Yung WH, Chow BK. Secretin: a pleiotrophic hormone. Ann N Y assessing multiple aspects of this peptide–ligand pair, Acad Sci 2006; 1070: 27–50. particularly their role in sodium homeostasis and the 13. Davis RJ, Page KJ, Dos Santos Cruz GJ et al. Expression and functions of the duodenal peptide secretin and its receptor in human lung. cardiovascular system. Alternatively, the generation of Am J Respir Cell Mol Biol 2004; 31: 302–308. transgenic mouse models could also provide proof-of- 14. Marinelli RA, Pham L, Agre P et al. Secretin promotes osmotic water transport in rat by increasing aquaporin-1 water channels principle insight for the development of new therapeutic in plasma membrane. Evidence for a secretin-induced vesicular strategies for certain disorders. For example, observation of translocation of aquaporin-1. J Biol Chem 1997; 272 : 12984–12988. the pathological symptoms that are characteristics of 15. Dragstedt CA, Owen SE. The diuretic action of secretin preparations. / Am J Physiol (Legacy) 1931; 97: 276–281. nephrogenic diabetic insipidus in SCTR mice has 16. Barbezat GO, Isenberg JI, Grossman MI. Diuretic action of secretin in dog. suggested the possibility that SCT could serve as a potential Proc Soc Exp Biol Med 1972; 139: 211–215. candidate in treating X-linked nephrogenic diabetic insipidus 17. Viteri AL, Poppell JW, Lasater JM et al. Renal response to secretin. J Appl Physiol 1975; 38: 661–664. with defective V2R signaling. Along with reported effects of 18. Charlton CG, Quirion R, Handelmann GE et al. Secretin receptors in the rat this peptide on secretion,42 it is also believed that kidney: adenylate cyclase activation and renal effects. Peptides 1986; 7: 865–871. alteration in the synthesis and/or secretion of SCT might 19. Chu JY, Chung SC, Lam AK et al. Phenotypes developed in secretin probably contribute to renal and metabolic perturbations receptor-null mice indicated a role for secretin in regulating renal water observed in diabetes as well as type D syndrome of reabsorption. Mol Cell Biol 2007; 27: 2499–2511. 20. Grekas DM, Raptis S, Tourkantonis AA. Plasma secretin, pancreozymin, inappropriate anti-diuretic hormone, in which no demon- and -like hormone in chronic renal failure patients. strable abnormality in the of Vp was Uremia Invest 1984; 8: 117–120.

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21. Hansky J. Effect of renal failure on gastrointestinal hormones. 32. Chu JY, Yung WH, Chow BK. Endogenous release of secretin from the World J Surg 1979; 3: 463–467. hypothalamus. Ann N Y Acad Sci 2006; 1070: 196–200. 22. Lameire N, Vanholder R, Ringoir S et al. Role of medullary hemodynamics 33. Lee SM, Chen L, Chow BK et al. Endogenous release and multiple actions in the natriuresis of drug-induced renal vasodilation in the rat. of secretin in the rat cerebellum. Neuroscience 2005; 134: 377–386. Circ Res 1980; 47: 839–844. 34. Mangiapane ML, Thrasher TN, Keil LC et al. Role for the subfornical 23. Marchand GR. Effect of secretin on glomerular dynamics in dogs. organ in vasopressin release. Brain Res Bull 1984; 13: 43–47. Am J Physiol 1986; 250: F256–F260. 35. Yang B, Goulet M, Boismenu R et al. Secretin depolarizes nucleus 24. Cheng CY, Chu JY, Chow BK. Vasopressin-independent mechanisms tractus solitarius neurons through activation of a nonselective cationic in controlling water homeostasis. J Mol Endocrinol 2009; 43: 81–92. conductance. Am J Physiol Regul Integr Comp Physiol 2004; 286: 25. Li C, Wang W, Summer SN et al. Hyperosmolality in vivo upregulates R927–R934. water channel and Na-K-2Cl co-transporter in Brattleboro 36. Yang H, Wang L, Wu SV et al. Peripheral secretin-induced Fos expression rats. J Am Soc Nephrol 2006; 17: 1657–1664. in the rat brain is largely vagal dependent. Neuroscience 2004; 128: 26. Jeon US, Joo KW, Na KY et al. induces apical and basolateral 131–141. redistribution of aquaporin-2 in rat kidney. Nephron Exp Nephrol 2003; 93: 37. Robberecht P, Gillet L, Chatelain P et al. Specific decrease of secretin/ e36–e45. VIP-stimulated adenylate cyclase in the heart from the Lyon strain of 27. Bauman Jr JW. Effect of hypophysectomy on the renal concentrating hypertensive rats. Peptides 1984; 5: 355–358. ability of the rat. 1965; 77: 496–500. 38. Fara JW, Madden KS. Effect of secretin and on small 28. Itoh N, Furuya T, Ozaki K et al. The secretin precursor gene. Structure of intestinal blood flow distribution. Am J Physiol 1975; 229: 1365–1370. the coding region and expression in the brain. J Biol Chem 1991; 266: 39. Gunnes P, Reikeras O. Distribution of the increased cardiac output 12595–12598. secondary to the vasodilating and inotropic effects of secretin. 29. O’Donohue TL, Charlton CG, Miller RL et al. Identification, Scand J Clin Lab Invest 1987; 47: 383–388. characterization, and distribution of secretin immunoreactivity in rat 40. Gunnes P, Reikeras O. Peripheral distribution of the increased cardiac and pig brain. Proc Natl Acad Sci USA 1981; 78: 5221–5224. output by secretin during acute ischemic left ventricular failure. 30. Charlton CG, O0Donohue TL, Miller RL et al. Secretin in the rat J Pharmacol Exp Ther 1988; 244: 1057–1061. hypothalamo-pituitary system: localization, identification and 41. Gunnes P, Rasmussen K. Haemodynamic effects of pharmacological characterization. Peptides 1982; 3: 565–567. doses of secretin in patients with impaired left ventricular function. 31. Chu JY, Lee LT, Lai CH et al. Secretin as a neurohypophysial factor Eur Heart J 1986; 7: 146–149. regulating body water homeostasis. Proc Natl Acad Sci USA 2009; 106: 42. Enk B. Secretin-induced insulin response. II. Dose-response relation. 15961–15966. Acta Endocrinol (Copenh) 1976; 82: 312–317.

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