Guanylin and uroguanylin induce natriuresis in mice lacking guanylyl cyclase-C receptor

Stephen L. Carrithers, Cobern E. Ott, Michael J. Hill, Brett R. Johnson, Weiyan Cai, Jason Chang, Rajesh G. Shah, Congmei Sun, Elizabeth A. Mann, Manasses C. Fonteles, Leonard R. Forte, Brian A. Jackson, Ralph A. Giannella, Richard N. Greenberg

Research output: Contribution to journalArticle

75 Citations (Scopus)

Abstract

Background. Guanylin (GN) and uroguanylin (UGN) are intestinally derived peptide hormones that are similar in structure and activity to the diarrhea-causing Escherichia coli heat-stable enterotoxins (STa). These secretagogues have been shown to affect fluid, Na+, K+, and Cl- transport in both the intestine and kidney, presumably by intracellular cyclic guanosine monophosphate (cGMP)-dependent signal transduction. However, the in vivo consequences of GN, UGN, and STa on renal function and their mechanism of action have yet to be rigorously tested. Methods. We hypothesized that intravenous administration of GN, UGN, or STa would cause an increase in natriuresis in wild-type mice via cGMP and guanylyl cyclase-C (GC-C, Gucy2c), the only known receptor for these peptide-hormones, and that the peptide-induced natriuresis would be blunted in genetically altered mice devoid of GC-C receptors (GC-C(-/-) null). Results. In wild-type mice using a modified renal clearance model, GN, UGN, and STa elicited significant natriuresis, kaliuresis, and diuresis as well as increased urinary cGMP levels in a time- and dose-dependent fashion. Absolute and fractional urinary sodium excretion levels were greatest ∼40 minutes following a bolus infusion with pharmacologic doses of these peptides. Unexpectedly, GC-C(-/-) null mice also responded to the GN peptides similarly to that observed in wild-type mice. Glomerular filtration rate (GFR), blood pressure, and plasma cGMP in the mice (wild-type or GC-C(-/-) null) did not significantly vary between the vehicle- and peptide-treatment groups. The effects of UGN may also influence long-term renal function due to down-regulation of the Na+/K+ ATPase γ-subunit and the Cl- channel ClC-K2 by 60% and 75%, respectively, as assessed by differential display polymerase chain reaction (PCR) (DD-PCR) and Northern blot analysis of kidney mRNA from mice treated with UGN. Conclusion. GN, UGN, and STa act on the mouse kidney, in part, through a cGMP-dependent, GC-C-independent mechanism, causing significant natriuresis by renal tubular processes. UGN may have further long-term effects on the kidney by altering the expression of such transport-associated proteins as Na+/K + ATPase and ClC-K2.

Original languageEnglish (US)
Pages (from-to)40-53
Number of pages14
JournalKidney International
Volume65
Issue number1
DOIs
StatePublished - Jan 2004
Externally publishedYes

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Natriuresis
Enterotoxins
Cyclic GMP
Kidney
Peptides
Polymerase Chain Reaction
Peptide Receptors
guanylin
uroguanylin
enterotoxin receptor
Peptide Hormones
Diuresis
Glomerular Filtration Rate
Northern Blotting
Intravenous Administration
Intestines
Diarrhea
Signal Transduction
Carrier Proteins
Down-Regulation

Keywords

  • cGMP
  • DD-PCR
  • Guanylyl cyclase
  • Kidney
  • Renal clearance
  • Sodium

ASJC Scopus subject areas

  • Nephrology

Cite this

Carrithers, S. L., Ott, C. E., Hill, M. J., Johnson, B. R., Cai, W., Chang, J., ... Greenberg, R. N. (2004). Guanylin and uroguanylin induce natriuresis in mice lacking guanylyl cyclase-C receptor. Kidney International, 65(1), 40-53. https://doi.org/10.1111/j.1523-1755.2004.00375.x

Guanylin and uroguanylin induce natriuresis in mice lacking guanylyl cyclase-C receptor. / Carrithers, Stephen L.; Ott, Cobern E.; Hill, Michael J.; Johnson, Brett R.; Cai, Weiyan; Chang, Jason; Shah, Rajesh G.; Sun, Congmei; Mann, Elizabeth A.; Fonteles, Manasses C.; Forte, Leonard R.; Jackson, Brian A.; Giannella, Ralph A.; Greenberg, Richard N.

