Ingestion of a salty meal induces secretion of guanylin (GN)and uroguanylin (UGN) into the intestinal lumen, where theyinhibit Na+ absorption and induce Cl–, HCO3–, andwater secretion. Simultaneously, these hormones stimulate renalelectrolyte excretion by inducing natriuresis, kaliuresis, anddiuresis. GN and UGN therefore participate in the preventionof hypernatremia and hypervolemia after salty meals. The signalingpathway of GN and UGN in the intestine is well known. They activateenterocytes via guanylate cyclase C (GC-C), which leads to cGMP-dependentinhibition of Na+/H+ exchange and activation of the cystic fibrosistransmembrane regulator. In GC-C–deficient mice, GN andUGN still produce renal natriuresis, kaliuresis, and diuresis,suggesting different signaling pathways in the kidney comparedwith the intestine. Signaling pathways for GN and UGN in thekidney differ along the various nephron segments. In proximaltubule cells, a cGMP- and GC-C–dependent signaling wasdemonstrated for both peptides. In addition, UGN activates apertussis toxin–sensitive G-protein–coupled receptor.A similar dual signaling pathway is also known for atrial natriureticpeptide. Recently, a cGMP-independent signaling pathway forGN and UGN was also shown in principal cells of the human andmouse cortical collecting duct. Because GN and UGN activatedifferent signaling pathways in specific organs and even withinthe kidney, this review focuses on more recent findings on cellulareffects and signaling mechanisms of these peptides and theirpathophysiologic implications in the intestine and the kidney.
Guanylin peptides, guanylin (GN) and uroguanylin (UGN) are small,heat-stable peptides with 15 to 19 amino acids. Human GN consistsof 15 amino acids and possesses two disulfide bonds betweenthe cysteins in positions 4 to 12 and 7 to 15 (1). Human UGNconsists of 16 amino acids and also has two disulfide bondsat the same positions (2). These disulfide bonds are essentialfor the activity of the peptides. The genes for guanylin peptidesare located on the human chromosome 1 (p33 to p36) and the mousechromosome 4 (3). Human GN and UGN are coded by different butsimilar genes that consist of three exons and two introns. Bothpeptides are synthesized as prepropeptide. Guanylin peptidesare produced in the intestine after ingestion of a salty mealand secreted into the intestinal lumen (4). In the intestine,GN and UGN activate enterocytes via guanylate cyclase C (GC-C),with cGMP as second messenger (5,6). Activation of this pathwayleads to the secretion of Cl– and HCO3– and to theinhibition of Na+ absorption, which drives water secretion.In addition, these hormones induce an increased salt and waterexcretion in the kidney (7). The decrease of salt absorptionin the intestine together with the increase of renal salt excretionprevents the development of hypernatremia after ingestion ofhigh amounts of salt.
GC-C was first described as a receptor for the exogenous heat-stableenterotoxin of Escherichia coli (STa) (8). Unlike the endogenouspeptides GN and UGN, STa contains three disulfide bonds. Itis presumed that this is the reason for its stronger and uncontrolledactivation of GC-C that leads to marked intestinal secretionof electrolytes and water and is manifested as secretory diarrhea(9). The identification of a receptor for the exogenous enterotoxinin the intestine and in other tissues (kidney, reproductivesystem, and lung) led to the search for endogenous ligands forGC-C and their physiologic function. In the early 1990s, GNwas isolated from rat intestine (5) and UGN from opossum urine(6). Other recently discovered new members of this peptide familyare renoguanylin (10) and lymphoguanylin (11). Like GN and UGN,renoguanylin has two disulfide bonds, whereas lymphoguanylinpossesses only one. Lymphoguanylin is less potent than GN andUGN in the intestine (11). As guanylin peptides regulate electrolyteexcretion by the intestine and the kidney, they complement otherwell-known hormonal systems that are involved in regulationof water and electrolyte homeostasis, such as the renin-angiotensin-aldosteronesystem, adiuretin (vasopressin) or atrial natriuretic peptide(ANP), brain natriuretic peptide (BNP), and C type natriureticpeptide (CNP).
