A mouse model for cystic biliary dysgenesis in autosomal recessive polycystic kidney disease (ARPKD)†

Moser, Markus; Matthiesen, Sonja; Kirfel, Jutta; Schorle, Hubert; Bergmann, Carsten; Senderek, Jan; Rudnik‐Schöneborn, Sabine; Zerres, Klaus; Buettner, Reinhard

doi:10.1002/hep.20655

Cited by 80 publications

(68 citation statements)

References 19 publications

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“…This result is consistent with studies in which transient small interference RNA-mediated inhibition of Pkhd1 in cholangiocytes resulted in shortening and decreased formation of cilia, 29 but spatial and environmental differences between in vivo tissues and in vitro cell culture may lead to different results. Mouse models with a deletion of Pkhd1 exon 40 44 and genetargeted mutations in Pkd2 that cause distinct liver and/or kidney cysts 33,45,46 do not exhibit defects in ciliary structure in the affected epithelial cells, suggesting that the failure of renal epithelia to assemble primary cilia may not be the only factor leading to cyst formation in the kidneys. For example, a recent study showed that disruption of the extracellular matrix protein laminin ␣5, which is a major component of the tubular and glomerular basement membranes, also produces cystic kidneys in Lama5 mutant mice.…”

Section: Discussionmentioning

confidence: 99%

Fibrocystin/Polyductin Modulates Renal Tubular Formation by Regulating Polycystin-2 Expression and Function

Kim

Fu²,

Hui

et al. 2008

Journal of the American Society of Nephrology

129

105

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Autosomal recessive polycystic kidney disease is caused by mutations in PKHD1, which encodes the membrane-associated receptor-like protein fibrocystin/polyductin (FPC). FPC associates with the primary cilia of epithelial cells and co-localizes with the Pkd2 gene product polycystin-2 (PC2), suggesting that these two proteins may function in a common molecular pathway. For investigation of this, a mouse model with a gene-targeted mutation in Pkhd1 that recapitulates phenotypic characteristics of human autosomal recessive polycystic kidney disease was produced. The absence of FPC is associated with aberrant ciliogenesis in the kidneys of Pkhd1-deficient mice. It was found that the COOH-terminus of FPC and the NH2-terminus of PC2 interact and that lack of FPC reduced PC2 expression but not vice versa, suggesting that PC2 may function immediately downstream of FPC in vivo. PC2-channel activities were dysregulated in cultured renal epithelial cells derived from Pkhd1 mutant mice, further supporting that both cystoproteins function in a common pathway. In addition, mice with mutations in both Pkhd1 and Pkd2 had a more severe renal cystic phenotype than mice with single mutations, suggesting that FPC acts as a genetic modifier for disease severity in autosomal dominant polycystic kidney disease that results from Pkd2 mutations. It is concluded that a functional and molecular interaction exists between FPC and PC2 in vivo.

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Section: Discussionmentioning

confidence: 99%

Fibrocystin/Polyductin Modulates Renal Tubular Formation by Regulating Polycystin-2 Expression and Function

Kim

Fu²,

Hui

et al. 2008

Journal of the American Society of Nephrology

129

105

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“…Interestingly, another published Pkhd1 mouse model, generated by disrupting exon 40, also yielded an in-frame product with the loss of amino acids 2160 to 2223 and resulted in cystic liver disease and portal tract fibrosis but no pancreatic or kidney abnormalities. 24 Two other murine models, Pkhd1 del2 25 and Pkhd1 del3-4 26 develop renal cysts but only in aged mice; none of the orthologous models recapitulate the severe neonatal phenotype seen in humans suggesting the possibility that species differences may play a role in the relative resistance of mouse kidneys to cyst formation because of mutation in Pkhd1. The location of the mutations in the genes may also affect the severity of the disease, hence the clinical lesion in mice, and this is borne out in human studies in which genotype-phenotype interactions have been reported.…”

Section: Discussionmentioning

confidence: 99%

“…An engineered mouse mutation with disruption of exon 40 still produces a modified transcript because of exon skipping. 24 This mouse model shows bile duct proliferation with associated portal tract fibrosis and portal hypertension but does not have discernible abnormalities in the kidney. 24 More recently renal phenotypes have been described in two mouse models harboring hypomorphic mutations in Pkhd1.…”

mentioning

confidence: 99%

“…24 This mouse model shows bile duct proliferation with associated portal tract fibrosis and portal hypertension but does not have discernible abnormalities in the kidney. 24 More recently renal phenotypes have been described in two mouse models harboring hypomorphic mutations in Pkhd1. 25,26 The Pkhd1 del2/del2 mouse develops renal cysts in the S3 segment of the proximal tubule but not in the collecting duct system.…”

mentioning

confidence: 99%

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Biliary and Pancreatic Dysgenesis in Mice Harboring a Mutation in Pkhd1

