A novel role for uroguanylin in the regulation of sodium balance Leonard R. Forte J Clin Invest. 2003;112(8):1138-1141. https://doi.org/10.1172/JCI20057. Commentary Uroguanylin is a peptide hormone that regulates sodium excretion by the kidney when excess NaCl is consumed. A new study demonstrates that mice deficient in uroguanylin have blunted urinary sodium excretion responses to oral sodium loads in addition to elevated blood pressure (see related article beginning on page 1244). A physiological role for uroguanylin is discussed, linking the intestine and kidney in an endocrine axis for the maintenance of sodium balance. Find the latest version: https://jci.me/20057/pdf A novel role for uroguanylin in the interest in uroguanylin as a novel play- er in the complex physiological scheme regulation of sodium balance that has evolved to regulate the urinary excretion of sodium chloride and thus Leonard R. Forte to influence sodium balance and blood pressure in the body (7). Medical Research Service, Truman Memorial Veterans Administration Hospital and Radiopharmaceutical Sciences Institute and Department of Medical Pharmacology and Uroguanylin deficiency impairs Physiology, School of Medicine, University of Missouri, Columbia, Missouri, USA sodium excretion Inactivation of uroguanylin genes in Uroguanylin is a peptide hormone that regulates sodium excretion by mice produces an animal model with the kidney when excess NaCl is consumed. A new study demonstrates an impaired capacity to excrete NaCl that mice deficient in uroguanylin have blunted urinary sodium excre- in urine when salt loads are adminis- tion responses to oral sodium loads in addition to elevated blood pres- tered orally (7). However, intravenous sure (see related article beginning on page 1244). A physiological role for administration of NaCl to uroguan- uroguanylin is discussed, linking the intestine and kidney in an ylin–/– mice elicits a natriuresis equiva- endocrine axis for the maintenance of sodium balance. lent to that of wild-type animals. This novel finding seems surprising, yet J. Clin. Invest. 112:1138–1141 (2003). doi:10.1172/JCI200320057. had, in a sense, been predicted. The surprise comes in the authors’ obser- Three different families of first mes- and/or uroguanylin should have been vations that inactivation of genes senger molecules are known to influ- identified next as endogenous ST-like encoding guanylyl cyclase C receptor ence cellular function through media- agonists for this orphan R-GC. If this (R-GC-C) results in an animal that no tion by the intracellular second had happened, guanylin and uroguan- longer exhibits intestinal secretion messenger, cGMP. The regulatory mol- ylin would be quite familiar to scien- responses to these agonists, but appears ecules consist of guanylin, uroguanylin, tists at the present time. However, two to have no other physiological abnor- NO, and the atriopeptins. These hor- events occurred at the beginning of the malities or morphological changes mone-like molecules bind selectively to 1980s that shifted the emphasis of (8, 9). R-GC-C–/– animals have normal and activate specific forms of recep- what was at that time a much smaller blood pressure. One explanation for tor–guanylate cyclases (R-GCs) to pro- body of investigators working in the the normal blood pressure and renal duce and signal via cGMP within target field of cGMP signaling. Endothelium- sodium excretion observed in the cells. Guanylin and uroguanylin are the derived relaxing factor (EDRF) and R-GC-C–/– mice is that regulation of newest members of the greater family atrial natriuretic factor (ANF) were dis- renal sodium transport and thus uri- of cGMP-regulating agonists that have covered (3, 4). These factors spawned nary sodium excretion is not mediated been identified. However, guanylin and two large investigations that ultimate- by R-GC-C, but through another uroguanylin also belong to a class of ly identified EDRF as NO and ANF as receptor for uroguanylin that has not peptides that were actually the first rec- three different atriopeptins, while also been identified. Consistent with this ognized agonists for activation of an elucidating that two different types of concept are the findings of Carrithers R-GC pathway. It was first reported in R-GCs are regulated by NO and atri- et al. that intravenous treatment of 1978 that a heat-stable (ST) peptide opeptins. Much later, investigations R-GC-C–/– mice with uroguanylin, guan- produced by Escherichia coli activated an into endogenous ST-like agonists for ylin, or ST peptides elicits saliuretic intestinal R-GC, thus raising intracel- the intestinal R-GC pathway came and diuretic responses that are quanti- lular levels of cGMP, which then led to back into focus when guanylin was