A number of excellent reviews on various aspects of guanylinpeptides exist (12,13); however, recent growing understandingof cellular signaling mechanisms also in humans is not coveredin these reviews. Therefore, the aim of this review is to summarizethe current knowledge on cellular effects of guanylin peptidesand their signaling pathways and possible pathophysiologic implicationsin different organs, mainly the intestine and the kidney ofdifferent species including man.
The big family of guanylate cyclases consists of one cytoplasmic(soluble) guanylate cyclase, which is the receptor for nitricoxide and carbonic monoxide, and six isoforms of membrane guanylatecyclases. GC-A, GC-B, and GC-C are receptors for natriureticpeptides that regulate electrolyte and water homeostasis andcontrol BP (14). GC-A (or NPR-A) is the receptor for ANP andBNP; GC-B (or NPR-B) is the receptor for CNP. A third receptorthat binds these three peptides, the so-called clearance receptor(or NPR-C), has no guanylate cyclase activity, and hormone bindingto this receptor leads to endocytosis of the hormone-receptorcomplex and activation of a pertussis toxin–sensitiveG-protein. The latter mediates an inhibition of adenylate cyclase(15,16). Guanylate cyclases D, E, and F (GC-D, GC-E, and GC-F)are expressed in sensory organs, and, until now, their agonistsand functions are not known (17–20). GC-G is also an orphanreceptor without known agonist, and it is present in skeletalmuscles, lungs, and intestine. Hirsch et al. (21) showed forthe first time the presence of GC-G also in the kidney and identifiedthis guanylate cyclase as the only membrane-bound isoform presentin principal cells of rat cortical collecting duct (CCD). Table 1summarizes the tissue distribution and known agonists forthe eight guanylate cyclases identified (22,23).
GC-C is the main receptor for guanylin peptides in the intestine(Figure 1). GC-C forms dimers, trimers, or tetramers when insertedinto the plasma membrane (24). mRNA for GC-C is present alsoin adrenal glands, brain, the embryonic or regenerating butnot adult liver, placenta, testis, airways, spleen, thymus,and lymphatic nodes (25–27). Human and rat GC-C have 71%homology in the extracellular domain and 91% in the intracellulardomain. The extracellular domain must be glycosylated for completereceptor activity (28,29), and dephosphorylation caused by bindingof an agonist to the extracellular domain leads to loss of receptorsensitivity (30).
Figure 1. Guanylate cyclase C (GC-C) forming a dimer. The binding of guanylin (GN), uroguanylin (UGN), or heat-stable enterotoxin of Escherichia coli (STa) to the extracellular domain of GC-C leads to activation of the catalytic domain with the production of cGMP and the dephosphorylation of the kinase homology domain with receptor desensitization. For details, see text. L, ligand.
The most studied regulator of GC-C activity is protein kinaseC (PKC). GC-C phosphorylation by PKC leads to an increase incGMP accumulation. PKC-induced phosphorylation at the C-terminaltail increased STa-mediated cGMP generation by 70% when comparedwith the nonphosphorylated receptor (31,32).
The existence of additional receptors for guanylin peptidesbecame evident when, for example, intestinal and renal effectsof these peptides were examined in GC-C–deficient mice.These mice are resistant to intestinal secretion produced bySTa (33–35), but approximately 10% of the intestinal bindingsites for these peptides are still present when compared withwild-type mice. In the kidney, guanylin peptides still inducesaluresis and diuresis in these GC-C–deficient mice (36),strongly suggesting an additional receptor and possibly signalingcascade for guanylin peptides at least in the kidney and tosome extent also in the intestine. That renal effects of guanylinpeptides are maintained when GC-C is absent also indicates thatGC-C plays no or only a minor role for these peptides in thekidney.
