The rat kidney contains high levels of prouroguanylin (the uroguanylin precursor) but does not express GC-C (the enteric uroguanylin receptor)

Qian, Xun; Moss, Nicholas; Fellner, Robert C.; Taylor-Blake, Bonnie; Goy, Michael F.

doi:10.1152/ajprenal.00282.2010

Cited by 11 publications

(23 citation statements)

References 92 publications

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“…Further, eliminating uroguanylin, but not GUCY2C, expression produces hypertension in mice (40). Moreover, while the evidence base has been ambiguous, recent studies have confirmed the absence of GUCY2C expression in kidney in placental mammals (41). Taken together, these observations demonstrate that renal effects of these peptides are mediated by paracrine signaling that is independent of GUCY2C and cGMP.…”

Section: Discussionmentioning

confidence: 92%

A uroguanylin-GUCY2C endocrine axis regulates feeding in mice

Valentino

Lin²,

Snook³

et al. 2011

J. Clin. Invest.

138

275

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Intestinal enteroendocrine cells are critical to central regulation of caloric consumption, since they activate hypothalamic circuits that decrease appetite and thereby restrict meal size by secreting hormones in response to nutrients in the gut. Although guanylyl cyclase and downstream cGMP are essential regulators of centrally regulated feeding behavior in invertebrates, the role of this primordial signaling mechanism in mammalian appetite regulation has eluded definition. In intestinal epithelial cells, guanylyl cyclase 2C (GUCY2C) is a transmembrane receptor that makes cGMP in response to the paracrine hormones guanylin and uroguanylin, which regulate epithelial cell dynamics along the crypt-villus axis. Here, we show that silencing of GUCY2C in mice disrupts satiation, resulting in hyperphagia and subsequent obesity and metabolic syndrome. This defined an appetite-regulating uroguanylin-GUCY2C endocrine axis, which we confirmed by showing that nutrient intake induces intestinal prouroguanylin secretion into the circulation. The prohormone signal is selectively decoded in the hypothalamus by proteolytic liberation of uroguanylin, inducing GUCY2C signaling and consequent activation of downstream anorexigenic pathways. Thus, evolutionary diversification of primitive guanylyl cyclase signaling pathways allows GUCY2C to coordinate endocrine regulation of central food acquisition pathways with paracrine control of intestinal homeostasis. Moreover, the uroguanylin-GUCY2C endocrine axis may provide a therapeutic target to control appetite, obesity, and metabolic syndrome.

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Section: Discussionmentioning

confidence: 92%

A uroguanylin-GUCY2C endocrine axis regulates feeding in mice

Valentino

Lin²,

Snook³

et al. 2011

J. Clin. Invest.

138

275

View full text Add to dashboard Cite

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“…The activation of this receptor promotes an increase of cGMP intracellular content, which activates PKG. Although several studies demonstrated that the guanylin classic receptor GC-C is expressed in rat renal cortex (10,18), a recent study suggested otherwise (45). As seen in Fig.…”

Section: Resultsmentioning

confidence: 92%

Mechanisms underlying the inhibitory effects of uroguanylin on NHE3 transport activity in renal proximal tubule

Lessa

Carraro‐Lacroix

Crajoinas

et al. 2012

American Journal of Physiology-Renal Physiology

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-We previously demonstrated that uroguanylin (UGN) significantly inhibits Na ϩ /H ϩ exchanger (NHE)3-mediated bicarbonate reabsorption. In the present study, we aimed to elucidate the molecular mechanisms underlying the action of UGN on NHE3 in rat renal proximal tubules and in a proximal tubule cell line (LLC-PK1). The in vivo studies were performed by the stationary microperfusion technique, in which we measured H ϩ secretion in rat renal proximal segments, through a H ϩ -sensitive microelectrode. UGN (1 M) significantly inhibited the net of proximal bicarbonate reabsorption. The inhibitory effect of UGN was completely abolished by either the protein kinase G (PKG) inhibitor KT5823 or by the protein kinase A (PKA) inhibitor H-89. The effects of UGN in vitro were found to be similar to those obtained by microperfusion. Indeed, we observed that incubation of LLC-PK1 cells with UGN induced an increase in the intracellular levels of cAMP and cGMP, as well as activation of both PKA and PKG. Furthermore, we found that UGN can increase the levels of NHE3 phosphorylation at the PKA consensus sites 552 and 605 in LLC-PK1 cells. Finally, treatment of LLC-PK1 cells with UGN reduced the amount of NHE3 at the cell surface. Overall, our data suggest that the inhibitory effect of UGN on NHE3 transport activity in proximal tubule is mediated by activation of both cGMP/PKG and cAMP/PKA signaling pathways which in turn leads to NHE3 phosphorylation and reduced NHE3 surface expression. Moreover, this study sheds light on mechanisms by which guanylin peptides are intricately involved in the maintenance of salt and water homeostasis. NHE3; uroguanylin; renal microperfusion; bicarbonate reabsorption; cGMP; cAMP IN THE PAST DECADES, IT HAS been postulated that Sta-like guanylin peptides participate in a control system regulating salt balance in response to oral salt intake, linking intestine and kidney in the process of salt and water homeostasis (8,19,22). These peptides are known as endogenous agonists for the Escherichia coli heatstable toxin receptor, guanylate cyclase C (GC-C), uroguanylin (UGN) being its most potent member (12,18,20,27). UGN is a 16 amino acid peptide (27), expressed throughout the intestinal tract, secreted by enterochromaffin cells as prouroguanylin that undergoes postsecretory proteolytic cleavage, generating the active form (15,28,41). Recently, Qian and colleagues (44) demonstrated that the conversion of prouroguanylin to UGN occurs within the lumen of renal tubules.Renal effects of UGN include natriuresis, kaliuresis, diuresis, and increased excretion of cGMP (17,26). In a previous work using stationary in vivo microperfusion, our group demonstrated that UGN perfusion stimulates potassium secretion through Maxi-K channels in connecting and cortical collecting ducts (2). Furthermore, this study demonstrated that UGN perfusion also leads to an inhibition of bicarbonate reabsorption in proximal tubules by reducing the activity of the Na ϩ /H ϩ exchanger, NHE3 isoform (2). In renal proximal tubule cells, NHE...

