Skip to main content
PMC home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2017 Apr 1.
Published in final edited form as: Exp Physiol. 2016 Mar 2;101(4):465–470. doi: 10.1113/EP085286

The importance of the gastrorenal axis in the control of body sodium homeostasis

Pedro A Jose 1, Zhiwei Yang 2, Chunyu Zeng 3, Robin A Felder 4
PMCID: PMC4818653  NIHMSID: NIHMS758477  PMID: 26854262

Abstract

Hypertension develops with chronically increased sodium intake when sodium that accumulates in the body can no longer be sequestered, extracellular fluid is expanded, and compensatory neural, hormonal, and pressure-natriuresis mechanisms fail. Sensing the amount of ingested sodium, by the stomach, is one mechanism by which sodium balance is regulated. The natriuresis following the ingestion of a certain amount of sodium may be due to an enterokine, gastrin, secreted by G-cells in the stomach and duodenum and released into the circulation. Circulating gastrin levels are 10–20-fold higher than those for cholecystokinin. Of all the gut hormones circulating in the plasma, gastrin is the one that is reabsorbed to the greatest extent by renal tubules. Gastrin, via its receptor, the cholecystokinin type B receptor (CCKBR), is natriuretic, in mammals including humans, caused by inhibition of renal sodium transport. Germline deletion of gastrin (Gast) or Cckbr gene in mice causes salt-sensitive hypertension. Selective silencing of Gast in the stomach and duodenum impairs the ability to excrete an oral sodium load and also increases blood pressure. Thus, the gastro-renal axis, mediated by gastrin, can complement pronatriuretic hormones, such as dopamine to increase sodium excretion after an oral sodium load. These studies in mice may be translatable to humans because the chromosomal loci of CCKBR and GAST are linked to human essential hypertension. Understanding the role of genes in the regulation of renal function and blood pressure may lead to the tailoring of anti-hypertensive treatment based on genetic make-up.

Keywords: dopamine, gastrin, gastro-renal axis, salt sensitivity

Introduction

Forty percent of the world’s population has hypertension and is responsible for about 12.8 % of annual deaths (Alwan, 2010). However, these statistics do not distinguish salt-sensitive from salt-resistant hypertension or include normotensives who are salt-sensitive. Almost half of the US population has hypertension, salt sensitivity, or both (Sullivan, 1991, Weinberger et al, 2001). Salt sensitivity, independent of blood pressure, is a risk factor for cardiovascular morbidity and mortality (Weinberger et al, 2001) and other diseases, e.g., asthma, gastric carcinoma, osteoporosis, and renal dysfunction (de Wardener et al, 2002, Franco et al, 2006). Salt sensitivity has also been claimed to interfere with the normal circadian rhythm of blood pressure (Logan et al, 2009). A normal dip in nocturnal blood pressure - a 10% fall in blood pressure relative to day time blood pressure - is important because the failure of the normal night-time dip in blood pressure is associated with an increase in cardiovascular morbidity and mortality (Logan et al, 2009, O’Brien E, 2009).

The World Health Organization recommends reducing sodium consumption to less than 87 mmol per day in adults, to help prevent hypertension, heart disease, and stroke (www.who.int/global.../global-status-report-ncds, 2014). In a recent meta-analysis of randomized controlled trials, it was concluded that in the normotensive population, there is no relation between the amount of sodium restriction (136–188 mmol/day) and blood pressure level. However, in the prehypertensive and hypertensive populations, reduction in sodium intake (77–140 mmol/day) correlated with the decrease in blood pressure (Graudal et al, 2015). Another meta-analysis indicated that a modest reduction in salt intake for 4 or more weeks causes a decrease in blood pressure levels in in both hypertensive and normotensive individuals (He et al, 2013). However, these meta-analyses do not take into account the influence of genetics and epigenetics on blood pressure response to sodium intake. A lower limit of the daily NaCl intake is also not defined (Institute of Medicine, 2013), although the relationship between sodium intake and blood pressure may not be linear but more of a J-shaped curve. There is an increase in cardiovascular risk at very low levels of sodium intake (Mente et al, 2014). Sodium restriction (<40 mmol/day) may increase the blood pressure in 15 to 20% of the population and may be more apparent in normotensive than hypertensive individuals (Ruppert et al, 1993, Montasser et al, 2011, Gildea et al, 2013).

