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Uroguanylin: Physiological Role As a Natriuretic Hormone

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Uroguanylin: Physiological Role As a Natriuretic Hormone JASN Express. Published on January 12, 2005 as doi: 10.1681/ASN.2004121061 Editorial Uroguanylin: Physiological Role as a Natriuretic Hormone Leonard Ralph Forte, Jr. Harry S Truman Memorial Veteran’s Hospital and the Department of Medical Pharmacology and Physiology, and the Radiopharmaceutical Sciences Institute, School of Medicine, University of Missouri, Columbia, Missouri J Am Soc Nephrol 16: 291–292, 2005. doi: 10.1681/ASN.2004121061 research group from Miyazaki, Japan, previously guanylin and uroguanylin may exist, including the regulation demonstrated that the nephrotic syndrome is associ- of kidney function. A ated with increased levels of uroguanylin (1). Kikuchi Evidence for renal actions of the guanylin peptides stems et al. return to the topic in this issue of JASN with a report that from the discovery of receptors for E. coli ST peptides located in a model of nephrosis, which was induced in rats by treatment the apical membranes of proximal tubules in opossum kidney with puromycin, also causes marked perturbations in the levels (4). Since then, a number of studies have shown that guanylin, of circulating and urinary uroguanylin. To most nephrologists, uroguanylin, and the uroguanylin-like peptide, E. coli ST, elicit the primary questions that come to mind will be: What is increases in the urinary excretion of sodium, potassium, chlo- uroguanylin and why do pathophysiological changes in a gut- ride, and water (11–13). Therefore, it was postulated that derived peptide occur in nephrosis? uroguanylin acts on the kidney through a novel endocrine axis Human uroguanylin is a 16–amino-acid peptide that reaches linking the GI tract with the kidney via circulating levels of its highest abundance in mucosae of the stomach and intestinal uroguanylin and/or guanylin (14). Because the kidney ex- tract (reviewed in 2,3). The existence of uroguanylin and its presses mRNA transcripts for uroguanylin and guanylin, local cousin, guanylin, was foreshadowed by the discovery of an effects of these peptides on the nephron could also play a role orphan receptor-guanylate cyclase (R-GC) in opossum kidney in the tubular actions of these cGMP-regulating peptides (3,4). (4). These cell-surface R-GC signaling molecules are markedly Why then does nephrosis elicit increases in the plasma and activated by heat-stable enterotoxin (stable toxin, [ST]) peptides urinary levels of uroguanylin and also stimulate the expression produced by strains of Escherichia coli, which cause a cholera- of uroguanylin mRNA in the kidney? While the answer to this like form of secretory diarrhea (5). Pursuit of the endogenous question is still evolving, some bits of evidence now exist to peptide hormones that serve as natural agonists for this R-GC form a reasonable hypothesis. Uroguanylin probably acts in the of kidney, intestine, and other epithelia led first to the isolation body as a natriuretic hormone when excess sodium chloride of guanylin from the jejunum of rats, followed closely by the (NaCl) is consumed in the diet. Uroguanylin is one component purification of uroguanylin from opossum urine (6,7). The ex- of a complex physiologic mechanism that balances urinary traordinary abundance of both guanylin and uroguanylin in sodium excretion to match the levels of NaCl absorbed into the the intestinal epithelium combined with a remarkably high body via the GI tract. Thus, uroguanylin may be thought of as density of a cognate receptor-guanylate cyclase (R-GC-C) in a counter-regulatory hormone that opposes the sodium-retain- cells comprising the intestinal mucosa was the most fascinating ing actions of hormones like aldosterone. Recent experiments observation made in the early years following discovery of with uroguanylin gene knock-out mice are consistent with this Ϫ Ϫ these signaling molecules. These findings, together with a body concept. Uroguanylin / animals had impaired saliuretic re- of older literature defining the biologic activities of E. coli ST sponses to an oral NaCl load and exhibited elevated BP (10). peptides as diarrhea-inducing enterotoxin peptides, misled this The nephrotic syndrome may cause increases in uroguanylin field for quite a long time. Initially, it was considered that a levels secondary to the retention of NaCl by the kidney, which physiologic role of guanylin and uroguanylin was to regulate leads to an increase in total body sodium. Uroguanylin levels in the secretion of fluid and electrolytes by the intestinal epithe- the urine are also increased markedly in patients with sodium lium. Some residual belief may remain for such an action of the retention secondary to heart failure (15). Thus, physiological guanylin peptides that influence cellular functions via the in- mechanisms exist, which regulate the production and/or secre- tracellular second messenger, cyclic GMP (cGMP). However, tion