Signaling Pathways of Guanylin Peptides in the Intestine
Guanylin peptides secreted into the intestinal lumen in responseto high oral salt intake bind to GC-C localized in the luminalmembrane of enterocytes and induce electrolyte and water excretionby a complex signaling cascade (Figure 2):
Increase of the intracellularconcentration of cGMP (5,6,8)
Inhibition of Na+/H+ exchange,which results in decreased Na+reabsorption (37)
Activation of PKA directly (40,41) or indirectlyvia inhibitionof phosphodiesterase III (PDE III), which leadsto an increaseof cellular cAMP and activation of PKA (39)
PKGII and PKA activate cystic fibrosis transmembrane regulator(CFTR) in the luminal membrane (42), leading to Cl– secretioninto the intestinal lumen
CFTR activates the Cl–/HCO3–exchanger, which leadsto bicarbonate secretion into the intestinallumen (43)
Figure 2. Signaling pathway of guanylin peptides in the intestine. GN, UGN, and STa activate membrane-bound GC-C, which increases the intracellular concentration of cGMP. cGMP inhibits the Na+/H+ exchanger (NHE) and activates protein kinase G type II (PKG II) and protein kinase A (PKA). Both protein kinases activate Cl– and HCO3– secretion via activation of cystic fibrosis transmembrane regulator (CFTR) followed by an activation of the Cl–/HCO3– exchanger. Depicted is a schematic drawing of an enterocyte including the major components necessary for electrolyte transport. PDE III, phosphodiesterase type III (inhibited by cGMP). Illustration by Josh Gramling—Gramling Medical Illustration.
GN and UGN are expressed along the intestinal tract (Figure 3)together with GC-C (44–46), which is the major intestinalreceptor for GN and UGN. However, the expression pattern ofthese two hormones is differential, i.e., highest expressionof UGN in the jejunum and highest expression of GN in ileumto proximal colon. The distal colon expresses only small amountsof both hormones.
Figure 3. Relative expression of GN () and UGN () mRNA along the intestinal tract. Adapted from reference (46).
As indicated above, a few studies show the existence of a signalingpathway at least for STa distinct of GC-C (33–35). Furthermore,binding sites for guanylin peptides that are distinct from GC-Care also located on the basolateral membrane of colonocytes(47). STa also activates the Ca2+ signaling pathway with activationof PKC (48,49), which could be independent of GC-C activation.
The effects of GN and UGN on cellular cGMP via GC-C depend onextracellular pH. UGN is more potent at pH 5 compared with pH8. Conversely, GN is more potent at pH 8 compared with pH 5(Figure 4). As this pH dependence affects the ligand/receptorinteraction, it was suggested that the N-terminal ends of theUGN and GN molecules are responsible for this pH dependence(50). The duodenum secretes bicarbonate to neutralize the acidicpH of the stomach contents that enter the duodenum. This acid-stimulatedduodenal mucosal bicarbonate secretion is cGMP dependent. UGNregulates the luminal pH in the duodenum by activation of bicarbonatesecretion and inhibition of H+ secretion because unlike GN,UGN is localized predominantly in the proximal part of intestinaltract (Figure 3). This effect is enhanced as UGN has higheractivity at acidic pH and leads to stronger HCO3– secretioninto duodenal lumen.
Figure 4. GN and UGN increase the cellular concentration of cGMP pH-dependently. GN is more potent at pH 8.0, and UGN is more potent at pH 5.0. Adapted from reference (50).
Signaling Mechanisms of Guanylin Peptides in the Kidney
Guanylin peptides increase the secretion of Na+, K+, and waterin the kidney without changes in GFR or renal blood flow (7,36).UGN is proposed to be an intestinal natriuretic peptide, asnatriuresis produced by oral salt load is decreased in UGN-deficientmice (51). Thus, the action of UGN in the kidney can be endocrine(produced in the intestine with actions in the kidney), paracrine(produced by the kidney), or both. Kinoshita et al. (52) showedhigher UGN concentration in blood and urine of individuals whowere on a high-salt diet compared with those who were on a low-saltdiet, which speaks in favor of an endocrine function of UGN.Recently, Fukae et al. (53) showed that rats that are fed ahigh-salt diet have higher UGN and cGMP concentrations in theurine but show no changes in the concentration of UGN in theplasma compared with control animals. UGN is expressed in thekidney, and its expression is higher in animals that are ona high-salt diet (53,54). It is still not clear whether theincrease in the urinary concentrations of UGN and cGMP (52,53)are due to local production and secretion of UGN within thekidney or to filtration in the glomerulus.
