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


CONCLUSIONS
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.
Carrithers
Stephen L
SL
Department of Internal Medicine, Division of Infectious Diseases, Lexington VA Medical Center and University of Kentucky, Lexington, Kentucky 40506, USA. SLCARU0@uky.edu
Ott
Cobern E
CE
Hill
Michael J
MJ
Johnson
Brett R
BR
Cai
Weiyan
W
Chang
Jason J
JJ
Shah
Rajesh G
RG
Sun
Congmei
C
Mann
Elizabeth A
EA
Fonteles
Manasses C
MC
Forte
Leonard R
LR
Jackson
Brian A
BA
Giannella
Ralph A
RA
Greenberg
Richard N
RN
D000818:Animals; D000833:Animals, Suckling; D001427:Bacterial Toxins / Q000378:metabolism / Q000494:pharmacology; D015152:Blotting, Northern; D004768:Enterotoxins / Q000378:metabolism / Q000494:pharmacology; D029968:Escherichia coli Proteins; D005768:Gastrointestinal Hormones / Q000378:metabolism / Q000494:pharmacology*; D006162:Guanylate Cyclase / Q000235:genetics* / Q000378:metabolism; D007275:Injections, Intravenous; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D009318:Natriuresis / Q000187:drug effects* / Q000502:physiology*; D045265:Natriuretic Peptides; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled; D018000:Receptors, Peptide / Q000235:genetics* / Q000378:metabolism
D001427:Bacterial Toxins; D004768:Enterotoxins; D029968:Escherichia coli Proteins; D005768:Gastrointestinal Hormones; D045265:Natriuretic Peptides; D010455:Peptides; D012333:RNA, Messenger; D018000:Receptors, Peptide; C034151:heat stable toxin (E coli); C072685:guanylin; C084362:uroguanylin; D006162:Guanylate Cyclase; C000613655:Gucy2c protein, mouse; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled