TY - JOUR
T1 - Biliary dysgenesis in the PCK rat, an orthologous model of autosomal recessive polycystic kidney disease
AU - Masyuk, Tatyana V.
AU - Huang, Bing Q.
AU - Masyuk, Anatoliy I.
AU - Ritman, Erik L.
AU - Torres, Vicente E.
AU - Wang, Xiaofang
AU - Harris, Peter C.
AU - LaRusso, Nicholas F.
N1 - Funding Information:
Supported by the National Institutes of Health (grants DK24031 to N.F.L., DK44863 to V.E.T., DK59597 to P.C.H., and EB000305 to E.L.R. ), the Polycystic Kidney Disease Foundation (postdoctoral fellowship to T.V.M.), and the Mayo Foundation.
PY - 2004/11
Y1 - 2004/11
N2 - Hepatic polycystic disease occurs alone or in combination with polycystic kidney disease (PKD). In autosomal recessive PKD (ARPKD), liver lesions are the major cause of morbidity and mortality in older patients. ARPKD is caused by a mutation to PKHD1 and the PCK rat is an orthologous model of disease. Recently, we showed that fibrocystin, Pkhd1 protein, is localized to primary cilia in rat cholangiocytes and that disruption of its ciliary expression results in biliary cystogenesis. This study describes biliary phenotype in the PCK rat using micro-computed tomography scanning and three-dimensional reconstruction, and light, scanning, and transmission microscopy. Our results show that the biliary tree undergoes extensive remodeling resulting in bile duct dilatation, focal budding, and formation of cysts that are initially connected to bile ducts, but throughout time separate from them. Progressive liver enlargement results from massive cyst formation while liver parenchymal volume remains unchanged. Cilia in cystic cells are abnormal consistent with the notion that the primary defect in ARPKD resulting in cystogenesis may be linked to ciliary dysfunction. Our results suggest that the PCK rat is a useful model for studies of biliary cystogenesis and treatment options of inherited cystic liver disease.
AB - Hepatic polycystic disease occurs alone or in combination with polycystic kidney disease (PKD). In autosomal recessive PKD (ARPKD), liver lesions are the major cause of morbidity and mortality in older patients. ARPKD is caused by a mutation to PKHD1 and the PCK rat is an orthologous model of disease. Recently, we showed that fibrocystin, Pkhd1 protein, is localized to primary cilia in rat cholangiocytes and that disruption of its ciliary expression results in biliary cystogenesis. This study describes biliary phenotype in the PCK rat using micro-computed tomography scanning and three-dimensional reconstruction, and light, scanning, and transmission microscopy. Our results show that the biliary tree undergoes extensive remodeling resulting in bile duct dilatation, focal budding, and formation of cysts that are initially connected to bile ducts, but throughout time separate from them. Progressive liver enlargement results from massive cyst formation while liver parenchymal volume remains unchanged. Cilia in cystic cells are abnormal consistent with the notion that the primary defect in ARPKD resulting in cystogenesis may be linked to ciliary dysfunction. Our results suggest that the PCK rat is a useful model for studies of biliary cystogenesis and treatment options of inherited cystic liver disease.
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U2 - 10.1016/S0002-9440(10)63427-X
DO - 10.1016/S0002-9440(10)63427-X
M3 - Article
C2 - 15509540
AN - SCOPUS:7244231107
SN - 0002-9440
VL - 165
SP - 1719
EP - 1730
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 5
ER -