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A novel role for uroguanylin in the regulation of sodium balance
Leonard R. Forte
Medical Research Service, Truman Memorial Veterans Administration Hospital and Radiopharmaceutical Sciences Institute and Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, Missouri, USA
Address correspondence to: Leonard R. Forte, University of Missouri, M-517 Medical Sciences Building, One Hospital Drive, Columbia, Missouri 65212, USA. Phone: (573) 814-6000; Fax: (573) 814-6551; E-mail: lrf@missouri.edu.
Find articles by Forte, L. in: JCI | PubMed | Google Scholar
Published October 15, 2003 - More info
J Clin Invest. 2003;112(8):1138–1141. https://doi.org/10.1172/JCI20057.
© 2003 The American Society for Clinical Investigation
Three different families of first messenger molecules are known to influence cellular function through mediation by the intracellular second messenger, cGMP. The regulatory molecules consist of guanylin, uroguanylin, NO, and the atriopeptins. These hormone-like molecules bind selectively to and activate specific forms of receptor–guanylate cyclases (R-GCs) to produce and signal via cGMP within target cells. Guanylin and uroguanylin are the newest members of the greater family of cGMP-regulating agonists that have been identified. However, guanylin and uroguanylin also belong to a class of peptides that were actually the first recognized agonists for activation of an R-GC pathway. It was first reported in 1978 that a heat-stable (ST) peptide produced by Escherichia coli activated an intestinal R-GC, thus raising intracellular levels of cGMP, which then led to the stimulation of intestinal secretion and diarrhea (1, 2). With the power of hindsight, it can be seen that guanylin and/or uroguanylin should have been identified next as endogenous ST-like agonists for this orphan R-GC. If this had happened, guanylin and uroguanylin would be quite familiar to scientists at the present time. However, two events occurred at the beginning of the 1980s that shifted the emphasis of what was at that time a much smaller body of investigators working in the field of cGMP signaling. Endothelium-derived relaxing factor (EDRF) and atrial natriuretic factor (ANF) were discovered (3, 4). These factors spawned two large investigations that ultimately identified EDRF as NO and ANF as three different atriopeptins, while also elucidating that two different types of R-GCs are regulated by NO and atriopeptins. Much later, investigations into endogenous ST-like agonists for the intestinal R-GC pathway came back into focus when guanylin was isolated from rat intestine (5), an event which was soon followed by the isolation of uroguanylin from opossum urine (6). Guanylin and uroguanylin have striking similarities in structure and biological activity to the ST peptides of enteric bacteria (Figure 1). For example, these peptides are agonists of intestinal R-GC activation and also stimulate chloride secretion, indicating that ST peptides are simply molecular mimics of uroguanylin and guanylin. The intriguing findings of Lorenz and his colleagues reported in this issue of the JCI will help to raise new levels of interest in uroguanylin as a novel player in the complex physiological scheme that has evolved to regulate the urinary excretion of sodium chloride and thus to influence sodium balance and blood pressure in the body (7).
Figure 1Primary structures of guanylin, uroguanylin, and bacterial ST peptides. Single letter abbreviations for the amino acids are used. The peptides are aligned using the conserved cysteine residues found in the three classes of peptides. Sequences for Zebrafish and Fugu peptides were derived from their respective genome sequencing projects, and those for eel peptides were taken from Yuge et al. (17).
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Uroguanylin deficiency impairs sodium excretion
Inactivation of uroguanylin genes in mice produces an animal model with an impaired capacity to excrete NaCl in urine when salt loads are administered orally (7). However, intravenous administration of NaCl to uroguanylin–/– mice elicits a natriuresis equivalent to that of wild-type animals. This novel finding seems surprising, yet had, in a sense, been predicted. The surprise comes in the authors’ observations that inactivation of genes encoding guanylyl cyclase C receptor (R-GC-C) results in an animal that no longer exhibits intestinal secretion responses to these agonists, but appears to have no other physiological abnormalities or morphological changes (8, 9). R-GC-C–/– animals have normal blood pressure. One explanation for the normal blood pressure and renal sodium excretion observed in the R-GC-C–/– mice is that regulation of renal sodium transport and thus urinary sodium excretion is not mediated by R-GC-C, but through another receptor for uroguanylin that has not been identified. Consistent with this concept are the findings of Carrithers et al. that intravenous treatment of R-GC-C–/– mice with uroguanylin, guanylin, or ST peptides elicits saliuretic and diuretic responses that are quantitatively equal to the renal responses of R-GC-C+/+ animals (10). Clearly, the molecular identification of a second receptor for uroguanylin in the kidney is an important objective for those working in this area. Hints of such a receptor and signaling mechanism can be found in a study by Sindic et al., who report that a pertussis toxin–sensitive pathway is utilized in kidney cells for signal transduction initiated by uroguanylin (11). On the other hand, perhaps we should not be surprised by the report by Lorenz et al. (7) because Forte et al. had predicted that uroguanylin could serve in an endocrine axis connecting the gastrointestinal (GI) tract to the kidney for regulation of NaCl excretion (12). This hypothesis is based, at least in part, on observations made almost three decades ago that oral administration of NaCl induces a natriuresis that greatly exceeds the increase in urine sodium elicited by intravenous NaCl (13). An intestinal natriuretic factor was postulated to exist as one explanation for this finding. The factor is released from the GI system when NaCl is consumed and travels in the bloodstream to the kidney, where this substance could act as a natriuretic hormone. The current findings in uroguanylin–/– animals reported by Lorenz et al. are consistent with the hypothesis that one physiological role for uroguanylin is regulating kidney function and helping to maintain body sodium balance (Figure 2). Such an intestine-kidney axis will likely be an oversimplification of the physiological mechanism that operates in vivo because uroguanylin is also produced in the kidney where it may act locally. Increases in dietary NaCl raise uroguanylin mRNA levels in the intestine and kidney, suggesting that both endocrine and paracrine/autocrine actions of uroguanylin could participate in tubular signaling mechanisms that govern renal sodium transport (14, 15).
Figure 2An endocrine axis linking together the GI system and kidney via uroguanylin produced in the stomach and/or intestine and secreted into the circulatory system. The studies of Lorenz et al. (7) support the concept that uroguanylin may play a key physiological role serving as a natriuretic hormone produced by the GI system and released into the circulatory system when excess NaCl is ingested. Atriopeptin-A (ANP), atriopeptin-B (BNP), and uroguanylin derived from the myocardium may, in some circumstances, also contribute to the natriuresis elicited by high salt loads in the postprandial state. Not shown in this model is the renal production of uroguanylin, guanylin, and atriopeptins, which could participate in intra-renal mechanisms that regulate tubular sodium transport and thus contribute to the saliuresis elicited by oral salt loads. A potential role for uroguanylin and/or guanylin in the CNS to influence the appetite for salt should also be considered in future studies. Figure modified with permission from the American Journal of Physiology (24).
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