Hypertension and salt sensitivity are complex diseases that are probably caused by genetics, epigenetics, and lifestyles, e.g., excessive sodium consumption and sedentary lifestyles. The precise genetic modifications that affect the regulatory mechanisms that lead to salt sensitivity in human essential hypertension remain unknown. However, the importance of the kidney in blood pressure regulation (Hall et al, 2012) is supported by renal transplantation studies in humans (Curtis, 1983), rats (Bianchi et al, 1974, Morgan et al, 1990), and mice (Crowley et al 2005, Asico et al 2011). An inability of the kidney to excrete a sodium load would cause a positive sodium balance (Hall et al 2012).

Gut sodium sensing

There is a growing appreciation of a role of the gastrointestinal tract in the regulation of blood pressure because it is the first organ exposed to ingested nutrients and most likely to initially react to sodium load (Michell et al, 2008, Furness et al, 2013). Sensing the amount of ingested sodium may be an important mechanism by which sodium balance is regulated (Michell et al, 2008). Indeed, given the same amount of sodium load, an oral load may be more rapidly excreted than an intravenous load (Carey, 1978, Preston et al, 2012). The presence of a gut sodium sensor has been disputed (Furness et al, 2013, Andersen et al, 2000). However, a discrepancy between the rapidity of sodium excretion following an oral or an intravenous administration of sodium does not dispute the presence of a gut sodium sensor (Preston et al, 2012)

Gastrin as the effector of gut sodium sensor

Neural mechanisms (Furness et al, 2013), including the activation of the parasympathetic and inhibition of the sympathetic nervous system (Mailman, 1980), and gut hormones (e.g., uroguanylin [Guca2b], cholecystokinin [CCK]) have been proposed to mediate the natriuresis of an oral sodium load. However, the oral intake of sodium may not increase circulating proguanylin, prouroguanylin, or uroguanylin (GUCA2B) (Lorenz et al, 2003, Preston et al, 2012). Guca2b−/− mice have an impaired natriuretic response to an acute oral but not an intravenous sodium load. However, the blood pressure sensitivity to an increase in sodium intake is similar Guca2b−/− and Guca2b+/+ mice. Inactivating GUCA2B variants in humans are also not associated with salt-sensitive hypertension. CCK is natriuretic but circulating CCK levels are not increased by oral sodium load and CCK is not reabsorbed by renal tubules (Melis et al, 2007). By contrast, the natriuresis following ingestion of a certain amount of sodium may be due to gastrin secreted by G-cells in the stomach and duodenum and released into the circulation (Michell et al, 2008, Pisegna et al, 1996). The oral intake of sodium, even in the absence of food, can stimulate gastrin secretion (Survé & Håkanson, 1998). Sodium, in conjunction with D1-like receptors in G-cells of the stomach, increases the expression of gastrin (Gildea et al, 2014, 2015).

The normal fasting plasma gastrin levels range from 100 to 200 pg/ml; the meal-stimulated blood gastrin concentration is about 2–4.5-fold higher, equivalent to a concentration of about 400 pM (Li et al, 2014 Saqui-Salces et al, 2012). Among the radiolabeled analogues of several enterokines (CCK, gastrin, bombesin, neurotensin, and somatostatin), gastrin is taken up and retained to the greatest extent by renal proximal tubules (100–1000-fold), presumably by reabsorption from the glomerular filtrate (Melis et al, 2005, Melicharova et al, 2014). Thus, gastrin levels in the kidney after feeding may be in the nanomolar range, concentrations we have used to study the ability of gastrin to inhibit NHE3 and Na+, K+-ATPase activities in human renal proximal tubule cells (Li & Jose, 2013, Li et al, 2016). Gastrin then acts on its receptor, the cholecystokinin B receptor, CCKBR, expressed in several nephron segments (Calam et al, 1987, Pisegna et al, 1996, von Schrenck et al 2000) to decrease renal sodium transport. Gastrin has also been shown to decrease ileal absorption of sodium by increasing its (sodium) secretion into the ileal lumen. The direct inhibitory effect of gastrin on sodium transport in the intestines may be complemented by gastrin-mediated stimulation of cholinergic nerves or inhibition of sympathetic nerves (Mailman, 1980). Gastrin is important in the natriuresis associated with high salt diet because a CCKBR antagonist, YF476, abrogates the natriuresis in salt-resistant BALB/c mice fed 3% NaCl diet for two weeks (Jiang et al, 2016). Gastrin is important in the regulation of sodium balance and blood pressure because germ-line deletion of Gast (i.e., Gast−/−) (Pisegna et al, 1996) or Cckbr (Yang et al, 2012, Jiang et al, 2016) or silencing Gast using siRNA selectively in the stomach (unpublished data) in mice prevents or minimizes the increase in sodium excretion after an oral sodium load. These mice also have increased blood pressure. Gast is also important in salt sensitivity because Gast−/− mice on low sodium intake are normotensive but become hypertensive with normal or high sodium intake (Pisegna et al, 1996 and unpublished data).

Gastrin needs a functioning renal dopaminergic system to exert is natriuretic effect. Gast−/− mice have decreased renal dopamine production (unpublished data). The natriuretic effect of gastrin, administered selectively into the kidney, via infusion into the right suprarenal artery, can be blocked not only by the CCKBR antagonist, CI-988, but also by the D1-like receptor antagonist, SCH23390. Moreover, the natriuretic effect of fenoldopam, a D1-like receptor agonist, also administered selectively into the kidney, via infusion into the right suprarenal artery, can be blocked not only by a D1-like receptor antagonist, SCH23390, but also by a CCKBR antagonist, CI-988, in normotensive Wistar-Kyoto rats (Chen et al, 2013). Gastrin and fenoldopam also interact to inhibit Na+-K+-ATPase activity in renal proximal tubule cells from Wistar-Kyoto rats. By contrast, the synergism between D1-like receptors and CCKBR in the regulation of renal sodium transport, in vivo and in vitro, in Wistar-Kyoto rats is not observed in spontaneously hypertensive rats. The synergistic interaction between D1-like receptors and CCKBR in renal proximal tubule cells from Wistar-Kyoto rats was related to a gastrin-induced increase in D1R and CCKBR colocalization at the plasma membrane in these renal proximal tubule cells. These effects were much less or not observed in renal proximal tubule cells from spontaneously hypertensive rats (Chen et al, 2013). The increased sodium excretion in mice fed a high salt diet is also abrogated by D1-like receptor or CCKBR antagonists (Jiang et al, 2016). We have also reported that the D1-like receptor agonist fenoldopam, or gastrin, inhibits NHE3 activity in human renal proximal tubule cells (Armando et al, 2011, Chen et al, 2013, Liu et al, 2013).

Products of the fermentation of nutrients by gut microbiota can influence blood pressure by regulating expenditure of energy, intestinal metabolism of catecholamines, and gastrointestinal and renal ion transport, and thus, salt sensitivity (Jose & Raj, 2015). Increased sodium transport in the gastrointestinal tract may contribute to salt sensitivity (Lienhard et al, 2012, Spencer et al, 2014, Li et al, 2015). Gastrin and dopamine can also decrease ion transport in the gastrointestinal tract. Dopamine, via D1-like receptors, inhibits jejunal Na+-K+-ATPase activity in young (20 days) but not older normotensive rats that is greater in those fed low than normal or high salt diet. The inhibitory effect of dopamine on jejunal Na+-K+-ATPase activity is not observed in spontaneously hypertensive rats (Lucas-Teixeira et al, 2000). However, the ability of dopamine to inhibit jejunal Na+-K+-ATPase activity persists in obese Zucker rats fed a high salt diet (Lucas-Teixeira et al 2002). In adult rats and dogs, gastrin can inhibit jejunal Na+-K+-ATPase activity (Mailman, 1980, Sharon et al, 1981). Although, gastrin does not inhibit electrolyte transport in the colon (Cummings, 1975), gastrin-releasing peptide stimulates sodium secretion in the distal colon (Traynor TR & O’Grady, 1996). D1-like receptors also simulate duodenal mucosal bicarbonate secretion (Safstein, 1993). Whether or not gastrin and dopamine interact to regulate intestinal ion transport remains to be determined.

