Nephrology Dialysis Transplantation

NDT Advance Access originally published online on August 18, 2006
Nephrology Dialysis Transplantation 2006 21(11):3007-3012; doi:10.1093/ndt/gfl314

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Mechanisms of action of uroguanylin and guanylin and their role in salt handling

Aleksandra Sini and Eberhard Schlatter

Universitätsklinikum Münster, Medizinische Klinik und Poliklinik D, Experimentelle Nephrologie, Domagkstrasse 3a, 48149 Münster, Germany

Correspondence and offprint requests to: Eberhard Schlatter. Email: eberhard.schlatter{at}uni-muenster.de

Keywords: arachidonic acid; cGMP; G-protein; guanylate cyclase C; kidney; natriuretic peptides

	Introduction

Top Introduction Endocrine function of guanylin... Signalling mechanisms of... Signalling mechanisms of... Involvement of guanylin peptides... Conclusion Acknowledgement References

 
Guanylin (GN) peptides belong to the growing family of natriuretic peptides. While atrial natriuretic peptide (ANP) is predominantly produced in the heart and causes natriuresis in the kidney [1], it was suggested that GN peptides are intestinal peptides that have effects on the kidney. GN peptides are small peptides with 15–19 amino acids. To this family belongs GN, originally isolated from rat intestine [2]. A second member of this family was isolated from opossum urine and is called uroguanylin (UGN) [3]. Two new members, renoguanylin [4] and lymphoguanylin [5], were recently discovered; however, their physiological role is still unknown.

The mechanism of the action of GN and UGN in the intestine is well-known. It is assumed that they act similarly in several other organs that express these peptides, like airways, pancreas, testis, salivary gland and sweat glands. In the kidney, however, the signalling mechanisms and their actions are diverse. Enterochromaffin cells along the intestine secrete GN and UGN into the intestinal lumen [6,7]. Both hormones activate the membrane-bound guanylate cyclase C (GC-C) and increase the intracellular concentration of cGMP [2,3], which inhibits Na⁺ absorption mediated via apical Na⁺/H⁺ exchange (NHE) and activates the protein kinase G II. In addition, cGMP increases cAMP in the cell via inhibition of phosphodiesterase III, which activates protein kinase A. Protein kinase G II and protein kinase A increase the secretion of Cl^–, and water via activation of the cystic fibrosis transmembrane conductance regulator (CFTR) (for a review see [8]).

The digestive system communicates with other organs in response to food via the secretion of hormones into the circulation, e.g. via gastric inhibitory polypeptide and glucagon-like peptide-1, which leads to increased insulin levels even before the glucose reaches the blood, preventing hyperglycaemia after a meal. The same mechanism seems to work in the case of salt intake. Salt taken orally leads to a more pronounced natriuresis than salt injected intravenously [9]. With the first description of GN peptides it was hypothesized that they act as intestinal natriuretic peptides. It is still not completely resolved whether GN peptides work in such an endocrine manner and/or whether their action is paracrine in those organs that express and secrete these peptides, such as the kidney.

	Endocrine function of guanylin peptides

Top Introduction Endocrine function of guanylin... Signalling mechanisms of... Signalling mechanisms of... Involvement of guanylin peptides... Conclusion Acknowledgement References

 
First UGN rather than GN was discovered to be an intestinal natriuretic peptide. GN mainly caused kaliuresis and diuresis with a less pronounced natriuretic effect [10]. Natriuresis which followed oral salt load, was decreased in UGN deficient mice [11]. It is also known that UGN, when applied intravenously in vivo or in the isolated perfused rat kidney, produced natriuresis, kaliuresis and diuresis [10,12–14]. There exist, however, additional findings which are not consistent with this hypothesis. Wang et al. [15] showed that intravenous and intraluminal administration of UGN in the kidney affects tubuloglomerular feedback, but they failed to reproduce a natriuresis and diuresis in rats. They used up to 100 nmol/kg/h UGN intravenously, which was far less than that used in previous studies [13,14]. This dose resulted in higher UGN concentrations than those physiologically measured in rat blood and urine, which was in the femtomolar range [16,17]. Furthermore, rats fed a high-salt diet had higher UGN and cGMP concentrations in the urine; however, the plasma concentration of UGN was not increased, which argues against an endocrine action of UGN [16]. UGN is expressed in the kidney and its expression is elevated in animals on a high-salt diet (Figure 1) [16,18], which could explain the increased urinary concentration of UGN and cGMP [16,19]. To definitely answer the question whether UGN is an intestinal natriuretic peptide, further studies, e.g. using conditional knockout mice lacking UGN expression only in the intestine or the kidney, are needed.

View larger version (10K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1. Expression of guanylin peptides in the kidney. Relative mRNA expression of (A) guanylin (open bar) and uroguanylin (dark bars) in various mouse nephron segments. Changes in UGN mRNA expression (B) in kidneys obtained from mice drinking water containing 1% NaCl (high-salt group) compared with mice drinking only water (normal-salt group). GL, glomerulus; PT, proximal tubule; TAL, thick ascending limb of Henle's loop; CD, collecting duct; GAPDH, glycerol-aldehyde-3-phosphate dehydrogenase. (Modified from [15].)

 

	Signalling mechanisms of guanylin peptides in renal proximal tubules

Top Introduction Endocrine function of guanylin... Signalling mechanisms of... Signalling mechanisms of... Involvement of guanylin peptides... Conclusion Acknowledgement References

 
Until recently, the only known signalling pathway for GN peptides involved GC-C as a receptor. Its activation leads to an increase in cellular cGMP as described for the intestine (see the preceding text). However, renal effects of GN peptides on the whole-organ level were still present in mice lacking GC-C, suggesting the existence of at least one GC-C-independent pathway in the kidney [12]. On the other hand, there exists clear evidence that cGMP and GC-C are part of the signalling pathway in proximal tubule cells of opossum kidneys [20–22], which is obviously not involved in the effects described in GC-C knockout mice. Recently, we demonstrated an increase in the cellular cGMP concentration induced by GN peptides also in a human proximal tubule cell line (IHKE1) [23] probably mediated via GC-C expressed in these cells. The physiological contribution of this GC-C-dependent signalling pathway for GN peptides in proximal tubules remains to be established.

In the kidney, mRNA for UGN is found predominantly in the proximal tubule [18,23], suggesting that UGN might act in a para- or autocrine way in this nephron segment. In addition to the GC-C/cGMP pathway mentioned previously, UGN activates K⁺-channels via a pertussis toxin-sensitive G-protein in human proximal tubule cells [23] (Figure 2). This mechanism could be responsible for at least a part of the kaliuresis produced by GN peptides. A similar G-protein-dependent signalling mechanism is also known for atrial natriuretic peptide mediated via NPR-C as receptor [24,25].

View larger version (25K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 2. Signalling pathway of guanylin peptides in proximal tubules. GN and UGN activate guanylate cyclase C (GC-C), which leads to an increase in the intracellular concentration of cGMP. It inhibits K+-channels and probably the Na+/H+ exchanger (NHE3) and the Na+/K+-ATPase. In addition, UGN activates a signalling pathway, which includes a PT-sensitive G-protein leading to the activation of K+ channels.

 

	Signalling mechanisms of guanylin peptides in collecting ducts

Top Introduction Endocrine function of guanylin... Signalling mechanisms of... Signalling mechanisms of... Involvement of guanylin peptides... Conclusion Acknowledgement References

 
As fine regulation of renal salt and water excretion occurs in the distal nephron and collecting duct, it is likely that this part of the nephron is also involved in the natriuresis, kaliuresis and diuresis caused by GN peptides. Indeed, we recently demonstrated that both UGN and GN regulate ion transport in isolated human and mouse cortical collecting ducts [26,27]. In addition, mRNA for GN but not UGN is expressed in the cortical collecting duct. The source of UGN reaching the lumen of the collecting duct, therefore, must originate from the blood after glomerular filtration and/or from secretion by proximal tubule cells [18]. Since UGN, in contrast to GN, is resistant to degradation by luminal proteases, UGN will be concentrated along the nephron due to volume reabsorption and reach the distal tubular lumen [28].

In line with the persistance of renal effects of these peptides in GC-C-deficient mice [12], the signalling pathways for GN peptides in human principal cells of cortical collecting ducts are GC-C-independent. The involvement of another GC in human collecting ducts appears unlikely, because the effects of GN peptides in this part of the nephron are cGMP-independent [26]. Recent data from the authors’ lab show, for the first time, membrane potentials of human principal cells of cortical collecting ducts isolated from the kidneys of patients undergoing tumour nephrectomies (Figure 2). Principal cells were identified by amiloride-dependent hyperpolarization (Figure 3A), caused by inhibition of epithelial sodium channels (ENaC). GN (Figure 3B) and UGN (Figure 3C) depolarized principal cells, but the membrane-permeable analogue of cGMP, 8Br-cGMP, hyperpolarized the same cells [26]. These effects of GN peptides in principal cells of the cortical collecting duct could be responsible for the natriuresis caused by these hormones via activation of a G-protein coupled receptor. Activation of such a receptor leads to an increase in phospholipase A₂ (PLA₂) and inhibition of ROMK channels via arachidonic acid [26,27,29]. Inhibition of ROMK depolarizes principal cells, decreases the driving force for Na⁺ reabsorption and leads to natriuresis (Figure 4). In GC-C-deficient mice, GN peptides still change the membrane potential of principal cells, which further supports this arachidonic acid-dependent and GC-C-independent signalling pathway for GN peptides as shown in human principal cells [27].