Both GN and UGN circulate in the plasma and can be filteredin the glomerulus into the primary urine. UGN is excreted viathe final urine, whereas hardly any GN can be found in the urine(6,55). A possible reason that GN is not present in the finalurine is its sensitivity to chymotrypsin, which quickly degradesGN after glomerular filtration or secretion of GN into the tubularlumen (9,56). These differences in the degradation and expressionpattern of GN and UGN suggest that GN probably acts strictlyautocrine, whereas UGN has paracrine activity in the kidney.The concentration of UGN in the urine correlates with that ofurinary cGMP, which again supports the hypothesis that cGMPand the GC-C signaling pathways are activated by UGN at leastin the cells of the proximal tubule. However, another possiblesource of cGMP in the urine could be the activation of othermembers of the guanylate cyclase family, such as the orphanreceptor GC-G, which is present in the luminal membrane of principalcells of rat and mouse CCD (21,57). The source of guanylin peptidesin the tubular lumen besides glomerular filtration from thecirculation could also be tubular cells because mRNA for GNand UGN is also expressed in kidney epithelial cells (54,58,59).Similar to the difference in the axial expression along theintestine, GN and UGN are not expressed equally along the differentnephron segments (Figure 5). UGN is present mostly in the proximaltubule, again comparable to the proximal intestine, and GN ismore pronounced in the collecting duct, in analogy to GN expressionin the colon.
Figure 5. Relative mRNA expression of GN (A) and UGN (B) in various mouse nephron segments. GL, glomerulus; PT, proximal tubule; TAL, thick ascending limb of Henle’s loop; CD, collecting duct; GAPDH, glyceraldehyde-3-phosphate dehydrogenase. Mean values ± SEM, n = 4. Adapted from reference (54).
Markedly different from the expression along the entire intestinaltract, GC-C, the first receptor for guanylin peptides identified,is not present in all nephron segments. Potthast et al. (54)localized GC-C in the mouse kidney only in glomeruli and proximaltubules. In the human kidney, we detected GC-C again only inthe kidney cortex and specifically in proximal tubules (Figure 6)(60,61). In contrary to these findings in mouse and human,in rat kidney, Carrithers et al. (58) found mRNA for GC-C inall nephron segments, suggesting differences in tissue distributionof GC-C in different species. A few years ago, it became evidentthat proximal tubules are targets of guanylin peptides. Guanylinpeptides increase the intracellular cGMP concentration in aproximal tubule cell line of opossum kidney (OK cells) via theopossum kidney GC-C (OK-GC), which is the analog to the humanGC-C (62). Recently, we demonstrated an increase in the cellularcGMP concentration induced by guanylin peptides also in a humanproximal tubule cell line (IHKE1) (61). In this cell line, GNand UGN also activated GC-C.
Figure 6. Expression of mRNA for GC-C in human nephron segments. G, glomeruli; CCD, cortical collecting ducts; M, marker; (–), negative control (no cDNA); (+), positive control. Adapted from reference (60).
The intestinal pH dependence for the binding of GN and UGN toGC-C (see above) probably also is relevant in the kidney. Inthe human proximal tubule cell line, UGN activated GC-C at pH5 more pronounced than at pH 8 (Figure 4). At alkaline pH, whenUGN effects on GC-C in these proximal tubular cells were lower,an additional signaling pathway via pertussis toxin–sensitiveG-proteins was revealed (61). Therefore, tubular pH can playan important role in activating GN versus UGN signaling pathwaysand activating different signaling pathways for UGN (Figure 7).This might be even more relevant along the medullary collectingduct, where tubular pH can be significantly acidic. Data oneffects of guanylin peptides along this nephron segment, however,are still completely missing.
