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The Guanylin Peptide Family and the Proposed Gastrointestinal–Renal Natriuretic Signaling Axis

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The Guanylin Peptide Family and the Proposed Gastrointestinal–Renal Natriuretic Signaling Axis View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector commentary 10. Jiang M, Liu K, Luo J et al. Autophagy is a regulate autophagy. Mol Cell Biol 2010; 30: expression of guanylin occurs in the renoprotective mechanism during in vitro 1049–1058. hypoxia and in vivo ischemia-reperfusion 12. Lieberthal W, Levine JS. The role of the ileum to the proximal colon, and of injury. Am J Pathol 2010; 176: 1181–1192. mammalian target of rapamycin (mTOR) in uroguanylin in the jejunum.6 As in the 11. Kamada Y, Yoshino K, Kondo C et al. Tor renal disease. J Am Soc Nephrol 2009; 20: gut, guanylin and uroguanylin are not directly controls the Atg1 kinase complex to 2493–2502. equally expressed along the different nephron segments. Guanylin is more pronounced in the collecting duct, and see original article on page 1313 uroguanylin is present mostly in the proximal tubule.6 In the classical point The guanylin peptide family of view, guanylin and proguanylin are primarily thought to participate in the and the proposed regulation of salt and water homeostasis in the intestine and the kidney.3,4,6 gastrointestinal–renal natriuretic Guanylin peptides produced in the intestine after ingestion of a salty meal signaling axis are secreted into the intestinal lumen. In the intestine, guanylin and urogua- Thomas Mueller1 and Benjamin Dieplinger1 nylin activate epithelial cells mainly via the guanylate cyclase C receptor According to a proposed concept of a gastrointestinal–renal natriuretic with cyclic guanosine monophosphate 3,4,6 signaling axis, natriuretic peptides are released from the intestine into (cGMP) as second messenger. Activation of this pathway leads to the the circulation in response to oral salt intake and act on the kidneys as À À secretion of Cl and HCO3 and to hormones to increase sodium excretion. The peptides guanylin and the inhibition of Na þ absorption, uroguanylin and their precursors proguanylin and prouroguanylin, which drives water secretion into the respectively, have been suggested to be the mediators of this axis. intestinal lumen.4,6 These mechanisms A study by Preston and co-workers, however, provides important are probably involved in the regulation data not supporting this putative concept. of salt and water transport across the intestinal epithelia and in the regu- Kidney International (2012) 82, 1253–1255. doi:10.1038/ki.2012.344 lation of intestinal pH. In addition, guanylin and uroguanylin target the renal tissue, eliciting natriuresis, kali- Studies in the 1970s demonstrated that renal endocrine axis.3,4 However, uresis, and diuresis, along with increas- an oral load of sodium evoked higher Preston et al.5 (this issue) now pro- ing urinary cGMP levels without natriuresis than did a similar intrave- vide results from a high-quality experi- changes in glomerular filtration rate nous load of sodium in humans.1,2 mental study in healthy subjects that do or renal blood flow.3,4,6 Thus, guanylin These observations have contributed not support the existence of such an peptides presumably induce increased to the concept of a gastrointestinal– acute gastrointestinal–renal natriuretic urinary salt and water excretion in renal natriuretic signaling axis. Accord- signaling axis. Most importantly, the order to prevent hypernatremia and ing to this concept, natriuretic peptides authors of this work cast doubt on a hypervolemia after enhanced salt are released from the intestine into the central role of guanylin peptide family uptake exceeding the body’s physio- circulation in response to oral salt members in such an axis if it really logical requirements. In contrast to the intake and thereafter act on the kidneys exists. intestine, where the guanylate cyclase C as hormones to increase sodium excre- The guanylin peptide family has receptor seems to be the most important tion. During the past 20 years, two several subclasses of peptides, including receptor by far, guanylin and uroguany- members of the guanylin peptide guanylin and uroguanylin.6 The sources lin can activate different pathways along family, guanylin and uroguanylin, have of these peptides are the intestine and the nephron. The guanylate cyclase C been suggested as candidates for mediat- the kidneys but also other epithelia. receptor has been suggested to play a ing this proposed postprandial entero- Guanylin mRNA has been detected minor role in the kidney, conceivably mainly in the gastrointestinal tract in restricted to the proximal tubule. In 1Department of Laboratory Medicine, numerous cell types and in the kidney. the kidney, additional receptors with Konventhospital Barmherzige Brueder