Circulating Prouroguanylin Is Processed to Its Active Natriuretic Form Exclusively within the Renal Tubules

Qian, Xun; Moss, Nicholas; Fellner, Robert C.; Goy, Michael F.

doi:10.1210/en.2007-1724

Cited by 32 publications

(49 citation statements)

References 69 publications

(97 reference statements)

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“…CCK and PYY were obtained from Phoenix Pharmaceuticals Inc. Prouroguanylin and proguanylin were obtained from BioVendor R&D. Exendin-4 was obtained from California Peptide Research Inc. The prouroguanylin antiserum (antibody 6910) was provided by Michael Goy (University of North Carolina, Chapel Hill, North Carolina, USA) (51).…”

Section: Methodsmentioning

confidence: 99%

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: Methodsmentioning

confidence: 99%

A uroguanylin-GUCY2C endocrine axis regulates feeding in mice

Valentino

Lin²,

Snook³

et al. 2011

J. Clin. Invest.

138

275

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“…Furthermore, Ugn knockout mice are hypertensive compared with wild-type controls and show an impaired natriuretic response to increased oral salt intake, whereas Gn knockout mice have normal blood pressures and sodium balance (10,31). Thus, Ugn has been credited with a regulatory role in sodium balance that is triggered by alterations in dietary salt intake per se, thereby differing from other sodium regulatory systems that respond to the subsequent changes in extracellular volume and arterial pressure (16,41).…”

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confidence: 99%

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confidence: 99%

“…Metabolic tracer studies reveal that proUgn is not converted to Ugn within the circulation, even after 60 min of infusion; instead, several metabolites of proUgn, including Ugn, are produced within the kidney and are excreted in urine (41). One or more of these metabolites, but principally the 15 amino acid form of Ugn (Ugn-15), has been presumed to be the active agent that is responsible for the natriuresis produced by this enterorenal endocrine axis (17,36,41). This is consistent with the activity of this system in the intestine and, accordingly, most previous studies used either opossum or human Ugn to investigate the role of this endocrine system in renal excretory function (1,5,13,14,19,36,37,45).…”

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confidence: 99%

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Natriuretic and antikaliuretic effects of uroguanylin and prouroguanylin in the rat

Moss

Riguera

Fellner

et al. 2010

American Journal of Physiology-Renal Physiology

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Moss NG, Riguera DA, Fellner RC, Cazzolla C, Goy MF. Natriuretic and antikaliuretic effects of uroguanylin and prouroguanylin in the rat. Am J Physiol Renal Physiol 299: F1433-F1442, 2010. First published September 22, 2010 doi:10.1152/ajprenal.00281.2010.-The peptide uroguanylin (Ugn) is stored and released as a propeptide (proUgn) by enterochromaffin cells in the intestine, and converted to Ugn and other metabolites in the renal tubules. Both proUgn and Ugn are natriuretic, although the response to proUgn is thought to depend on its conversion to Ugn within nephrons. To assess the efficiency of intrarenal conversion of proUgn to Ugn, we measured urinary Ugn excretion in rats following intravenous infusions of proUgn or Ugn. Infusion of 2 and 10 nmol proUgn/kg body wt increased plasma proUgn concentration from 2.2 Ϯ 0.3 to 5.6 Ϯ 1.3 pmol/ml and to 37 Ϯ 9.6 pmol/ml, respectively. No proUgn was detected in urine before, during, or after proUgn infusions. These two proUgn infusion doses resulted in total Ugn recovery in urine of 162 Ϯ 64 and 206 Ϯ 39 pmol/kg body wt (9 and 2% of the infused amount, respectively). By contrast, the same molar amounts of Ugn resulted in 1,009 Ϯ 477 and 5,352 Ϯ 2,133 pmol/kg body wt of Ugn in urine (recoveries of ϳ50%). Unexpectedly, comparisons of natriuretic dose-response curves for each peptide showed proUgn to be about five times more potent than Ugn, despite the relatively modest amount of Ugn generated from infused proUgn. In addition, both peptides were antikaliuretic at low doses, but in this case Ugn showed greater potency than proUgn. These data do not support Ugn as the primary active principle of proUgn for regulation of renal sodium excretion.

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“…Recently, Qian and colleagues (44) demonstrated that the conversion of prouroguanylin to UGN occurs within the lumen of renal tubules.…”

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confidence: 99%

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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Circulating Prouroguanylin Is Processed to Its Active Natriuretic Form Exclusively within the Renal Tubules

Cited by 32 publications

References 69 publications

A uroguanylin-GUCY2C endocrine axis regulates feeding in mice

A uroguanylin-GUCY2C endocrine axis regulates feeding in mice

Natriuretic and antikaliuretic effects of uroguanylin and prouroguanylin in the rat

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

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