Lack of guanylate cyclase C results in increased mortality in mice following liver injury.
BACKGROUND
Guanylate Cyclase C (GC-C) expression in the intestine plays a role in the regulation of fluid and ion transport, as well as epithelial cell apoptosis and proliferation. In the adult rat liver, GC-C expression is increased in response to injury. We hypothesized that GC-C is required for repair/recovery from liver injury.


METHODS
We subjected wild type (WT) and GC-C deficient mice to acute liver injury with a single injection of the hepatotoxin carbon tetrachloride. Changes in the level of expression of GC-C and its ligands uroguanylin and guanylin were quantified by real-time PCR. Liver morphology, and hepatocyte necrosis, apoptosis and proliferation, were examined at 1-3 days post-injury in mice on a mixed genetic background. Survival was followed for 14 days after carbon tetrachloride injection in wild type and GC-C deficient mice on both a mixed genetic background and on an inbred C57BL6/J background.


RESULTS
GC-C deficient mice on the mixed genetic background nearly all died (median survival of 5 days) following carbon tetrachloride injection while WT littermates experienced only 35% mortality. Elevated levels of TUNEL-positive hepatocyte death on post-injury day 1, increased apoptosis on day 2, and increased areas of centrilobular necrosis on days 2 and 3, were evident in livers from GC-C null mice compared to WT. Collectively these data suggest increased hepatocyte death in the GC-C null mice in the early time period after injury. This corresponds temporally with increased expression of GC-C and its ligands guanylin and uroguanylin in post-injury WT mouse liver. The hepatocyte proliferative response to injury was the same in both genotypes. In contrast, there was no difference in survival between GC-C null and WT mice on the inbred C57BL/6 J background in response to acute liver injury.


CONCLUSIONS
Signalling via GC-C promotes hepatocyte survival in vivo and is required for effective recovery from acute toxic injury to the liver in a strain-specific manner.
Mann
Elizabeth A
EA
Division of Gastroenterology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati, Cincinnati, OH, USA. elizabeth.mann@cchmc.org
Shanmukhappa
Kumar
K
Cohen
Mitchell B
MB
D000818:Animals; D017209:Apoptosis; D002251:Carbon Tetrachloride / Q000009:adverse effects*; D049109:Cell Proliferation; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D005260:Female; D005768:Gastrointestinal Hormones / Q000378:metabolism; D006162:Guanylate Cyclase / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D045265:Natriuretic Peptides / Q000378:metabolism; D015996:Survival Rate
D005768:Gastrointestinal Hormones; D045265:Natriuretic Peptides; C072685:guanylin; C084362:uroguanylin; D002251:Carbon Tetrachloride; D006162:Guanylate Cyclase