Evidence for a splanchnic sodium input monitor regulating renal sodium excretion in man. Lack of dependence upon aldosterone.

Carey, Robert M.

doi:10.1161/01.res.43.1.19

Cited by 71 publications

(57 citation statements)

References 13 publications

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“…The hypothesis of a regulatory mechanism linking the gastrointestinal tract and kidney is not new. Evidence of a gastrointestinal monitor for sodium balance was considered from the observation that an equivalent sodium load is more rapidly excreted after oral administration, compared with intravenous administration (6,34). Otherwise, it has been suggested that guanylin peptides are responsible for this regulatory mechanism linking intestinal and renal transport of water and electrolytes (19).…”

Section: Discussionmentioning

confidence: 99%

Mechanisms underlying the inhibitory effects of uroguanylin on NHE3 transport activity in renal proximal tubule

Lessa

Carraro‐Lacroix

Crajoinas

et al. 2012

American Journal of Physiology-Renal Physiology

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-We previously demonstrated that uroguanylin (UGN) significantly inhibits Na ϩ /H ϩ exchanger (NHE)3-mediated bicarbonate reabsorption. In the present study, we aimed to elucidate the molecular mechanisms underlying the action of UGN on NHE3 in rat renal proximal tubules and in a proximal tubule cell line (LLC-PK1). The in vivo studies were performed by the stationary microperfusion technique, in which we measured H ϩ secretion in rat renal proximal segments, through a H ϩ -sensitive microelectrode. UGN (1 M) significantly inhibited the net of proximal bicarbonate reabsorption. The inhibitory effect of UGN was completely abolished by either the protein kinase G (PKG) inhibitor KT5823 or by the protein kinase A (PKA) inhibitor H-89. The effects of UGN in vitro were found to be similar to those obtained by microperfusion. Indeed, we observed that incubation of LLC-PK1 cells with UGN induced an increase in the intracellular levels of cAMP and cGMP, as well as activation of both PKA and PKG. Furthermore, we found that UGN can increase the levels of NHE3 phosphorylation at the PKA consensus sites 552 and 605 in LLC-PK1 cells. Finally, treatment of LLC-PK1 cells with UGN reduced the amount of NHE3 at the cell surface. Overall, our data suggest that the inhibitory effect of UGN on NHE3 transport activity in proximal tubule is mediated by activation of both cGMP/PKG and cAMP/PKA signaling pathways which in turn leads to NHE3 phosphorylation and reduced NHE3 surface expression. Moreover, this study sheds light on mechanisms by which guanylin peptides are intricately involved in the maintenance of salt and water homeostasis. NHE3; uroguanylin; renal microperfusion; bicarbonate reabsorption; cGMP; cAMP IN THE PAST DECADES, IT HAS been postulated that Sta-like guanylin peptides participate in a control system regulating salt balance in response to oral salt intake, linking intestine and kidney in the process of salt and water homeostasis (8,19,22). These peptides are known as endogenous agonists for the Escherichia coli heatstable toxin receptor, guanylate cyclase C (GC-C), uroguanylin (UGN) being its most potent member (12,18,20,27). UGN is a 16 amino acid peptide (27), expressed throughout the intestinal tract, secreted by enterochromaffin cells as prouroguanylin that undergoes postsecretory proteolytic cleavage, generating the active form (15,28,41). Recently, Qian and colleagues (44) demonstrated that the conversion of prouroguanylin to UGN occurs within the lumen of renal tubules.Renal effects of UGN include natriuresis, kaliuresis, diuresis, and increased excretion of cGMP (17,26). In a previous work using stationary in vivo microperfusion, our group demonstrated that UGN perfusion stimulates potassium secretion through Maxi-K channels in connecting and cortical collecting ducts (2). Furthermore, this study demonstrated that UGN perfusion also leads to an inhibition of bicarbonate reabsorption in proximal tubules by reducing the activity of the Na ϩ /H ϩ exchanger, NHE3 isoform (2). In renal proximal tubule cells, NHE...

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Section: Discussionmentioning

confidence: 99%

Mechanisms underlying the inhibitory effects of uroguanylin on NHE3 transport activity in renal proximal tubule

Lessa

Carraro‐Lacroix

Crajoinas

et al. 2012

American Journal of Physiology-Renal Physiology

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“…Data suggest that other factors play a role in this process and that the role of aldosterone is minimal in the adaptation to high-sodium meals. Carey and others [2][3][4] have demonstrated that salt-depleted individuals who were given oral sodium chloride excreted much more sodium in their urine than did individuals who were given the same amount of sodium chloride intravenously. Plasma aldosterone Published online ahead of print.…”

Section: Enteric Modulation Of Renal Sodium and Potassiummentioning

confidence: 99%

“…This conclusively demonstrates that the exaggerated response to oral sodium chloride loading is independent of aldosterone. 2 Carey 2 suggested the data also indicate "the presence of a splanchnic input monitor for sodium which partially regulates renal sodium excretion and is not dependent upon a turn-off mechanism for sodium excretion." By implication, an effector substance or mechanism to signal the kidney to increase its capacity to increase sodium excretion must exist.…”