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“…Accumulating data have provided evidence that guanylin peptides are produced in the kidney (likely in response to hypernatremia) and have paracrine/autocrine functions in the cells along the nephron [5, 48, 49]. GN and UGN mRNAs are expressed in rodent and human kidney epithelial cells [3, 12, 15, 32, 50–52].…”

Section: The Guanylin Peptidesmentioning

confidence: 99%

“…Moreover, high extracellular [NaCl] influences UGN expression in cultured kidney cells [52, 53, 55, 56]. Qian et al [49] in a recent, thorough experimental study in rats, demonstrated high proUGN abundance locally synthesized in renal distal tubule segments. The authors provided evidence for an intrarenal UGN system that differs from the intestinal system in its regulatory mechanisms and in the receptor targeted by the peptide, which is not the enteric UGN receptor, GC-C.…”

Section: The Guanylin Peptidesmentioning

confidence: 99%

“…The CCD principal cell has been considered a target for GN/UGN action [3, 27, 58, 61]. The persistent natriuresis of GC-C knockout mice treated with UGN [25], and the lack of GC-C mRNA in the CCD [49, 52, 58] suggest GC-C and cGMP-independent signaling by UGN in this nephron segment. This signaling involves G-protein-dependent phospholipase A 2 (PLA 2 ) activation, generating arachidonic acid to inhibit luminal K + channels (ROMK) [61].…”

Section: The Guanylin Peptidesmentioning

confidence: 99%

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Pendrin, a Novel Transcriptional Target of the Uroguanylin System

Rozenfeld

Tal

Kladnitsky

et al. 2013

Cell Physiol Biochem

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Guanylin (GN) and uroguanylin (UGN) are low-molecular-weight peptide hormones produced mainly in the intestinal mucosa in response to oral salt load. GN and UGN (guanylin peptides) induce secretion of electrolytes and water in both intestine and kidney. Thought to act as “intestinal natriuretic factors”, GN and UGN modulate renal salt secretion by both endocrine mechanisms (linking the digestive system and kidney) and paracrine/autocrine (intrarenal) mechanisms. The cellular function of GN and UGN in intestine and proximal tubule is mediated by guanylyl cyclase C (GC-C)-, cGMP-, and G protein-dependent pathways, whereas, in principal cells of the cortical collecting duct (CCD), these peptide hormones act via GC-C-independent signaling through phospholipase A₂ (PLA₂). The Cl^-/HCO^-₃ exchanger pendrin (SLC26A4), encoded by the PDS gene, is expressed in non-α intercalated cells of the CCD. Pendrin is essential for CCD bicarbonate secretion and is also involved in NaCl balance and blood pressure regulation. Our recent studies have provided evidence that pendrin-mediated anion exchange in the CCD is regulated at the transcriptional level by UGN. UGN exerts an inhibitory effect on the pendrin gene promoter likely via heat shock factor 1 (HSF1) action at a defined heat shock element (HSE) site. Recent studies have unraveled novel roles for guanylin peptides in several organ systems including involvement in appetite regulation, olfactory function, cell proliferation and differentiation, inflammation, and reproductive function. Both the guanylin system and pendrin have also been implicated in airway function. Future molecular research into the receptors and signal transduction pathways involved in the action of guanylin peptides and the pendrin anion exchanger in the kidney and other organs, and into the links between them, may facilitate discovery of new therapies for hypertension, heart failure, hepatic failure and other fluid retention syndromes, as well as for diverse diseases such as obesity, asthma, and cancer.

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The rat kidney contains high levels of prouroguanylin (the uroguanylin precursor) but does not express GC-C (the enteric uroguanylin receptor)

Cited by 11 publications

References 92 publications

A uroguanylin-GUCY2C endocrine axis regulates feeding in mice

A uroguanylin-GUCY2C endocrine axis regulates feeding in mice

Mechanisms underlying the inhibitory effects of uroguanylin on NHE3 transport activity in renal proximal tubule

Pendrin, a Novel Transcriptional Target of the Uroguanylin System

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