Loss of Cilia Does Not Slow Liver Disease Progression in Mouse Models of Autosomal Recessive Polycystic Kidney Disease.

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary disorder characterized by abnormal cellular proliferation, cyst fluid accumulation, extracellular matrix remodeling, and fibrosis in the kidney and liver. ADPKD accounts for approximately 5% of the prevalent adult RRT (dialysis or transplantation) population, with most cases resulting from mutations in PKD1 or PKD2 , which encodes polycystin-1 (PC1) or polycystin-2 (PC2), respectively (1). In contrast, autosomal recessive polycystic kidney disease (ARPKD) is a rare and severe form of polycystic disease affecting the kidneys and biliary tract of children with an estimated incidence of 1 in 20,000 live births (2). ARPKD develops in utero and is diagnosed early in life, often prenatally. The clinical spectrum is widely variable, with approximately 20% of cases severely affected at birth, whereas the remainder are affected more as juveniles. Clinical findings in ARPKD include enlarged echogenic kidneys due to fusiform dilation of the collecting ducts and dilated bile ducts accompanied by congenital hepatic fibrosis resulting in portal hypertension (2). Mutations in PKHD1 are responsible for most typical cases of ARPKD (3,4). It encodes a heavily glycosylated approximately 450-kD single-pass transmembrane protein, fibrocystin (FPC), that localizes to the primary cilia, basal bodies, apical membrane, and exosome-like vesicles in kidney and liver epithelial cells (5⇓–7). The function of FPC is largely unknown, but it has been proposed to act as a ligand or cell surface coreceptor that undergoes Notch-like processing and plays a role in regulating mitotic spindle orientation (8⇓–10). Several rodent models for ARPKD have been reported with all but one targeting the 5′ region of the Pkhd1 gene. These models invariably exhibit biliary cysts accompanied by periportal fibrosis consistent with the human disease (5,11,12). The renal phenotype is mild in the rat model …