Section: Enteric Modulation Of Renal Sodium and Potassiummentioning

confidence: 99%

Control of Renal Solute Excretion by Enteric Signals and Mediators

Thomas

Kumar

2008

Journal of the American Society of Nephrology

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The renal response to ingested solutes and the regulation of nutrient and solute balance are vital for the well-being of an organism. Foods that contain protein, carbohydrate, and fat are processed to amino acids, monosaccharides, and fatty acids and triglycerides. These substances and electrolytes and minerals are absorbed with varying degrees of efficiency in the intestine, often in response to the perceived needs of the organism. In some instances, the amount of the nutrient absorbed in the intestine depends on the amount present in the diet, and with large influxes of nutrient materials into the extracellular fluid, it falls to the kidney to remove the excessive amounts absorbed by the intestine from the serum and extracellular fluid, either by increasing the amount excreted by tubular processes or by reducing the amount reabsorbed in the tubule after glomerular filtration.It is widely believed that the renal response to ingested solutes is regulated by hormones such as aldosterone, in the case of sodium and potassium, and parathyroid hormone and the vitamin D endocrine system, in the case of calcium and phosphate. New (and old) information also suggests that factors produced in the gastrointestinal tract are released after changes in intestinal luminal solute concentrations and mediate changes in renal solute transport. This "enteric-renal solute-transporting regulating axis" represents an underappreciated mechanism by which renal solute transport is regulated. ENTERIC MODULATION OF RENAL SODIUM AND POTASSIUMDietary sodium induces a more marked natriuresis than intravenous sodium. The regulation of renal excretory or reabsorptive processes exclusively depends on the activity of various hormones or local renal factors, the synthesis or release of which depends on alterations in the serum or extracellular fluid concentrations of the various ions. Decreases in renal sodium excretion in response to a low-salt diet depend on changes in aldosterone synthesis. 1 Indeed, a lack of aldosterone synthesis is responsible for many of the manifestations of Addison's disease. The role of aldosterone (and inhibition of its synthesis) in increasing salt excretion is less clearly defined when a high-salt diet is ingested. Data suggest that other factors play a role in this process and that the role of aldosterone is minimal in the adaptation to high-sodium meals. Carey and others 2-4 have demonstrated that salt-depleted individuals who were given oral sodium chloride excreted much more sodium in their urine than did individuals who were given the same amount of sodium chloride intravenously. Plasma aldosterone ABSTRACTRenal solute excretion is important for the homeostasis of various ions. It is widely believed that hormones such as aldosterone, parathyroid hormone, the vitamin D endocrine system, and growth factors are responsible for alterations in renal ion transport in response to increased absorption of enteric solutes. In the cases of sodium, potassium, and phosphorus, moieties produced in the gastrointestinal tract a...

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“…Thus, uroguanylin has biological activity consistent with a peptide hormone that influences renal function by regulating the urinary excretion of sodium chloride as a physiological mechanism that contributes to the maintenance of Na + balance in the body. A natriuretic peptide such as uroguanylin was predicted to exist in the digestive system for release into the bloodstream for the purpose of stimulating the urinary excretion of NaCl following a salty meal (26,27). Uroguanylin is a prime candidate for this intestinal natriuretic hormone because it is produced at extraordinarily high concentrations in the upper small intestine and is released following a high salt meal (28)(29)(30)(31)(32).…”

Section: Physiological Actions Of Guanylin Peptidesmentioning

confidence: 99%

“…Uroguanylin and prouroguanylin are also found in the circulation and it is likely that the gastrointestinal (GI) tract is a main source of the plasma peptides (7,33,34). Secretion of uroguanylin from GI mucosa into the plasma in response to oral NaCl may explain the prolonged increase in urinary sodium excretion that occurs following a high salt meal (26,27).…”

Section: Physiological Actions Of Guanylin Peptidesmentioning

confidence: 99%

Guanylin peptides: cyclic GMP signaling mechanisms

Forte¹,

Freeman²,

Krause³

et al. 1999

Braz J Med Biol Res

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Guanylate cyclases (GC) serve in two different signaling pathways involving cytosolic and membrane enzymes. Membrane GCs are receptors for guanylin and atriopeptin peptides, two families of cGMPregulating peptides. Three subclasses of guanylin peptides contain one intramolecular disulfide (lymphoguanylin), two disulfides (guanylin and uroguanylin) and three disulfides (E. coli stable toxin, ST). The peptides activate membrane receptor-GCs and regulate intestinal Cl -and HCO 3 -secretion via cGMP in target enterocytes. Uroguanylin and ST also elicit diuretic and natriuretic responses in the kidney. GC-C is an intestinal receptor-GC for guanylin and uroguanylin, but GC-C may not be involved in renal cGMP pathways. A novel receptor-GC expressed in the opossum kidney (OK-GC) has been identified by molecular cloning. OK-GC cDNAs encode receptor-GCs in renal tubules that are activated by guanylins. Lymphoguanylin is highly expressed in the kidney and heart where it may influence cGMP pathways. Guanylin and uroguanylin are highly expressed in intestinal mucosa to regulate intestinal salt and water transport via paracrine actions on GC-C. Uroguanylin and guanylin are also secreted from intestinal mucosa into plasma where uroguanylin serves as an intestinal natriuretic hormone to influence body Na + homeostasis by endocrine mechanisms. Thus, guanylin peptides control salt and water transport in the kidney and intestine mediated by cGMP via membrane receptors with intrinsic guanylate cyclase activity.

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Evidence for a splanchnic sodium input monitor regulating renal sodium excretion in man. Lack of dependence upon aldosterone.

Cited by 71 publications

References 13 publications

Mechanisms underlying the inhibitory effects of uroguanylin on NHE3 transport activity in renal proximal tubule

Mechanisms underlying the inhibitory effects of uroguanylin on NHE3 transport activity in renal proximal tubule

Control of Renal Solute Excretion by Enteric Signals and Mediators

Guanylin peptides: cyclic GMP signaling mechanisms

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