Linz, Linz, Uroguanylin mRNA is, for example, different messenger systems are Austria present in the gut, kidney, heart, activated by the guanylin peptides and Correspondence: Thomas Mueller, Department of Laboratory Medicine, Konventhospital Barmherzige reproductive system, and brain. The mediate complex effects on electrolyte 3,4,6 Brueder, Seilerstaette 2-4, Linz A-4020, Austria. expression pattern of both peptides is and water excretion. The molecular E-mail: [email protected] differential in the intestine: the highest identities of these renal receptors for Kidney International (2012) 82 1253 commentary Intracellular 1q43 1q42.12 1q24.3 1q31.1 1q23.2 1q32.2 1p36.32 1p36.21 1p35.3 1p34.2 1p32.2 1p31.1 1p21.3 1p12 1q21.2 1p36.23 1p35.1 1p31.3 1p33 1q22 1q24.1 1q25.2 1q31.3 1q42.2 1q41 e.g., intestine or kidney 1p36.12 1p22.2 1p13.2 1q12 Chromosome 1 (1p35–p34 and 1p34–p33) Translation H2N COOH2 H2N COOH2 Prepro-guanylin (115 aa) Prepro-uroguanylin (112 aa) Cleavage Cleavage Signal peptide (21 aa) Signal peptide (26 aa) H N COOH H2N COOH2 2 2 Proguanylin (94 aa) Prouroguanylin (86 aa) Secretion Secretion H N COOH 2 2 H2N COOH2 Extracellular Proguanylin (94 aa) Prouroguanylin (86 aa) e.g., interstitium, Cleavage Cleavage circulation, intestinal Pro-region (79 aa) Pro-region (70 aa) or renal lumen Guanylin (15 aa) Uroguanylin (16 aa) Several additional, yet Guanylate Peptide binding Guanylate undetermined receptor cyclase C cyclase C systems in the kidney receptor receptor ? Intracellular Intracellular GTP GTP Kidney cGMP Intestine cGMP Effects? Effects Effects • Natriuresis increased • Cl– secretion increased • Kaliuresis increased – • HCO3 secretion increased • Diuresis increased • Na+ absorption decreased • No changes in glomerular filtration rate • Water secretion driven • No changes in renal blood flow Figure 1 | Post-translational processing of guanylin and uroguanylin and their proposed effects in the kidney and intestine. aa, amino acids; cGMP, cyclic guanosine monophosphate; GTP, guanosine triphosphate. guanylin and uroguanylin still remain to terminal 16-amino acid peptide urogua- proguanylin, and prouroguanylin can be determined. nylin and a 70-amino acid pro-region be detected in human plasma. All four The genes for guanylin and (or probably several smaller fragments). peptides are freely filtered through uroguanylin are located at human In simplified terms, Figure 1 displays the glomerular barrier in the kidney. chromosome 1 (localization 1p35–p34 the post-translational processing of both However, urine contains only low and 1p34–p33, respectively).7,8 Both polypeptides and their effects in the amounts of guanylin and proguanylin, peptides are produced by translation intestine and the kidneys. probably because of degradation by as prepro-hormones. In humans, the Guanylin and uroguanylin but not chymotrypsin-like proteases or endo- precursor of guanylin is synthesized as proguanylin and prouroguanylin are cytosis.3,6 In contrast, uroguanylin and prepro-guanylin consisting of 115 thought to be the biologically active prouroguanylin can be found in amino acids. Intracellular cleavage of peptides.3,6 Human guanylin possesses higher concentrations in the urine. 21 NH2-terminal residues leads to for- two disulfide bonds between the This is most likely the consequence mation of proguanylin with 94 amino cysteines in positions 4 to 12 and 7 to of a key structural property uniquely acids. Further extracellular proteolytic 15.3,6 Human uroguanylin also has two found in uroguanylin peptides but processing reveals the small COOH- disulfide bonds at the same positions.3,6 not in guanylin peptides that makes terminal 15-amino acid peptide These disulfide bonds are essential for uroguanylin peptides highly resistant guanylin and a 79-amino acid pro- the activity of the peptides. Both to attack by endoproteases such as region. Similarly, human uroguanylin is proguanylin and prouroguanylin are chymotrypsin.6 derived from prepro-uroguanylin considered biologically inactive beca- In terms of their natriuretic proper- consisting of 112 amino acids. Post- use of structural interactions between ties, the question is whether guanylin translational intracellular cleavage the amino acid sequences related to and uroguanylin or proguanylin and reveals a 26-amino acid NH2-terminal active peptides and the NH2-terminal prouroguanylin, respectively, act as signal peptide and the 86-amino acid residues thereby covering the biologi- hormones or have merely autocrine/ prouroguanylin. Prouroguanylin is then cally active epitopes.9 paracrine functions in the kidney. In released into the extracellular space With several assays published in the first case the peptides should be and processed into the COOH- the literature, guanylin, uroguanylin, produced in the intestine in response 1254 Kidney International (2012) 82 commentary
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