Genome-wide association studies (GWAS) have identified only 2% of the genetic factors believed to influence blood pressure (Padmanabhan et al, 2015). This may be related to the fact that GWAS used screening platforms that did not consistently include genes that may be important in blood pressure regulation; e.g., CCKBR, GAST, and variants of other genes important in causing essential hypertension (e.g., G protein-coupled receptor kinase 4 [GRK4] which negatively regulates D1R and D3R [Armando et al, 2011]). Nevertheless, the chromosomal loci of CCKBR (11p15.5-p15.4) and GAST (17q21) are among those identified by GWAS that are linked to hypertension. However, CCKBR and GAST single nucleotide polymorphisms have not been associated with hypertension.

In summary, published and unpublished data suggest that gastrin produced by G-cells may be the effector of the sodium sensor in the stomach. However, the identification of the sodium sensor in the stomach remains to be determined. The presence of sodium sensors in other segments of the gastrointestinal tract also needs to be determined.

New Findings.

What is the topic of this review?

Sensing the amount of ingested sodium is one mechanism by which sodium balance is regulated. This review describes the role of gastrin in the cross-talk between the stomach and the kidney following the ingestion of sodium.

What advances does it highlight?

Neural mechanisms and several gut hormones, including cholecystokinin and uroguanylin, have been suggested to mediate the natriuresis after an oral sodium load. It is proposed that gastrin produced by G-cells via its receptor, cholecystokinin B receptor, interacts with renal D1-like dopamine receptors to increase renal sodium excretion.

Acknowledgments

Financial support

This work was supported, in part, by grants from the National Institutes of Health, R37 HL023081, R01DK039308, R01HL092196, P01HL068686, and P01 HL074940 and grants from the National Natural Science Foundation of China 81370358, 81300197, and 31130029.