Gallagher

Esquivel

Briere

et al. 2008

The American Journal of Pathology

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Autosomal recessive polycystic kidney disease is a hereditary fibrocystic disease that involves the kidneys and the biliary tract. Mutations in the PKHD1 gene are responsible for typical forms of autosomal recessive polycystic kidney disease. We have generated a mouse model with targeted mutation of Pkhd1 by disrupting exon 4, resulting in a mutant transcript with deletion of 66 codons and expression at ϳ30% of wild-type levels. Pkhd1 del4/del4 mice develop intrahepatic bile duct proliferation with progressive cyst formation and associated periportal fibrosis. In addition, these mice exhibit extrahepatic manifestations, including pancreatic cysts, splenomegaly, and common bile duct dilation. The kidneys are unaffected both histologically and functionally. Fibrocystin is expressed in the apical membranes and cilia of bile ducts and distal nephron segments but is absent from the proximal tubule. This pattern is unchanged in orthologous models of autosomal dominant polycystic kidney disease due to mutation in Pkd1 or Pkd2. Mutant fibrocystin in Pkhd1 del4/del4 mice also retains this expression pattern. The hypomorphic Pkhd1 del4/del4 mouse model provides evidence that reduced functional levels of fibrocystin are sufficient for cystogenesis and fibrosis in the liver and pancreas, but not the kidney, and supports the hypothesis of species-dependent differences in susceptibility of tissues to Pkhd1 mutations. (Am J

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“…8 Mice with targeted mutation of Pkhd1 develop cystic biliary dysgenesis and portal fibrosis. 9 In the PCK rat, cholangiocytes possess short and malformed cilia that do not express fibrocystin. 10 -12 Despite the identification of the genetic defect of the disease, the pathophysiology of the bile duct dilation and hepatic fibrosis are not fully understood.…”

mentioning

confidence: 99%

Cholangiocytes with Mesenchymal Features Contribute to Progressive Hepatic Fibrosis of the Polycystic Kidney Rat

Sato

Harada

Ozaki

et al. 2007

The American Journal of Pathology

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The polycystic kidney (PCK) rat is an animal model of Caroli's disease with congenital hepatic fibrosis, in which the mechanism of progressive hepatic fibrosis remains unknown. This study aimed to clarify the mechanism of hepatic fibrosis of the PCK rat from the viewpoint of the contribution of pathological cholangiocytes. In liver sections of the PCK rats, intrahepatic bile ducts were constituted by two different phenotypes: bile ducts lined by cuboidal-shaped and flat-shaped cholangiocytes. The flat-shaped cholangiocytes showed reduced immunohistochemical expression of the biliary epithelial marker cytokeratin 19 and positive immunoreactivity for vimentin and fibronectin. When cultured cholangiocytes of the PCK rat were treated with transforming growth factor (TGF)-␤1, a potent inducer of epithelial-mesenchymal transition, induction of vimentin, fibronectin, and collagen expression occurred in the PCK cholangiocytes. Although the TGF-␤1 treatment reduced cytokeratin 19 expression, the epithelial cell features characterized by the expression of E-cadherin and zonula occludens-1 was maintained, and ␣-smooth muscle actin expression was not induced in the cholangiocytes. Cholangiocytes of the PCK rat may acquire mesenchymal features in response to TGF-␤1 and participate in progressive hepatic fibrosis by producing extracellular matrix molecules, which seems to be a different event from epithelial-mesenchymal transition.

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A mouse model for cystic biliary dysgenesis in autosomal recessive polycystic kidney disease (ARPKD)†

Cited by 80 publications

References 19 publications

Fibrocystin/Polyductin Modulates Renal Tubular Formation by Regulating Polycystin-2 Expression and Function

Fibrocystin/Polyductin Modulates Renal Tubular Formation by Regulating Polycystin-2 Expression and Function

Biliary and Pancreatic Dysgenesis in Mice Harboring a Mutation in Pkhd1

Cholangiocytes with Mesenchymal Features Contribute to Progressive Hepatic Fibrosis of the Polycystic Kidney Rat

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