In: Kidney International, Vol. 65, No. 1, 01.2004, p. 40-53.

Research output: Contribution to journalArticle

Carrithers, SL, Ott, CE, Hill, MJ, Johnson, BR, Cai, W, Chang, J, Shah, RG, Sun, C, Mann, EA, Fonteles, MC, Forte, LR, Jackson, BA, Giannella, RA & Greenberg, RN 2004, 'Guanylin and uroguanylin induce natriuresis in mice lacking guanylyl cyclase-C receptor', Kidney International, vol. 65, no. 1, pp. 40-53. https://doi.org/10.1111/j.1523-1755.2004.00375.x
Carrithers, Stephen L. ; Ott, Cobern E. ; Hill, Michael J. ; Johnson, Brett R. ; Cai, Weiyan ; Chang, Jason ; Shah, Rajesh G. ; Sun, Congmei ; Mann, Elizabeth A. ; Fonteles, Manasses C. ; Forte, Leonard R. ; Jackson, Brian A. ; Giannella, Ralph A. ; Greenberg, Richard N. / Guanylin and uroguanylin induce natriuresis in mice lacking guanylyl cyclase-C receptor. In: Kidney International. 2004 ; Vol. 65, No. 1. pp. 40-53.
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abstract = "Background. Guanylin (GN) and uroguanylin (UGN) are intestinally derived peptide hormones that are similar in structure and activity to the diarrhea-causing Escherichia coli heat-stable enterotoxins (STa). These secretagogues have been shown to affect fluid, Na+, K+, and Cl- transport in both the intestine and kidney, presumably by intracellular cyclic guanosine monophosphate (cGMP)-dependent signal transduction. However, the in vivo consequences of GN, UGN, and STa on renal function and their mechanism of action have yet to be rigorously tested. Methods. We hypothesized that intravenous administration of GN, UGN, or STa would cause an increase in natriuresis in wild-type mice via cGMP and guanylyl cyclase-C (GC-C, Gucy2c), the only known receptor for these peptide-hormones, and that the peptide-induced natriuresis would be blunted in genetically altered mice devoid of GC-C receptors (GC-C(-/-) null). Results. In wild-type mice using a modified renal clearance model, GN, UGN, and STa elicited significant natriuresis, kaliuresis, and diuresis as well as increased urinary cGMP levels in a time- and dose-dependent fashion. Absolute and fractional urinary sodium excretion levels were greatest ∼40 minutes following a bolus infusion with pharmacologic doses of these peptides. Unexpectedly, GC-C(-/-) null mice also responded to the GN peptides similarly to that observed in wild-type mice. Glomerular filtration rate (GFR), blood pressure, and plasma cGMP in the mice (wild-type or GC-C(-/-) null) did not significantly vary between the vehicle- and peptide-treatment groups. The effects of UGN may also influence long-term renal function due to down-regulation of the Na+/K+ ATPase γ-subunit and the Cl- channel ClC-K2 by 60{\%} and 75{\%}, respectively, as assessed by differential display polymerase chain reaction (PCR) (DD-PCR) and Northern blot analysis of kidney mRNA from mice treated with UGN. Conclusion. GN, UGN, and STa act on the mouse kidney, in part, through a cGMP-dependent, GC-C-independent mechanism, causing significant natriuresis by renal tubular processes. UGN may have further long-term effects on the kidney by altering the expression of such transport-associated proteins as Na+/K + ATPase and ClC-K2.",
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T1 - Guanylin and uroguanylin induce natriuresis in mice lacking guanylyl cyclase-C receptor

AU - Carrithers, Stephen L.

AU - Ott, Cobern E.

AU - Hill, Michael J.

AU - Johnson, Brett R.

AU - Cai, Weiyan

AU - Chang, Jason

AU - Shah, Rajesh G.

AU - Sun, Congmei

AU - Mann, Elizabeth A.

AU - Fonteles, Manasses C.

AU - Forte, Leonard R.

AU - Jackson, Brian A.

AU - Giannella, Ralph A.

AU - Greenberg, Richard N.

