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

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 approximately 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 gamma-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.

• Authors: Stephen L Carrithers, Cobern E Ott, Michael J Hill, Brett R Johnson, Weiyan Cai, Jason J Chang, Rajesh G Shah, Congmei Sun, Elizabeth A Mann, Manasses C Fonteles, Leonard R Forte, Brian A Jackson, Ralph A Giannella, Richard N Greenberg
• Journal: Kidney international (Kidney Int) Vol. 65 Issue 1 Pg. 40-53 (Jan 2004) ISSN: 0085-2538 [Print] United States
• PMID: 14675035 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Bacterial Toxins
• Enterotoxins
• Escherichia coli Proteins
• Gastrointestinal Hormones
• Natriuretic Peptides
• Peptides
• RNA, Messenger
• Receptors, Peptide
• heat stable toxin (E coli)
• guanylin
• uroguanylin
• Guanylate Cyclase
• Gucy2c protein, mouse
• Receptors, Enterotoxin
• Receptors, Guanylate Cyclase-Coupled

Topics

• Animals
• Animals, Suckling
• Bacterial Toxins (metabolism, pharmacology)
• Blotting, Northern
• Enterotoxins (metabolism, pharmacology)
• Escherichia coli Proteins
• Gastrointestinal Hormones (metabolism, pharmacology)
• Guanylate Cyclase (genetics, metabolism)
• Injections, Intravenous
• Mice
• Mice, Inbred Strains
• Mice, Mutant Strains
• Natriuresis (drug effects, physiology)
• Natriuretic Peptides
• Peptides (metabolism, pharmacology)
• RNA, Messenger (analysis)
• Receptors, Enterotoxin
• Receptors, Guanylate Cyclase-Coupled
• Receptors, Peptide (genetics, metabolism)