Figure 7. pH dependence of effects of guanylin peptides on membrane voltages of human proximal tubule cells. At pH 5.5, UGN activated GC-C and depolarized cells; at pH 8.0, it activated a G-protein–coupled receptor and hyperpolarized the cells. GN and STa depolarize cells only via activation of the GC-C–dependent signaling pathway. Mean values ± SEM, n given in brackets. Adapted from reference (61).
Data from various proximal tubule cells in culture suggest thatguanylin peptides inhibit Na+ reabsorption in this nephron segment.UGN decreases the expression of the Na+/K+-ATPase, which wouldlower the concentration gradient for Na+ and therefore reduceNa+-coupled electrolyte and substrate reabsorption from thetubular lumen (63). According to our own observations in thehuman proximal tubule cell line, GN and UGN decrease the electricaldriving force for Na+ reabsorption by inhibiting K+ channelsvia cGMP and depolarizing cells (61). Finally, the increasein cellular cGMP by GN and UGN should, like in the intestine(37), inhibit luminal Na+/H+ exchange and thereby reduce Na+and volume reabsorption. Indeed, in the human proximal tubulecell line, UGN inhibited Na+/H+ exchange activity (SchlatterE., unpublished results). As mentioned above, guanylin peptidesstill cause natriuresis, kaliuresis, and diuresis in GC-C–deficientmice, suggesting a second receptor in the kidney for these peptides(36). In addition to this GC-C–and cGMP-dependent signalingpathway, UGN can activate a pertussis toxin–sensitiveG-protein that leads to activation of a K+ conductance (61).Which signaling pathway will be activated by UGN could dependon luminal pH (Figure 7). Figure 8 shows a summary of actionsof guanylin peptides on proximal tubular cells on ion and watertransport. The molecular identity of this second receptor, thephysiologic role of this cGMP-independent signaling pathway,and the relative contributions of these two signaling pathwaysremains to be elucidated.
Figure 8. Signaling pathways of guanylin peptides in renal proximal tubule cells. Guanylin peptides activate two signaling pathways. One is GC-C and cGMP dependent. cGMP decreases Na+ reabsorption by inhibiting different proteins in the membrane: K+ channels, Na+/H+ exchanger, and Na+/K+-ATPase. The other signaling pathway involves activation of a pertussis toxin–sensitive G-protein. AQP1, aquaporin 1; NBC, Na+/HCO3– co-transporter; NHE3, Na+/H+ exchanger; OK-GC, guanylate cyclase from opossum kidney. Illustration by Josh Gramling—Gramling Medical Illustration.
The presence of two receptors for one peptide even at the samecell is known for other hormones that also act in the kidney.ANP activates two different types of receptors (64); one isGC-A, and, like GC-C, its activation leads to the productionof cGMP (65). The other receptor is the natriuretic peptidereceptor type C, or clearance receptor (NPR-C), which is a pertussistoxin–sensitive G-protein–coupled receptor (15,16).It remains to be clarified whether the G-protein–coupledreceptors for UGN and ANP are the same or similar.