Footnotes

Competing Interests

None

References

  1. Alwan A. Global Status Report on noncommunicable diseases 2010. Vol. 2011. World Health Organization; 2011. [Google Scholar]
  2. Andersen LJ, Jensen TU, Bestle MH, Bie P. Gastrointestinal osmoreceptors and renal sodium excretion in humans. Am J Physiol Regul Integr Comp Physiol. 2000;278:R287–R294. doi: 10.1152/ajpregu.2000.278.2.R287. [DOI] [PubMed] [Google Scholar]
  3. Asico L, Zhang X, Jiang J, Cabrera D, Escano CS, Sibley DR, Wang X, Yang Y, Mannon R, Jones JE, Armando I, Jose PA. Lack of renal dopamine D5 receptors promotes hypertension. J Am Soc Nephrol. 2011;22:82–89. doi: 10.1681/ASN.2010050533. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Armando I, Villar VA, Jose PA. Dopamine and renal function and blood pressure regulation. Compr Physiol. 2011;1:1075–1117. doi: 10.1002/cphy.c100032. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bianchi G, Fox U, Di Francesco GF, Giovanetti AM, Pagetti D. Blood pressure changes produced by kidney cross-transplantation between spontaneously hypertensive rats and normotensive rats. Clin Sci Mol Med. 1974;47:435–448. doi: 10.1042/cs0470435. [DOI] [PubMed] [Google Scholar]
  6. Calam J, Gordon D, Peart WS, Taylor SA, Unwin RJ. Renal effects of gastrin C-terminal tetrapeptide (as pentagastrin) and cholecystokinin octapeptide in conscious rabbit and man. Br J Pharmacol. 1987;91:307–314. doi: 10.1111/j.1476-5381.1987.tb10285.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Carey RM. Evidence for a splanchnic sodium input monitor regulating renal sodium excretion in man. Lack of dependence upon aldosterone. Circ Res. 1978;43:19–23. doi: 10.1161/01.res.43.1.19. [DOI] [PubMed] [Google Scholar]
  8. Chen Y, Asico LD, Zheng S, Villar VA, He D, Zhou L, Zeng C, Jose PA. Gastrin and D1 dopamine receptor interact to induce natriuresis and diuresis. Hypertension. 2013;62:927–933. doi: 10.1161/HYPERTENSIONAHA.113.01094. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Crowley SD, Gurley SB, Oliverio MI, Pazmino AK, Griffiths R, Flannery PJ, Spurney RF, Kim HS, Smithies O, Le TH, Coffman TM. Distinct roles for the kidney and systemic tissues in blood pressure regulation by the renin-angiotensin system. J Clin Invest. 2005;115:1092–1099. doi: 10.1172/JCI200523378. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Cummings JH. Absorption and secretion by the colon. Gut. 1975;16:323–329. doi: 10.1136/gut.16.4.323. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Curtis JJ, Luke RG, Dustan HP, Kashgarian M, Whelchel JD, Jones P, Diethelm AG. Remission of essential hypertension after renal transplantation. N Engl J Med. 1983;309:1009–1015. doi: 10.1056/NEJM198310273091702. [DOI] [PubMed] [Google Scholar]
  12. de Wardener HE, MacGregor GA. Harmful effects of dietary salt in addition to hypertension. J Hum Hypertens. 2002;16:213–223. doi: 10.1038/sj.jhh.1001374. [DOI] [PubMed] [Google Scholar]
  13. Franco V, Oparil S. Salt sensitivity, a determinant of blood pressure, cardiovascular disease and survival. J Am Coll Nutr. 2006;25(3 Suppl):247S–255S. doi: 10.1080/07315724.2006.10719574. [DOI] [PubMed] [Google Scholar]
  14. Furness JB1, Rivera LR, Cho HJ, Bravo DM, Callaghan B. The gut as a sensory organ. Nat Rev Gastroenterol Hepatol. 2013;10:729–740. doi: 10.1038/nrgastro.2013.180. [DOI] [PubMed] [Google Scholar]
