A novel role for uroguanylin in the regulation of sodium balance

Forte, Leonard R.

doi:10.1172/jci20057

Cited by 28 publications

(24 citation statements)

References 27 publications

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“…Both peptides are produced in the gastrointestinal tract; Ugn primarily by enterochromaffin (EC) cells in the small intestine and Gn by goblet cells in the colon (6,27,28,39,40). Even though both peptides are natriuretic in the kidney, several lines of evidence support a role for Ugn, but not Gn, in volume homeostasis and sodium balance (15)(16)(17)38). For example, in contrast to Gn, Ugn is excreted in urine (11), where it is present at levels that are proportional to dietary sodium intake (18).…”

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confidence: 99%

“…Furthermore, Ugn knockout mice are hypertensive compared with wild-type controls and show an impaired natriuretic response to increased oral salt intake, whereas Gn knockout mice have normal blood pressures and sodium balance (10,31). Thus, Ugn has been credited with a regulatory role in sodium balance that is triggered by alterations in dietary salt intake per se, thereby differing from other sodium regulatory systems that respond to the subsequent changes in extracellular volume and arterial pressure (16,41).…”

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confidence: 99%

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Natriuretic and antikaliuretic effects of uroguanylin and prouroguanylin in the rat

Moss

Riguera

Fellner

et al. 2010

American Journal of Physiology-Renal Physiology

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Moss NG, Riguera DA, Fellner RC, Cazzolla C, Goy MF. Natriuretic and antikaliuretic effects of uroguanylin and prouroguanylin in the rat. Am J Physiol Renal Physiol 299: F1433-F1442, 2010. First published September 22, 2010 doi:10.1152/ajprenal.00281.2010.-The peptide uroguanylin (Ugn) is stored and released as a propeptide (proUgn) by enterochromaffin cells in the intestine, and converted to Ugn and other metabolites in the renal tubules. Both proUgn and Ugn are natriuretic, although the response to proUgn is thought to depend on its conversion to Ugn within nephrons. To assess the efficiency of intrarenal conversion of proUgn to Ugn, we measured urinary Ugn excretion in rats following intravenous infusions of proUgn or Ugn. Infusion of 2 and 10 nmol proUgn/kg body wt increased plasma proUgn concentration from 2.2 Ϯ 0.3 to 5.6 Ϯ 1.3 pmol/ml and to 37 Ϯ 9.6 pmol/ml, respectively. No proUgn was detected in urine before, during, or after proUgn infusions. These two proUgn infusion doses resulted in total Ugn recovery in urine of 162 Ϯ 64 and 206 Ϯ 39 pmol/kg body wt (9 and 2% of the infused amount, respectively). By contrast, the same molar amounts of Ugn resulted in 1,009 Ϯ 477 and 5,352 Ϯ 2,133 pmol/kg body wt of Ugn in urine (recoveries of ϳ50%). Unexpectedly, comparisons of natriuretic dose-response curves for each peptide showed proUgn to be about five times more potent than Ugn, despite the relatively modest amount of Ugn generated from infused proUgn. In addition, both peptides were antikaliuretic at low doses, but in this case Ugn showed greater potency than proUgn. These data do not support Ugn as the primary active principle of proUgn for regulation of renal sodium excretion.

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confidence: 99%

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confidence: 99%

Natriuretic and antikaliuretic effects of uroguanylin and prouroguanylin in the rat

Moss

Riguera

Fellner

et al. 2010

American Journal of Physiology-Renal Physiology

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“…The present study suggests that uroguanylin acts as a natriuretic factor also in the state with sodium/fluid retention, which was unrelated to enteral NaCl load. Further studies may clarify the role of uroguanylin that governs body sodium balance and BP as well as the other cGMP-regulating agonists, nitric oxide, and the atriopeptins (27). Although uroguanylin could be involved in the pathophysiology of PAN-treated rats as a natriuretic hormone, it is also possible that more fundamental mechanisms are involved.…”

Section: Discussionmentioning

confidence: 97%

Role of Uroguanylin, a Peptide with Natriuretic Activity, in Rats with Experimental Nephrotic Syndrome

Kikuchi¹,

Fujimoto²,

Fukae³

et al. 2005

Journal of the American Society of Nephrology

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Uroguanylin induces natriuresis and diuresis in vivo as well as in vitro and is found mainly in the intestine and the kidney. However, the roles of uroguanylin in nephrotic syndrome, which is associated with sodium and water retention, have not been determined. Therefore, changes in the urine and plasma concentration of immunoreactive uroguanylin (ir-uroguanylin) and its mRNA expression in the kidney and intestine were examined using rats with puromycin aminonucleoside (PAN)-induced nephrosis. Male Sprague-Dawley rats were separated into control and nephrotic groups, and then the urinary excretion of sodium, protein, and ir-uroguanylin was examined over time. The plasma levels and renal and intestinal mRNA expression of uroguanylin at the periods of sodium retention and remarkable natriuresis also were evaluated. The sequential changes of urinary ir-uroguanylin excretion in the nephrotic group were similar to those of urinary sodium excretion. When the urinary excretion of ir-uroguanylin and sodium peaked, the plasma level of ir-uroguanylin also increased compared with that of the control group. Uroguanylin mRNA expression in the kidney increased during the period of sodium retention and then decreased during the period of remarkable natriuresis. Uroguanylin mRNA expression in the small intestines of control and nephrotic rats were identical. However, in a unilateral PAN-induced proteinuria, uroguanylin expression significantly increased in the PAN-perfused kidney compared with that in the opposite kidney. Considering the natriuretic effect of uroguanylin, these results suggested that uroguanylin plays an important role as a natriuretic factor in nephrotic syndrome via both the circulation and the kidney itself. U roguanylin is a small peptide that activates transmembrane guanylate cyclase (GC) C, influences cellular function via intracellular cyclic guanosine monophosphate (cGMP) (1), and induces the urinary excretion of sodium and water in isolated perfused rat kidneys (2) and in mice in vivo (3). Uroguanylin and guanylin are major hormones in one family of cGMP agonists, whereas atriopeptins (atrial natriuretic peptide [ANP], brain natriuretic peptide, and C-type natriuretic peptide) are a separate and distinct family of peptides that act on different GC (GC-A, -B) to signal via cGMP. We reported that uroguanylin excretion into the urine is increased in humans and rats on a high-salt diet compared with those on a low-salt diet (4,5), indicating that uroguanylin functions as an intestinal natriuretic peptide. Moreover, uroguanylin levels are increased in the circulation of patients with renal disease and congestive heart failure (6,7). Forte et al. (8) suggested that uroguanylin participates in the physiologic maintenance of the sodium balance. However, how uroguanylin functions in the pathophysiologic mechanism of nephrotic syndrome, a condition associated with sodium and water retention, remains obscure. The present study examined serial changes in the urine and plasma concentration of immunoreactive urogua...