Fine regulation of renal electrolyte and water excretion takesplace in the collecting duct. Principal cells of the CCD areresponsible for K+ secretion (via K+ channels [ROMK]), Na+ reabsorption(via epithelial Na+ channels [ENaC]), and water reabsorption(via aquaporins 2, 3, and 4). In line with the observation thatGC-C–deficient mice still exert natriuresis, kaliuresis,and diuresis upon infusion of guanylin peptides (36) is theabsence of mRNA for GC-C in CCD of mouse and man (54,60). However,guanylin peptides induce changes in membrane voltages of principalcells of mouse and human CCD both in wild-type and in GC-C–deficientmice, suggesting modification of electrogenic ion transportalso in this nephron segment (57,60). Similar to the situationin the human proximal tubule cell line, in principal cells ofisolated mouse and human CCD segments, guanylin peptides activatea signaling pathway distinct from GC-C and independent of cGMP.Guanylin peptides depolarize these cells, whereas the membrane-permeableanalog of cGMP, 8Br-cGMP, hyperpolarizes the same cells, excludingcGMP as a possible second messenger in this signaling pathwayfor guanylin peptides in these cells (60). This pathway of GNand UGN in the CCD involves again a G-protein–coupledreceptor, like in the proximal tubule cell line. Activationof this receptor leads to stimulation of phospholipase A2 (PLA2)and liberation of arachidonic acid. It has been reported beforethat arachidonic acid inhibits the secretory ROMK channels locatedat the luminal membrane of principal cells (66). Inhibitionof the secretory K+ channels by guanylin peptides thereforedecreases K+ secretion and lowers the electrical driving forcefor Na+ reabsorption that results in natriuresis. In mouse principalcells of the CCD, apparently in addition to this cGMP-independentsignaling pathway, another pathway for guanylin peptides exists.This pathway is cGMP dependent but GC-C independent (57). Thereceptor that is activated by guanylin peptides in the mouseCCD and leads to cGMP and PKG activation is still not identified.A possible candidate for this receptor is the orphan receptorguanylate cyclase G (21,57). Activation of this pathway resultsin activation of cGMP-dependent K+ channels in the basolateralmembrane of principal cells and cell hyperpolarization.
Figure 9 shows a model of a principal cell of the CCD indicatingall mechanisms of actions of guanylin peptides identified sofar. It is evident from this scheme that the guanylin peptidesare the first peptides identified that act in this nephron segmentprimarily on K+ channels without directly affecting Na+ channels.In the human CCD, the depolarization of principal cells viainhibition of the secretory K+ channels results in natriuresisas the predominant effect observed in vivo with these peptides(7,36,67). Reduced Na+ reabsorption also decreases water reabsorptionin this nephron segment and thus causes diuresis. GN was shownto decrease the cell volume and increase the luminal space ina concentration- and time-dependent manner, which suggests secretionof water and consequently diuresis (68). However, the kaliuresisalso caused by guanylin peptides cannot be explained from thedata obtained in the CCD and may be due to effects of thesepeptides in other parts of the nephron, e.g., the thick ascendinglimb or the medullary collecting duct. Again, the physiologicrole of the second cGMP-dependent signaling pathway and therelative contributions of these two signaling pathways in theCCD of the mouse remains to be elucidated. This second pathwayinvolves an activation of basolateral K+ channels and therebyshould increase Na+ reabsorption without an increase in K+ secretion.
Figure 9. Signaling pathways of GN and UGN in a principal cell of the CCD. Guanylin peptides activate phospholipase A2 (PLA2), which leads to an increase in the intracellular concentration of arachidonic acid and an inhibition of luminal ROMK K+ channels. ENaC, epithelial sodium channels; AQP 2, 3, 4, aquaporins 2, 3, and 4; NKA, Na+/K+ ATPase. Illustration by Josh Gramling—Gramling Medical Illustration.
Cellular Effects of Guanylin Peptides in Other Organs
Patients with cystic fibrosis undergo changes in water and electrolytesecretion in the liver, the pancreas, the lung, and the intestine.Thus, it might be speculated whether guanylin peptides are alsoinvolved in the regulation of electrolyte and water secretionin those organs via CFTR. Guanylin peptides and parts of theirsignaling pathway are present in the pancreas. John et al. (69)showed that GN and STa increase intracellular cGMP via GC-Cin a human pancreatic cell line. Kulaksiz et al. (70,71) detectedmRNA for GC-C and UGN in cells of the exocrine part of the pancreas,and guanylin peptides increase cGMP, which leads to activationof CFTR in these cells.
Guanylin peptides and parts of the GC-C–dependent signalingpathway are also found in airways (26,27), sweat glands, theadrenal medulla, and the male reproductive system (72–74).According to this limited information on effects of guanylinpeptides in various organs, the GC-C–dependent signalingpathway seems to be the predominant signaling pathway in mostorgans and only in the kidney does the signaling involve differentreceptors and signaling mechanisms.
