Increased expression of sulfated gp300 and acinar tissue pathology in pancreas of CFTR(-/-) mice.

The CFTR (-/-) mouse model of cystic fibrosis (CF) has revealed that the mouse pancreatic duct has a Ca(2+)-regulated chloride conductance that allows ductal electrolyte transport to remain unaffected by loss of the cystic fibrosis transmembrane conductance regulator (CFTR). Therefore, this model provides a unique opportunity to investigate effects of CF on the acinar tissue. It has been reported that exocrine secretions contain higher levels of sulfate in CF. We discovered in CFTR(-/-) acini that gp300, the major sulfated glycoprotein of the mouse acinar cell, has increased steady-state and biosynthetic levels. However, there are no apparent changes in sulfate or carbohydrate composition of gp300, indicating that posttranslational processing of this sulfated glycoprotein is not altered in CF. In addition to the increase in gp300, the morphology of CF acinar tissue is dramatically altered: acinar lumina of CFTR(-/-) mice are greatly dilated and filled with aggregated protein. gp300, which in the normal tissue is mainly localized to the zymogen granule membrane, was found to line the distended luminal membranes in the CF tissue. These results demonstrate that the acinar tissue is affected in the CF mouse and that expression of the major sulfated glycoprotein is also increased. It is suggested that increased expression of gp300 in CFTR(-/-) mice may cause poorly soluble exocrine protein secretion, contributing to the development of CF in the pancreas.