The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein.

Autosomal recessive polycystic kidney disease (ARPKD) is characterized by dilation of collecting ducts and by biliary dysgenesis and is an important cause of renal- and liver-related morbidity and mortality. Genetic analysis of a rat with recessive polycystic kidney disease revealed an orthologous relationship between the rat locus and the ARPKD region in humans; a candidate gene was identified. A mutation was characterized in the rat and screening the 66 coding exons of the human ortholog (PKHD1) in 14 probands with ARPKD revealed 6 truncating and 12 missense mutations; 8 of the affected individuals were compound heterozygotes. The PKHD1 transcript, approximately 16 kb long, is expressed in adult and fetal kidney, liver and pancreas and is predicted to encode a large novel protein, fibrocystin, with multiple copies of a domain shared with plexins and transcription factors. Fibrocystin may be a receptor protein that acts in collecting-duct and biliary differentiation.

Probiotics promote rapid-turnover protein production by restoring gut flora in patients with alcoholic liver cirrhosis.

BACKGROUND AND AIMS: Accumulating evidence suggests that deterioration of the gut flora contributes to the pathogenesis of alcoholic liver cirrhosis (ALC). However, the ALC flora profile and its response to probiotic treatment have not been fully examined. This double-blind placebo-controlled study aimed to evaluate whether the probiotic beverage Yakult 400 (Y400), which contains Lactobacillus casei strain Shirota, improves liver function in ALC patients, and to analyze the precise gut flora profile by real-time quantitative PCR (qPCR). METHODS: A total of 37 hospitalized ALC patients were randomly allocated to Y400 (n = 18) and placebo (n = 19) groups. Y400 or placebo was served twice a day during the first half of the four-week study. Serum concentrations of rapid-turnover proteins (i.e., transthyretin and transferrin), hypersensitive C-reactive protein, and interleukin-6 were measured weekly. qPCR analysis of fecal bacteria was performed biweekly; stocked fecal samples from 46 healthy subjects were used as references. RESULTS: Serum transthyretin levels significantly increased in the Y400 group in week 3; similar-although statistically insignificant-increases were seen for transferrin and albumin. Levels of hypersensitive C-reactive protein, but not interleukin-6, significantly decreased in week 4. Before treatment, populations of obligate anerobic bacteria were significantly smaller and those of Enterobacteriaceae were larger in patients than in healthy subjects examined in a previous study. Y400 corrected this imbalance. CONCLUSIONS: This is the first report describing the unique gut flora of ALC patients. Y400 treatment normalized the gut flora and improved liver function. These promising findings warrant further investigation in larger, multicenter studies.

Activation of the MEK5/ERK5 cascade is responsible for biliary dysgenesis in a rat model of Caroli's disease.

Polycystic kidney (PCK) rats exhibit a multiorgan cyst pathology similar to human autosomal recessive polycystic kidney disease, and are proposed as an animal model of Caroli's disease with congenital hepatic fibrosis (CHF). This study investigated the expression and function of selected components of the mitogen activated protein kinase (MAPK) pathway in cultured intrahepatic biliary epithelial cells (BECs) of PCK rats. Compared to the proliferative activity of cultured BECs of control rats, those of the PCK rats were hyperresponsive to epidermal growth factor (EGF). The increase in BEC proliferation was accompanied by overexpression of MAPK/extracellular signal-regulated protein kinase (ERK) kinase 5 (MEK5), and subsequent phosphorylation of ERK5 in vitro. The increased proliferative activity was significantly inhibited by the transfection of short interfering RNA against MEK5 mRNA. An EGF receptor tyrosine kinase inhibitor, gefitinib ("Iressa", ZD1839), also significantly inhibited the abnormal growth of cultured BECs of PCK rats. By contrast, treatment with PD98059 and U0126, inhibitors for MEK1/2, was less effective. These results suggest that the activation of the MEK5-ERK5 cascade plays a pivotal role in the biliary dysgenesis of PCK rats, and also provide insights into the pathogenesis of Caroli's disease with CHF. As the MEK5-ERK5 interaction is highly specific, it may represent a potential target of therapy.