Exiting observations are the involvement of guanylin peptidesin the development and possible treatment of intestinal tumors.GN and UGN are less expressed or they are not present at allin colon adenocarcinoma, adenoma, and intestine polyps in humanand mouse (75–77). The gene for GN is located at 1 p34–35,which is a tumor-modifying region. One can presume that lossof GN activity leads to or is the result of tumor development.Pitari et al. (78) hypothesized that the reason for the lowerincidence of intestinal tumors in third-world countries is thehigher incidence of intestinal infections that stimulate intestinalGC-C and lead to an increase in cGMP. Guanylin peptides andalso STa in addition regulate proliferation and differentiation,prolonging the cell cycle, and induce apoptosis of T84, CaCo2cells, and mouse intestinal cells (78–81). Shailubahaiet al. (77) showed that oral application of UGN leads to andecrease in number and size of polyps in mice that develop intestinalpolyposis, which allows us to speculate on the possible usageof UGN in the treatment of intestinal tumors.
The involvement of guanylin peptides was suggested also in differentkidney diseases. More than 11 yr ago, Nakazato et al. (82) showedthat human GN increases in patients who have chronic renal failureand undergo hemodialysis. The UGN concentration in plasma and/orin urine is increased in patients with chronic renal failureand glomerulonephritis and in patients on hemodialysis (52,83–85).In patients with nephrotic syndrome, UGN plasma concentrationwas higher and urinary concentration was lower compared withvalues in healthy volunteers (84). Possible explanations forthese observations are kidney damages and reduced capabilityto metabolize and excrete guanylin peptides. Recently, Kikuchiet al. (86) suggested that UGN plays a role as a natriureticfactor in nephrotic syndrome. In experimental nephrotic syndrome,induced by intraperitoneal injection of puromycin aminonucleoside(PAN), changes in UGN concentrations in urine and plasma correspondedto changes in Na+ excretion. In the same animals, the expressionof mRNA for UGN changed in the kidney but not in the intestine,and it was not seen in control animals.
In contrast to other natriuretic peptides, like ANP, the connectionbetween guanylin peptides and hypertension is not well understood.UGN-deficient mice have increased mean arterial pressure, whichis salt insensitive (51). However, GC-C–deficient miceshow no difference in BP compared with wild-type mice (33,34),which rules out a significant involvement of GC-C in the regulationof BP. As shown in this review, guanylin peptides activate atleast one cGMP-, GC-C–independent signaling pathway. Liberationof arachidonic acid in the renal collecting duct by guanylinpeptides inhibits the secretory ROMK channels, which lowersthe electrical driving force for Na+ reabsorption, resultingin natriuresis. In UGN-deficient mice, UGN cannot activate thissignaling pathway, which will lead to higher reabsorption ofNa+ and possibly induce hypertension (51).
GN and UGN regulate electrolyte and water transport in the intestineand cause kaliuresis, natriuresis, and diuresis in the kidney.The membrane-bound GC-C is the receptor for these peptides inthe intestine. In the kidney, these peptides activate differentsignaling pathways along the nephron. Although GC-C is the predominantreceptor mediating the effects of guanylin peptides in the intestine,it plays only a minor role in the kidney, probably restrictedto the proximal tubule. Whereas in the intestine the signalingpathway of guanylin peptides is singular, in the kidney, atleast three different receptors with different second messengersystems are activated and mediate complex effects on electrolyteand water excretion. The molecular identity of these renal receptorsfor guanylin peptides remains to be determined. First indicationsof an involvement of these peptides in various diseases indicatealso a pathophysiologic role and possibly a therapeutic valueof these peptides.
Acknowledgments
The data of the authors laboratory cited and presented in thisreview were funded by a grant of the Medical Faculty of theUniversity of Münster (IMF, KU 21 98 09) and by grantsof the Deutsche Forschungsgemeinschaft (Schl 277/11-1 to 11-3).
Footnotes
Published online ahead of print. Publication date availableat www.jasn.org.
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Abstract
Introduction
) and UGN (
) mRNA along the intestinal tract. Adapted from reference (
