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

Kidney Int. 2004 Jan;65(1):40-53. doi: 10.1111/j.1523-1755.2004.00375.x.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

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


  • 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