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“…Recombinant proguanylin, proguanylin-C48S/C61S, and proguanylin-C86S/C94S were expressed as thioredoxin fusion proteins in E. coli AD494-(DE3) cells (Novagen) and purified as described previously (18). For uniform (>95%) 15 N labeling, the recombinant proteins were isolated and purified from E. coli cultures grown in M9 minimal medium enriched with 15 NH 4 Cl using the same purification protocol. As the expression strain lacks the ability to synthesize leucine, 15 N-labeled leucine was added to the medium according to the manufacturer's instructions (Novagen).…”

Section: Construction Of Expression Vectorsmentioning

confidence: 99%

“…The peptide hormone guanylin is the first identified endogenous ligand of intestinal guanylyl cyclase C (GC-C) (1) and is part of a newly discovered entero-endocrine axis connecting intestine and kidney by regulating electrolyte and fluid secretion in the intestine (2) as well as kaliuresis and diuresis in the kidney (3)(4)(5)(6). In the intestine, binding of guanylin to GC-C leads to an increased level of intracellular cGMP that subsequently activates the cystic fibrosis transmembrane conductance regulator chloride channel, resulting in an increased level of secretion of Cl -, HCO 3 -, and water into the intestinal lumen, and simultaneously inhibits sodium absorption (7,8).…”

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Role of Disulfide Bonds for the Structure and Folding of Proguanylin

et al. 2004

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The intestinal peptide hormone guanylin circulates mainly as its corresponding prohormone of 94 amino acids and is the first identified endogenous ligand of intestinal guanylyl cyclase C. While the prohormone is biologically inactive, it is processed to the fully functional form with 15 amino acid residues corresponding to the COOH terminus of the precursor protein. In addition to this inactivation of the hormone region, the prosequence makes an essential contribution to the disulfide-coupled folding of the hormone. On the basis of the recently determined solution structure of proguanylin, explanations for these functions of the prosequence were found, indicating that interstrand contacts between the NH 2 -terminal -hairpin of the prosequence and the COOH-terminal hormone region are crucial for formation of the correct disulfide bonds of guanylin. To further investigate the role of individual disulfide bonds upon stabilization of the overall three-dimensional structure of proguanylin and to test the assumption of a direct effect of the prosequence on the structure of the hormone region, we studied the cysteine double mutant proteins proguanylin-C48S/C61S and proguanylin-C86S/C94S. Disulfide determination as well as CD and NMR spectroscopy of proguanylin-C48S/C61S reveals an essential function of the Cys48-Cys61 disulfide bond for the stability of the hydrophobic core and thereby for the stability of the overall three-dimensional structure of proguanylin. Furthermore, sequence specific resonance assignment of the second disulfide deletion mutant, proguanylin-C86S/C94S, and comparison of the NMR spectra of this protein with those of the wild-type protein demonstrate that the rigid helical core structure of proguanylin is not affected by the mutation. Additionally, analysis of the interstrand contacts between the termini reveals a direct effect of the prosequence on the conformation of the hormone region. On the basis of these results, we propose a cooperative mechanism that leads to formation of the correct disulfide pattern of guanylin.The peptide hormone guanylin is the first identified endogenous ligand of intestinal guanylyl cyclase C (GC-C) (1) and is part of a newly discovered entero-endocrine axis connecting intestine and kidney by regulating electrolyte and fluid secretion in the intestine (2) as well as kaliuresis and diuresis in the kidney (3-6). In the intestine, binding of guanylin to GC-C leads to an increased level of intracellular cGMP that subsequently activates the cystic fibrosis transmembrane conductance regulator chloride channel, resulting in an increased level of secretion of Cl -, HCO 3 -, and water into the intestinal lumen, and simultaneously inhibits sodium absorption (7,8). For GC-C binding and activation, formation of the correct 1-3/2-4 disulfide bond pattern of guanylin is required (1, 9), allowing formation of two interconvertable topological stereoisomers (10), with only one of them (Aisomer) showing biological activity (11).The main circulating form of guanylin is the cor...

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A novel role for uroguanylin in the regulation of sodium balance

Cited by 28 publications

References 27 publications

Natriuretic and antikaliuretic effects of uroguanylin and prouroguanylin in the rat

Natriuretic and antikaliuretic effects of uroguanylin and prouroguanylin in the rat

Role of Uroguanylin, a Peptide with Natriuretic Activity, in Rats with Experimental Nephrotic Syndrome

Role of Disulfide Bonds for the Structure and Folding of Proguanylin

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