iso- tatively equal to the renal responses of the stimulation of intestinal secretion lated from rat intestine (5), an event R-GC-C+/+ animals (10). Clearly, the and diarrhea (1, 2). With the power of which was soon followed by the isola- molecular identification of a second hindsight, it can be seen that guanylin tion of uroguanylin from opossum receptor for uroguanylin in the kidney urine (6). Guanylin and uroguanylin is an important objective for those Address correspondence to: Leonard R. have striking similarities in structure working in this area. Hints of such a Forte, University of Missouri, M-517 Medical Sciences Building, One Hospital Drive, and biological activity to the ST pep- receptor and signaling mechanism can Columbia, Missouri 65212, USA. tides of enteric bacteria (Figure 1). For be found in a study by Sindic et al., Phone: (573) 814-6000; Fax: (573) 814-6551; example, these peptides are agonists of who report that a pertussis toxin–sen- E-mail: [email protected]. intestinal R-GC activation and also sitive pathway is utilized in kidney Conflict of interest: The author has declared that no conflict of interest exists. stimulate chloride secretion, indicating cells for signal transduction initiated Nonstandard abbreviations used: that ST peptides are simply molecular by uroguanylin (11). On the other receptor–guanylate cyclase (R-GC); heat stable mimics of uroguanylin and guanylin. hand, perhaps we should not be sur- (ST); endothelium-derived relaxing factor The intriguing findings of Lorenz and prised by the report by Lorenz et al. (7) (EDRF); atrial natriuretic factor (ANF); guanylyl cyclase C receptor (R-GC-C); his colleagues reported in this issue of because Forte et al. had predicted that gastrointestinal (GI). the JCI will help to raise new levels of uroguanylin could serve in an endo- 1138 The Journal of Clinical Investigation | October 2003 | Volume 112 | Number 8 for uroguanylin in the regulation of body sodium balance may be the mammalian counterpart to the possi- ble contribution of uroguanylin to the processes controlling osmoregulation in euryhaline fish, which can adapt to living in either freshwater or seawater conditions. For example, uroguanylin mRNA levels are upregulated in the intestine and kidney when freshwater- adapted eels are exposed to the con- siderably higher NaCl concentration of seawater (16, 17). This finding sug- gests that uroguanylin may function in fish to regulate body sodium levels in a fashion similar to the physiologi- cal role that Lorenz et al. (7) suggest for uroguanylin in the mouse, where the expression of uroguanylin mRNAs may also be under the influence of NaCl in the diet (14, 15). Might Figure 1 Primary structures of guanylin, uroguanylin, and bacterial ST peptides. Single letter abbrevi- uroguanylin serve to regulate body ations for the amino acids are used. The peptides are aligned using the conserved cysteine sodium balance in mammals by some residues found in the three classes of peptides. Sequences for Zebrafish and Fugu peptides common regulatory mechanism(s) were derived from their respective genome sequencing projects, and those for eel peptides similar to those involved in the com- were taken from Yuge et al. (17). plicated physiology underlying osmo- regulation in fish? If so, we can antici- pate that this type of biological role for crine axis connecting the gastroin- endocrine and paracrine/autocrine uroguanylin could be the main selec- testinal (GI) tract to the kidney for reg- actions of uroguanylin could partici- tive pressure that has contributed to ulation of NaCl excretion (12). This pate in tubular signaling mecha- conservation and maintenance of the hypothesis is based, at least in part, on nisms that govern renal sodium primary structures of uroguanylin observations made almost three transport (14, 15). during vertebrate evolution. decades ago that oral administration of NaCl induces a natriuresis that Uroguanylin and osmoregulation Properties of uroguanylin greatly exceeds the increase in urine A fundamental question is: What spe- versus guanylin sodium elicited by intravenous NaCl cific physiological roles are played by A specific feature of the structure- (13). An intestinal natriuretic factor uroguanylin versus guanylin in the activity relationship for uroguanylin was postulated to exist as one explana- body? It is quite clear that some selec- relates to specific residues within this tion for this finding. The factor is tive process has been in effect for molecule that contribute to its bio- released from the GI system when approximately the past 300 million logical activity in the kidney. Studies NaCl is consumed and travels in the years of vertebrate evolution to main- using the T84 colon cell model may bloodstream to the kidney,