View larger version (83K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 3. Effects of guanylin peptides on membrane voltages (Vm) of principal cells of isolated human cortical collecting ducts. Principal cells were detected by (A) hyperpolarization caused by amiloride (Am). Principal cells revealed a hyperpolarized membrane, dominated by a K+-conductance (ROMK) as shown by depolarization in the presence of high extracellular K+. The depolarizations caused by (B) guanylin (GN) and by (C) uroguanylin (UGN) are opposite to the hyperpolarization caused by 8-Br-cGMP. (Modified from [23].)

 

View larger version (20K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 4. Signalling pathway of guanylin peptides in the cortical collecting duct. GN and UGN activate phospholipase A2 (PLA2), which increases the intracellular concentration of arachidonic acid, inhibits ROMK channels and depolarizes principal cells of cortical collecting ducts.

 
GN peptides might also increase diuresis by translocation retrieval of aquaporin 2 from the luminal membrane of principal cells along the collecting duct, especially in the inner medullary collecting duct (IMCD) [30]. It has been reported that GN decreases the cell volume and increases the luminal space in a concentration- and time-dependent manner, which suggest reduced reabsorption or secretion of water and consequently diuresis [30]. Certainly the signalling mechanism of GN peptides in the IMCD needs further investigation.

	Involvement of guanylin peptides in renal pathology

Top Introduction Endocrine function of guanylin... Signalling mechanisms of... Signalling mechanisms of... Involvement of guanylin peptides... Conclusion Acknowledgement References

 
GN peptides are involved in various pathological conditions mostly in the digestive tract. Shailubahai et al. [31] showed that oral application of UGN leads to a decrease in number and size of polyps in mice with intestinal polyposis [31], which allows us to speculate on the possible oral application of UGN as a treatment for intestinal tumours. Involvement of GN peptides in renal pathophysiology has been known for almost 12 years. The UGN concentration in plasma and urine is increased in patients with chronic renal failure, glomerulonephritis and in patients on haemodialysis [19,32–35]; however, detailed studies, especially on the mechanisms involved, are still to be done. As possible explanations for these observations, kidney damage and/or reduced capability to metabolizeand excrete GN peptides have been discussed.

More is known about the involvement of UGN in nephrotic syndrome. In such patients, the UGN plasma concentration was higher and the urinary concentration was lower than that of healthy volunteers [34]. In an animal model of nephrotic syndrome, reduced expression levels of mRNA for UGN in the kidney, but not the intestine, have been reported [36], which could also explain the respective findings in humans. UGN could also play a role as natriuretic factor in those animals because changes in UGN concentrations in urine and plasma corresponded to changes in Na⁺ excretion [36]. To better understand the involvement of GN peptides in human pathology, further studies are definitely needed.

	Conclusion

Top Introduction Endocrine function of guanylin... Signalling mechanisms of... Signalling mechanisms of... Involvement of guanylin peptides... Conclusion Acknowledgement References

 
Compared with other organs expressing GN peptides, the signalling pathway of these peptides in the kidney seems to be far more complicated and far from being completely understood. The main signalling pathway in the intestine is cGMP- and GC-C-dependent. In the kidney, this pathway does not seem to be very important. In proximal tubules GN peptides act via activation of a guanylate cyclase receptor (GC-C) and an additional G-protein coupled receptor, similar to the dual effects known for other natriuretic peptides, such as ANP. On the other hand, in human principal cells of cortical collecting ducts only a cGMP-independent signalling pathway exists. Activation of PLA₂ leads to the production of arachidonic acid and inhibition of luminal K⁺-channels (ROMK). These effects of GN peptides in the collecting duct of the human kidney are compatible with the reported natriuresis and diuresis in vivo. The mechanisms leading to kaliuresis induced by GN peptides are still not completely understood.

Although numerous studies on the effects of GN peptides have been published, even 14 years after the discovery of GN in the intestine we still have no definite answer to the question whether GN peptides are intestinal natriuretic peptides.

	Acknowledgement

Top Introduction Endocrine function of guanylin... Signalling mechanisms of... Signalling mechanisms of... Involvement of guanylin peptides... Conclusion Acknowledgement References

 
Work cited from the authors’ laboratory has been supported by grants from the Deutsche Forschungsgemeinschaft (Schl 277/11-1 to 11-3).

Conflict of interest statement. None declared.

	References

Top Introduction Endocrine function of guanylin... Signalling mechanisms of... Signalling mechanisms of... Involvement of guanylin peptides... Conclusion Acknowledgement References

 

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Received for publication: 7. 2.06
Accepted in revised form: 3. 5.06

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