Polycystic Kidney Rat Is a Novel Animal Model of Caroli’s Disease Associated with Congenital Hepatic Fibrosis

Sanzen, Takahiro; Harada, Kenichi; Yasoshima, Mitsue; Kawamura, Yasuhito; Ishibashi, Masahiko; Nakanuma, Yasuni

doi:10.1016/s0002-9440(10)64116-8

Cited by 83 publications

(96 citation statements)

References 30 publications

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“…More recently, the PCK-rat was postulated as a useful and promising animal model of Caroli syndrome, on the basis of the observation of constant association in PCK-rats between cystic dilatation of renal tubules and extensive hepatoportal fibrosis with multiple dysplastic and sacculated bile ducts. 5 The finding in our case of hepatorenal lesions is identical to those described previously 2,5 suggesting that in an European standard colony of Sprague-Dawley rats, the same mutation described and breeded by Katsuyama and colleagues 2 has occurred incidentally.…”

supporting

confidence: 88%

Bile Duct Dysplasia and Congenital Hepatic Fibrosis Associated with Polycystic Kidney (Caroli Syndrome) in a Rat

Bettini¹,

Mandrioli²,

Morini³

2003

Vet Pathol

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Abstract. Hepatic fibrosis with bile duct ectasia and hyperplasia associated with polycystic kidney disease, analogous to Caroli syndrome in humans, was observed in a rat used as a control in a subchronic toxicity study. Light microscopy of liver sections showed multiple cystic and segmental saccular dilatations and hyperplasia of the intrahepatic bile ducts associated with overgrowth of portal connective tissue; the kidneys had diffuse cystic dilatation of cortical renal tubules. The lesions resembled those of human cases of the fibropolycystic disease termed as Caroli syndrome, which is thought to be the result of a pathologic developmental process known as ductal plate malformation. Recently, an animal model of Caroli syndrome has been described in mutant rats from a colony that constantly showed renal and hepatic cysts and an autosomal recessive mode of inheritance. The finding in our case of identical hepatorenal lesions suggests that the same mutation has occurred incidentally in a standard colony.Key words: Caroli disease; congenital hepatic fibrosis; polycystic kidney; rats. A 5-month-old male Sprague-Dawley rat, included as a control case in a subchronic toxicity study to test plastic material for vascular prosthesis, was euthanatized with CO 2 at the end of the study. At necropsy, moderate enlargement of the liver in association with an irregularly lobular, gray pattern and increased firmness of the hepatic parenchyma was noted (Fig. 1); furthermore, both kidneys were moderately enlarged and bilaterally presented multiple cortical cysts ranging in size from 3 to 5 mm in diameter (Fig. 2). Tissue samples were fixed in 10% neutral buffered formalin, embedded in paraffin, sectioned at 4 m, and stained with hematoxylin-eosin and Masson trichrome. In histologic sections of the liver the connective tissue in portal tracts was widened and formed thick bands that surrounded bile ducts and ductules (portal fibrosis); bile ducts were increased in number (bile duct hyperplasia) and markedly dilated (bile duct ectasia) (Fig. 3). The irregularly shaped bile ducts were lined by normal cuboidal epithelium, but there were bulbar protrusions of the duct wall into the lumen and occasional bridge formation of the duct wall across the lumen (bile duct dysplasia suggestive of ductal plate malformation) in more dilated bile ducts. The lumen of dilated bile ducts occasionally contained amorphous or globular weakly eosinophilic material. In some portal tracts, there was hypoplasia of portal vein branches in association with supernumerary hepatic artery branches. Occasionally, portal tracts showed mild lymphocytic infiltration. The hepatic parenchyma lacked regenerative features, and the lobular pattern was maintained. The kidneys showed multiple cystic dilatations of renal tubules, particularly marked at the cortical-medullary junction, that tended to spread to the cortex; glomeruli were spared, and there were no glomerulocystic lesions (Fig. 4). Some dilated tubules contained amorphous eosinophilic proteinaceous material; mu...