PY - 2004/1

Y1 - 2004/1

N2 - Background. Guanylin (GN) and uroguanylin (UGN) are intestinally derived peptide hormones that are similar in structure and activity to the diarrhea-causing Escherichia coli heat-stable enterotoxins (STa). These secretagogues have been shown to affect fluid, Na+, K+, and Cl- transport in both the intestine and kidney, presumably by intracellular cyclic guanosine monophosphate (cGMP)-dependent signal transduction. However, the in vivo consequences of GN, UGN, and STa on renal function and their mechanism of action have yet to be rigorously tested. Methods. We hypothesized that intravenous administration of GN, UGN, or STa would cause an increase in natriuresis in wild-type mice via cGMP and guanylyl cyclase-C (GC-C, Gucy2c), the only known receptor for these peptide-hormones, and that the peptide-induced natriuresis would be blunted in genetically altered mice devoid of GC-C receptors (GC-C(-/-) null). Results. In wild-type mice using a modified renal clearance model, GN, UGN, and STa elicited significant natriuresis, kaliuresis, and diuresis as well as increased urinary cGMP levels in a time- and dose-dependent fashion. Absolute and fractional urinary sodium excretion levels were greatest ∼40 minutes following a bolus infusion with pharmacologic doses of these peptides. Unexpectedly, GC-C(-/-) null mice also responded to the GN peptides similarly to that observed in wild-type mice. Glomerular filtration rate (GFR), blood pressure, and plasma cGMP in the mice (wild-type or GC-C(-/-) null) did not significantly vary between the vehicle- and peptide-treatment groups. The effects of UGN may also influence long-term renal function due to down-regulation of the Na+/K+ ATPase γ-subunit and the Cl- channel ClC-K2 by 60% and 75%, respectively, as assessed by differential display polymerase chain reaction (PCR) (DD-PCR) and Northern blot analysis of kidney mRNA from mice treated with UGN. Conclusion. GN, UGN, and STa act on the mouse kidney, in part, through a cGMP-dependent, GC-C-independent mechanism, causing significant natriuresis by renal tubular processes. UGN may have further long-term effects on the kidney by altering the expression of such transport-associated proteins as Na+/K + ATPase and ClC-K2.

AB - Background. Guanylin (GN) and uroguanylin (UGN) are intestinally derived peptide hormones that are similar in structure and activity to the diarrhea-causing Escherichia coli heat-stable enterotoxins (STa). These secretagogues have been shown to affect fluid, Na+, K+, and Cl- transport in both the intestine and kidney, presumably by intracellular cyclic guanosine monophosphate (cGMP)-dependent signal transduction. However, the in vivo consequences of GN, UGN, and STa on renal function and their mechanism of action have yet to be rigorously tested. Methods. We hypothesized that intravenous administration of GN, UGN, or STa would cause an increase in natriuresis in wild-type mice via cGMP and guanylyl cyclase-C (GC-C, Gucy2c), the only known receptor for these peptide-hormones, and that the peptide-induced natriuresis would be blunted in genetically altered mice devoid of GC-C receptors (GC-C(-/-) null). Results. In wild-type mice using a modified renal clearance model, GN, UGN, and STa elicited significant natriuresis, kaliuresis, and diuresis as well as increased urinary cGMP levels in a time- and dose-dependent fashion. Absolute and fractional urinary sodium excretion levels were greatest ∼40 minutes following a bolus infusion with pharmacologic doses of these peptides. Unexpectedly, GC-C(-/-) null mice also responded to the GN peptides similarly to that observed in wild-type mice. Glomerular filtration rate (GFR), blood pressure, and plasma cGMP in the mice (wild-type or GC-C(-/-) null) did not significantly vary between the vehicle- and peptide-treatment groups. The effects of UGN may also influence long-term renal function due to down-regulation of the Na+/K+ ATPase γ-subunit and the Cl- channel ClC-K2 by 60% and 75%, respectively, as assessed by differential display polymerase chain reaction (PCR) (DD-PCR) and Northern blot analysis of kidney mRNA from mice treated with UGN. Conclusion. GN, UGN, and STa act on the mouse kidney, in part, through a cGMP-dependent, GC-C-independent mechanism, causing significant natriuresis by renal tubular processes. UGN may have further long-term effects on the kidney by altering the expression of such transport-associated proteins as Na+/K + ATPase and ClC-K2.

KW - cGMP

KW - DD-PCR

KW - Guanylyl cyclase

KW - Kidney

KW - Renal clearance

KW - Sodium

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