Increases in Guanylin and Uroguanylin in a Mouse Model of Osmotic Diarrhea Are Guanylate Cyclase C-Independent☆☆☆

Background & Aims: 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.