  15. Gildea JJ, Lahiff DT, Van Sciver RE, Weiss RS, Shah N, McGrath HE, Schoeffel CD, Jose PA, Carey RM, Felder RA. A linear relationship between the ex-vivo sodium mediated expression of two sodium regulatory pathways as a surrogate marker of salt sensitivity of blood pressure in exfoliated human renal proximal tubule cells: the virtual renal biopsy. Clin Chim Acta. 2013;421:236–242. doi: 10.1016/j.cca.2013.02.021. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Gildea JJ, Zhang C, Wang DB, Tran HT, Felder RA. Intestinal cell gastrin secretion is regulated by a sodium-induced increase in PPAR-α that is mediated by dopaminergic stimulation. Hypertension. 2014;64:A516. [Google Scholar]
  17. Gildea JJ, Xu P, Zhang C, Wang DB, Tran HT, Jose PA, Felder RA. Human stomach cell gastrin inhibits renal NHE3 and NaKATPase in concert with the renal D1R. Hypertension. 2015;66:A087. [Google Scholar]
  18. Global status report on noncommunicable diseases. 2014 www.who.int/global.../global-status-report-ncds.
  19. Graudal N, Hubeck-Graudal T, Jürgens G, McCarron DA. The significance of duration and amount of sodium reduction intervention in normotensive and hypertensive individuals: a meta-analysis. Adv Nutr. 2015;6:69–77. doi: 10.3945/an.114.007708. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hall JE, Granger JP, do Carmo JM, da Silva AA, Dubinion J, George E, Hamza S, Speed J, Hall ME. Hypertension: physiology and pathophysiology. Compr Physiol. 2012;2:2393–2442. doi: 10.1002/cphy.c110058. [DOI] [PubMed] [Google Scholar]
  21. He FJ, Li J, Macgregor GA. Effect of longer-term modest salt reduction on blood pressure. Cochrane Database Syst Rev. 2013;4:CD004937. doi: 10.1002/14651858.CD004937.pub2. [DOI] [PubMed] [Google Scholar]
  22. Institute of Medicine. Sodium intake in populations: assessment of evidence. Washington (DC): National Academies Press; 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Jiang X, Chen W, Liu X, Wang Z, Liu Y, Felder RA, Gildea JJ, Jose PA, Qin C, Yang Z. The synergistic roles of cholecystokinin B and dopamine D5 Receptors on the regulation of renal sodium excretion. PLoS One. 2016;11:e0146641. doi: 10.1371/journal.pone.0146641. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Jose PA, Raj D. Gut microbiota in hypertension. Curr Opin Nephrol Hypertens. 2015;24:403–409. doi: 10.1097/MNH.0000000000000149. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Li XC, Shull GE, Miguel-Qin E, Chen F, Zhuo JL. Role of the Na+/H+ exchanger 3 in angiotensin II-induced hypertension in NHE3-deficient mice with transgenic rescue of NHE3 in small intestines. Physiol Rep. 2015;3 doi: 10.14814/phy2.12605. pii: e12605. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Lienhard D, Lauterburg M, Escher G, Frey FJ, Frey BM. High salt intake down-regulates colonic mineralocorticoid receptors, epithelial sodium channels and 11β-hydroxysteroid dehydrogenase type 2. PLoS One. 2012;7:e37898. doi: 10.1371/journal.pone.0037898. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Liu T, Jose PA. Gastrin induces sodium-hydrogen exchanger 3 phosphorylation and mTOR activation via a phosphoinositide 3-kinase-/protein kinase C-dependent but AKT-independent pathway in renal proximal tubule cells derived from a normotensive male human. Endocrinology. 2013;154:865–875. doi: 10.1210/en.2012-1813. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Liu T, Konkalmatt PR, Yang Y, Jose PA. Gastrin decreases Na+, K+-ATPase activity via a PI3 Kinase- and PKC-dependent pathway in human renal proximal tubule cells. Am J Physiol Endocrinol Metab 2016. 2016 Jan 19; doi: 10.1152/ajpendo.00360.2015. ajpendo.00360.2015. Epub ahead of print. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Logan AG, Friedman O. Can nocturnal hypertension predict cardiovascular risk? Integrated Blood Pressure Control. 2009;2:25–37. doi: 10.2147/ibpc.s4364. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Lorenz JN, Nieman M, Sabo J, Sanford LP, Hawkins JA, Elitsur N, Gawenis LR, Clarke LL, Cohen MB. Uroguanylin knockout mice have increased blood pressure and impaired natriuretic response to enteral NaCl load. J Clin Invest. 2003;112:1244–1254. doi: 10.1172/JCI18743. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Lucas-Teixeira VA, Hussain T, Serrão P, Soares-da-Silva P, Lokhandwala MF. Intestinal dopaminergic activity in obese and lean Zucker rats: response to high salt intake. Clin Exp Hypertens. 2002;24:383–396. doi: 10.1081/ceh-120004799. [DOI] [PubMed] [Google Scholar]
  32. Lucas-Teixeira VA, Vieira-Coelho MA, Serrão P, Pestana M, Soares-da-Silva P. Salt intake and sensitivity of intestinal and renal Na+-K+ atpase to inhibition by dopamine in spontaneous hypertensive and Wistar-Kyoto rats. Clin Exp Hypertens. 2000;22:455–469. doi: 10.1081/ceh-100100084. [DOI] [PubMed] [Google Scholar]
  33. Mailman D. Effects of pentagastrin on intestinal absorption and blood flow in the anaesthetized dog. J Physiol. 1980;307:429–442. doi: 10.1113/jphysiol.1980.sp013444. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Melis M, Krenning EP, Bernard BF, Barone R, Visser TJ, de Jong M. Localisation and mechanism of renal retention of radiolabelled somatostatin analogues. Eur J Nucl Med Mol Imaging. 2005;32:1136–1143. doi: 10.1007/s00259-005-1793-0. [DOI] [PubMed] [Google Scholar]
  35. Melicharova L, Laznickova A, Laznicek M. Preclinical evaluation of gastrin derivatives labelled with 111In: radiolabelling, affinity profile and pharmacokinetics in rats. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2014;154:544–551. doi: 10.5507/bp.2013.064. [DOI] [PubMed] [Google Scholar]
  36. Melis M, Krenning EP, Bernard BF, de Visser M, Rolleman E, de Jong M. Renal uptake and retention of radiolabeled somatostatin, bombesin, neurotensin, minigastrin and CCK analogues: species and gender differences. Nucl Med Biol. 2007;34:633–641. doi: 10.1016/j.nucmedbio.2007.05.002. [DOI] [PubMed] [Google Scholar]
  37. Mente A, O’Donnell MJ, Rangarajan S, McQueen MJ, Poirier P, Wielgosz A, Morrison H, Li W, Wang X, Di C, Mony P, Devanath A, Rosengren A, Oguz A, Zatonska K, Yusufali AH, Lopez-Jaramillo P, Avezum A, Ismail N, Lanas F, Puoane T, Diaz R, Kelishadi R, Iqbal R, Yusuf R, Chifamba J, Khatib R, Teo K, Yusuf S PURE Investigators. Association of urinary sodium and potassium excretion with blood pressure. N Engl J Med. 2014;371:601–611. doi: 10.1056/NEJMoa1311989. [DOI] [PubMed] [Google Scholar]
  38. Michell AR, Debnam ES, Unwin RJ. Regulation of renal function by the gastrointestinal tract: potential role of gut-derived peptides and hormones. Annu Rev Physiol. 2008;70:379–403. doi: 10.1146/annurev.physiol.69.040705.141330. [DOI] [PubMed] [Google Scholar]
  39. Montasser ME, Douglas JA, Roy-Gagnon MH, Van Hout CV, Weir MR, Vogel R, Parsa A, Steinle NI, Snitker S, Brereton NH, Chang YP, Shuldiner AR, Mitchell BD. Determinants of blood pressure response to low-salt intake in a healthy adult population. J Clin Hypertens (Greenwich) 2011;13:795–800. doi: 10.1111/j.1751-7176.2011.00523.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Morgan DA, DiBona GF, Mark AL. Effects of interstrain renal transplantation on NaCl-induced hypertension in Dahl rats. Hypertension. 1990;15:436–442. doi: 10.1161/01.hyp.15.4.436. [DOI] [PubMed] [Google Scholar]
  41. O’Brien E. Dipping comes of age. The importance of nocturnal blood pressure. Hypertension. 2009;53:446–447. doi: 10.1161/HYPERTENSIONAHA.108.127571. [DOI] [PubMed] [Google Scholar]
  42. Padmanabhan S, Caulfield M, Dominiczak AF. Genetic and molecular aspects of hypertension. Circ Res. 2015;116:937–959. doi: 10.1161/CIRCRESAHA.116.303647. [DOI] [PubMed] [Google Scholar]
  43. Pisegna JR, Tarasova NI, Kopp JA, Asico LD, Jose P, Farnsworth DW, Michejda CJ, Wank SA. Postprandial changes in renal function are mediated by elevated serum gastrin acting at cholecystokinin type B receptors (CCKBR) in the kidney (Abstract) Gastroenterology. 1996;110:1106A. [Google Scholar]
  44. Preston RA, Afshartous D, Forte LR, Rodco R, Alonso AB, Garg D, Raij L. Sodium challenge does not support an acute gastrointestinal-renal natriuretic signaling axis in humans. Kidney Int. 2012;82:1313–1320. doi: 10.1038/ki.2012.269. [DOI] [PubMed] [Google Scholar]
  45. Ruppert M, Overlack A, Kolloch R, Kraft K, Göbel B, Stumpe KO. Neurohormonal and metabolic effects of severe and moderate salt restriction in non-obese normotensive adults. J Hypertens. 1993;11:743–749. doi: 10.1097/00004872-199307000-00010. [DOI] [PubMed] [Google Scholar]
  46. Säfsten B. Duodenal bicarbonate secretion and mucosal protection. Neurohumoral influence and transport mechanisms. Acta Physiol Scand Suppl. 1993;613:1–4. [PubMed] [Google Scholar]
  47. Saqui-Salces M, Dowdle WE, Reiter JF, Merchant JL. A high-fat diet regulates gastrin and acid secretion through primary cilia. FASEB J. 2012;26:3127–3139. doi: 10.1096/fj.11-197426. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Sharon P, Karmeli F, Rachmilewitz D. PGE2 mediates the effect of pentagastrin on intestinal adenylate cyclase and Na-K-ATPase activities. Prostaglandins. 1981;21(Suppl):81–7. doi: 10.1016/0090-6980(81)90122-2. [DOI] [PubMed] [Google Scholar]
  49. Spencer AG, Labonte ED, Rosenbaum DP, Plato CF, Carreras CW, Leadbetter MR, Kozuka K, Kohler J, Koo-McCoy S, He L, Bell N, Tabora J, Joly KM, Navre M, Jacobs JW, Charmot D. Intestinal inhibition of the Na+/H+ exchanger 3 prevents cardiorenal damage in rats and inhibits Na+ uptake in humans. Sci Transl Med. 2014;6:227ra36. doi: 10.1126/scitranslmed.3007790. [DOI] [PubMed] [Google Scholar]
  50. Sullivan JM. Salt sensitivity. Definition, conception, methodology, and long-term issues. Hypertension. 1991;17(1 Suppl):I61–I68. doi: 10.1161/01.hyp.17.1_suppl.i61. [DOI] [PubMed] [Google Scholar]
  51. Survé VV, Håkanson R. Evidence that peroral calcium does not activate the gastrin-ECL-cell axis in the rat. Regul Pept. 1998;73:177–82. doi: 10.1016/s0167-0115(98)00002-0. [DOI] [PubMed] [Google Scholar]
  52. Traynor TR, O’Grady SM. Regulation of colonic ion transport by GRP. I. GRP stimulates transepithelial K and Na secretion. Am J Physiol. 1996;270(3 Pt 1):C848–C865. doi: 10.1152/ajpcell.1996.270.3.C848. [DOI] [PubMed] [Google Scholar]
  53. von Schrenck T, Ahrens M, de Weerth A, Bobrowski C, Wolf G, Jonas L, Jocks T, Schulz M, Bläker M, Neumaier M, Stahl RA. CCKB/gastrin receptors mediate changes in sodium and potassium absorption in the isolated perfused rat kidney. Kidney Int. 2000;58:995–1003. doi: 10.1046/j.1523-1755.2000.00257.x. [DOI] [PubMed] [Google Scholar]
  54. Weinberger MH, Fineberg NS, Fineberg SE, Weinberger M. Salt sensitivity, pulse pressure, and death in normal and hypertensive humans. Hypertension. 2001;37:429–432. doi: 10.1161/01.hyp.37.2.429. [DOI] [PubMed] [Google Scholar]
  55. Yang Y, Evans S, Escano C, Asico L, Zhang S, Cuevas Gonzales S, Villar VA, Wang X, Pisegna JR, Wank I, Armando I, Jose PA. Expression of gastrin in the thin descending limb of Henle’s loop in the mouse kidney: a molecular, localization, and functional study. FASEB J. 2012;26:688.4. [Google Scholar]

RESOURCES