of uroguanylin when sodium retention occurs secondary to transgenic mice lacking R-GC-C, guanylin, or uroguanylin ap- diseases of the kidney, heart, or other organs, as well as in times pear to have no abnormalities of intestinal fluid secretion (8– of excess NaCl consumption in the diet. From the report by 10). These findings suggest that other physiologic roles for Kikuchi et al. in this issue, it can now be accepted that sodium retention elicited by nephrosis leads to a stimulation of urogua- Published online ahead of print. Publication date available at www.jasn.org. nylin mRNA expression in the kidney. Prior studies in patients with congestive heart failure did not explore the sources of Address correspondence to: Professor Leonard R. Forte, Jr., University of Mis- souri, School of Medicine, One Hospital Drive, Columbia, MO 65212. Phone: elevated uroguanylin found in urine (15). Therefore, it is pos- 573-814-6000; Fax: 573-814-6551, E-mail: [email protected] sible that sodium retention per se leads to an increase in the Copyright © 2005 by the American Society of Nephrology ISSN: 1046-6673/1602-0291 292 Journal of the American Society of Nephrology J Am Soc Nephrol 16: 291–292, 2005 production of uroguanylin by the kidney, which contributes to 6. Currie MG, Fok KF, Kato J, Moore RJ, Hamra FK, Duffin the increased urinary excretion of uroguanylin observed in KL, Smith CE: Guanylin: An endogenous activator of in- both the nephrotic syndrome and congestive heart failure. Al- testinal guanylate cyclase. Proc Natl Acad Sci U S A 89: though uroguanylin expression in the intestine of nephrotic rats 947–951, 1992 was not increased in the present study, it is likely that sodium- 7. Hamra FK, Forte LR, Eber SL, Pidhorodeckyj NV, Krause retaining diseases may enhance the expression of uroguanylin WJ, Freeman RH, Chin DT, Tompkins JA, Fok KF, Smith (and guanylin) in the GI tract as well as in the kidney. The report CE, Duffin KL, Siegel NR, Currie MG: Uroguanylin: Struc- ture and activity of a second endogenous peptide that by Kikuchi et al. did not rigorously examine this possibility. stimulates intestinal guanylate cyclase. Proc Natl Acad Sci Uroguanylin is expressed throughout the GI tract, whereas Kiku- USA90: 10464–10468, 1993 chi et al. only measured uroguanylin mRNAs by RT-PCR in the 8. Schulz S, Lopez MJ, Kuhn M,Garbers DL: Disruption of the small intestine. Other parts of the GI tract, such as the gastric guanylyl cyclase-C gene leads to a paradoxical phenotype mucosa, could contribute to elevated levels of uroguanylin in the of viable but heat-stable enterotoxin-resistant mice. J Clin circulation of rats with puromycin-induced nephrosis. Invest 100: 1590–1595, 1997 In summary, Kikuchi et al. have advanced our understanding 9. Steinbrecher KA, Wowk SA, Rudolph JA, Witte DP, Cohen of the potential physiologic roles for uroguanylin as a natri- MB: Targeted inactivation of the mouse guanylin gene uretic hormone that regulates the renal excretion of NaCl to results in altered dynamics of colonic epithelial prolifera- help maintain sodium balance. The functional significance of tion. Am J Pathol 161: 2169–2178, 2002 uroguanylin clearly includes actions on the kidney to enhance 10. Lorenz JN, Nieman M, Sabo J, Sanford LP, Hawkins JA, urinary sodium excretion, both in times when excess NaCl is Elitsur N, Gawenis LR, Clarke LL, Cohen MB: Uroguanylin consumed in the diet and in diseases such as nephrosis and knockout mice have increased blood pressure and im- heart failure, when sodium retention leads to the pathophysi- paired natriuretic response to enteral NaCl load. J Clin ological accumulation of salt and water. Invest 112: 1244–1254, 2003 11. Lima AAM, Monteiro HSA, Fonteles MC: The effects of References Escherichia coli heat-stable enterotoxin in renal sodium tu- bular transport. Pharmacol Toxicol 70:163–167, 1992 1. Kinoshita H, Fujimoto S, Fukae H, Yokota N, Hisanaga S, Nakazato M, Eto T: Plasma and urine levels of uroguany- 12. Fonteles MC, Greenberg RN, Monteiro HS, Currie MG, lin, a new natriuretic peptide, in nephrotic syndrome. Forte LR: Natriuretic and kaliuretic activities of guanylin Nephron 8: 160–164, 1999 and uroguanylin in the isolated perfused rat kidney. Am J 2. Forte LR, London RM, Freeman RH, Krause WJ: Guanylin Physiol 275: F191–F197, 1998 peptides: Renal actions mediated by cyclic GMP. Am J 13. Carrithers SL, Hill MJ, Johnson BJ, O’Hara SM, Jackson BA, Physiol Renal Physiol 278: F180–F191, 2000 Ott CE, Lorenz J, Mann EA, Giannella RA, Forte LR, Green- 3. Forte LR, London RM, Krause WJ, Freeman RH: Mecha- berg RN: Renal effects of uroguanylin and guanylin in nisms of guanylin action via cyclic GMP in the kidney. vivo. Braz J Med Biol Res 32: 1337–1344, 1999 Annu Rev Physiol 62: 673–695, 2000 14. Forte LR, Fan X, Hamra FK: Salt and water homeostasis: 4. Forte LR, Krause WJ, Freeman RH. Receptors and cGMP Uroguanylin is a circulating peptide hormone with natri- signaling mechanism for E. coli enterotoxin in opossum uretic activity.
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