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confidence: 88%

Bile Duct Dysplasia and Congenital Hepatic Fibrosis Associated with Polycystic Kidney (Caroli Syndrome) in a Rat

Bettini¹,

Mandrioli²,

Morini³

2003

Vet Pathol

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“…25 Interestingly, this cholangitis was frequently associated with intestinal metaplasia with goblet cells, and MUC2 and CDX2 at protein and mRNA levels were detectable. MUC2 was mainly expressed in goblet cells, and CDX2 was detectable in nuclei of goblet cells and also surrounding columnar cells.…”

Section: Discussionmentioning

confidence: 90%

“…25 At around 6 weeks, variable lymphocytic infiltration was focally seen around the dilated bile ducts (Figure 1a). After 4-7 months, chronic cholangitis with suppurative changes and polymorphonuclear leukocytes (PMNs) in duct lumen (chronic suppurative cholangitis) became frequent, and at around 12-18 months, such changes were widespread in all PCK rats (Figure 1b).…”

Section: Animal Studiesmentioning

confidence: 99%

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Interaction of Toll-like receptors with bacterial components induces expression of CDX2 and MUC2 in rat biliary epithelium in vivo and in culture

Ikeda

Sasaki

Ishikawa

et al. 2007

Laboratory Investigation

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The mechanism of transformation of biliary epithelium leading to intestinal metaplasia, which is significantly involved in biliary diseases, remains unclear. CDX2, an intestine-specific transcription factor, is thought to regulate intestinal mucin MUC2 (mucus core protein) expression. We took advantage of polycystic kidney (PCK) rats as a model of chronic suppurative cholangitis with intestinal metaplasia and of cultured biliary epithelial cells (BECs) from PCK rats to clarify the causal relation between bacterial components such as pathogen-associated molecular patterns (PAMPs) and the development of intestinal metaplasia of bile ducts. Histological, immunohistochemical, and in situ hybridization studies were conducted in PCK rat livers. In cultured BECs, CDX2 and MUC2 were expressed following treatment with PAMPs and inhibitors (anti-Toll-like receptor (TLR)2/TLR4 antibody, nuclear factor-kB (NF-kB) inhibitor MG132). Chronic suppurative cholangitis with intestinal metaplasia developed as the PCK rats aged, and intestinal metaplasia and aberrant CDX2 and MUC2 expression developed in parallel. Intraluminal bacteria and the expression of TLR2 and TLR4 in BECs were demonstrated in the bile ducts, showing chronic suppurative cholangitis. In cultured BECs, treatment with PAMPs induced upregulation of CDX2 and MUC2 expression, and this effect was abolished by pretreatment with anti-TLR2 and anti-TLR4 antibody and MG132. A knockdown of CDX2 by CDX2 small interfering RNA inhibited MUC2 expression in cultured BECs induced by PAMPs, and transfection of CDX2 expression vector induced MUC2 expression. In conclusion, bacterial components may induce upregulation of the CDX2 expression followed by MUC2 expression via TLR and the NF-kB system in cultured BECs, and could be related to the development of intestinal metaplasia of the bile ducts. Intestinal metaplasia associated with the aberrant expression of MUC2 1-4 is reportedly involved in tumorigenesis in several organs. Recent studies revealed that CDX2, a caudalrelated homeobox gene encoding an intestine-specific transcription factor, is a regulatory factor of intestinal development and expression of intestinal genes including MUC2 and is involved in intestinal metaplasia. 2,4,5-8 CDX2-dependent intestinal metaplasia is noted in Barrett's esophagus with MUC2 expression, and bile acid and chronic acid exposure have been reported to induce CDX2 expression. 2,[4][5][6]8,9 Intestinal metaplasia is also involved in the pathogenesis of biliary diseases. For example, in chronic cholangitis such as hepatolithiasis, intestinal metaplasia with goblet cells occurs, and MUC2 is aberrantly expressed in goblet cells colocalized with CDX2.

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“…1 Caroli's disease with CHF is a hepatic manifestation of ARPKD, and the hepatic lesions of ARPKD are characterized by multiple segmental and saccular dilation of the intrahepatic bile ducts and progressive and unresolving portal fibrosis. [2][3][4] Persistence or lack of remodeling of the embryonic ductal plate is regarded as an essential precursor of the hepatic lesions of Caroli's disease.…”

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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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Polycystic Kidney Rat Is a Novel Animal Model of Caroli’s Disease Associated with Congenital Hepatic Fibrosis

Cited by 83 publications

References 30 publications

Bile Duct Dysplasia and Congenital Hepatic Fibrosis Associated with Polycystic Kidney (Caroli Syndrome) in a Rat

Bile Duct Dysplasia and Congenital Hepatic Fibrosis Associated with Polycystic Kidney (Caroli Syndrome) in a Rat

Interaction of Toll-like receptors with bacterial components induces expression of CDX2 and MUC2 in rat biliary epithelium in vivo and in culture

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

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