Increases in guanylin and uroguanylin in a mouse model of osmotic diarrhea are guanylate cyclase C-independent.
OBJECTIVE
Guanylin and uroguanylin are peptide hormones that are homologous to the diarrhea-causing Escherichia coli enterotoxins. These secretagogues are released from the intestinal epithelia into the intestinal lumen and systemic circulation and bind to the receptor guanylate cyclase C (GC-C). We hypothesized that a hypertonic diet would result in osmotic diarrhea and cause a compensatory down-regulation of guanylin/uroguanylin.


METHODS
Gut-to-carcass weights were used to measure fluid accumulation in the intestine. Northern and/or Western analysis was used to determine the levels of guanylin, uroguanylin, and GC-C in mice with osmotic diarrhea.


RESULTS
Wild-type mice fed a polyethylene glycol or lactose-based diet developed weight loss, diarrhea, and an increased gut-to-carcass ratio. Unexpectedly, 2 days on either diet resulted in increased guanylin/uroguanylin RNA and prohormone throughout the intestine, elevated uroguanylin RNA, and prohormone levels in the kidney and increased levels of circulating prouroguanylin. GC-C-deficient mice given the lactose diet reacted with higher gut-to-carcass ratios. Although they did not develop diarrhea, GC-C-sufficient and -deficient mice on the lactose diet responded with elevated levels of guanylin and uroguanylin RNA and protein. A polyethylene glycol drinking water solution resulted in diarrhea, higher gut-to-carcass ratios, and induction of guanylin and uroguanylin in both GC-C heterozygous and null animals.


CONCLUSIONS
We conclude that this model of osmotic diarrhea results in a GC-C-independent increase in intestinal fluid accumulation, in levels of these peptide ligands in the epithelia of the intestine, and in prouroguanylin in the kidney and blood.
Steinbrecher
K A
KA
Division of Pediatric Gastroenterology, Hepatology and Nutrition and Graduate Program in Molecular and Developmental Biology, Children's Hospital Research Foundation, Cincinnati, Ohio, USA.
Mann
E A
EA
Giannella
R A
RA
Cohen
M B
MB
D000818:Animals; D017920:Antiporters; D002352:Carrier Proteins / Q000235:genetics; D003967:Diarrhea / Q000378:metabolism*; D005260:Female; D005768:Gastrointestinal Hormones; D006162:Guanylate Cyclase; D007413:Intestinal Mucosa / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D045265:Natriuretic Peptides; D009997:Osmotic Pressure; D010455:Peptides / Q000032:analysis* / Q000235:genetics / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D011956:Receptors, Cell Surface / Q000502:physiology*; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled; D018000:Receptors, Peptide; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics; D000076988:Sulfate Transporters
D017920:Antiporters; D002352:Carrier Proteins; D005768:Gastrointestinal Hormones; D008565:Membrane Proteins; D045265:Natriuretic Peptides; D010455:Peptides; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D018000:Receptors, Peptide; C489860:Slc26a3 protein, mouse; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D000076988:Sulfate Transporters; C072685:guanylin; C084362:uroguanylin; D006162:Guanylate Cyclase; C000613655:Gucy2c protein, mouse; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled