Disease Stage Characterization of Hepatorenal Fibrocystic Pathology in the PCK Rat Model of ARPKD

Mason, Stephen B.; Liang, Yun; Sinders, Rachel M.; Miller, Caroline; Eggleston-Gulyas, Tracy; Crisler-Roberts, Robin; Harris, Peter C.; Gattone, Vincent H.

doi:10.1002/ar.21166

Cited by 29 publications

(35 citation statements)

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“…In contrast, and as expected, chronic treatment of PCK rats with UDCA did not affect the renal cystogenesis that is also apparent in PCK rats [16]. However, UDCA diminished the increased [BA] in the kidneys of PCK rats, particularly the levels of the most cytotoxic, suggesting that UDCA may facilitate the exit of BAs in the kidney through the urine.…”

Section: Discussionsupporting

confidence: 75%

“…The PCK rat (Charles River Laboratory) is a well characterized animal model of ARPKD that presents a spontaneous mutation in the PKHD1 orthologous gene [16, 17]. Hepatic cystogenesis and fibrosis, as well as serum biochemical markers were analyzed in non-treated wild-type (n=12) and PCK (n=10) rats, as well as in PCK rats (n=10) orally-treated with UDCA (25 mg/kg/day) for 5 months.…”

Section: Methodsmentioning

confidence: 99%

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Ursodeoxycholic acid inhibits hepatic cystogenesis in experimental models of polycystic liver disease

Munoz‐Garrido¹,

Marin²,

Perugorria³

et al. 2015

Journal of Hepatology

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Background & Aims Polycystic liver diseases (PLDs) are genetic disorders characterized by progressive biliary cystogenesis. Current therapies show short-term and/or modest beneficial effects. Cystic cholangiocytes hyperproliferate as a consequence of diminished intracellular calcium levels ([Ca2+]i). Here, the therapeutic value of ursodeoxycholic acid (UDCA) was investigated. Methods Effect of UDCA was examined in vitro and in polycystic (PCK) rats. Hepatic cystogenesis and fibrosis, and the bile acid (BA) content were evaluated in liver, bile, serum and kidneys by HPLC-MS/MS. Results Chronic treatment of PCK rats with UDCA inhibits hepatic cystogenesis and fibrosis, and improves their motor behaviour. As compared to wild-type animals, PCK rats show increased BA concentration ([BA]) in liver, similar hepatic Cyp7a1 mRNA levels, and diminished [BA] in bile. Likewise, [BA] is increased in cystic fluid of PLD patients compared to their matched serum levels. In PCK rats, UDCA decreases the intrahepatic accumulation of cytotoxic BA, normalizes their diminished [BA] in bile, increases the BA secretion in bile and diminishes the increased [BA] in kidneys. In vitro, UDCA inhibits the hyperproliferation of polycystic human cholangiocytes via a PI3K/AKT/MEK/ERK1/2-dependent mechanism without affecting apoptosis. Finally, the presence of glycodeoxycholic acid promotes the proliferation of polycystic human cholangiocytes, which is inhibited by both UDCA and tauro-UDCA. Conclusions UDCA was able to halt the liver disease of a rat model of PLD through inhibiting cystic cholangiocyte hyperproliferation and decreasing the level of cytotoxic BA species in the liver, which suggests the use of UDCA as a potential therapeutic tool for PLD patients.

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Section: Discussionsupporting

confidence: 75%

Section: Methodsmentioning

confidence: 99%

Ursodeoxycholic acid inhibits hepatic cystogenesis in experimental models of polycystic liver disease

Munoz‐Garrido¹,

Marin²,

Perugorria³

et al. 2015

Journal of Hepatology

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“…Similar to what is observed in human PCLD patients; we found a large inter- and intra-litter variation of the severity of hepatic polycystic disease in the PCK model, which had previously also been found by Mason et al[ 21 ]. Therefore, there is a great need for a reliable technique that can accurately assess LV in this animal model and further that allows repeated measurements during drug treatment.…”

Section: Discussionsupporting

confidence: 90%

Everolimus halts hepatic cystogenesis in a rodent model of polycystic-liver-disease

Temmerman¹,

Chen²,

Libbrecht³

et al. 2017

WJG

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AIMTo develop a MRI-based method for accurate determination of liver volume (LV) and to explore the effect of long-term everolimus (EVR) treatment on LV in PCK rats with hepatomegaly.METHODSThirty-one female PCK rats (model for polycystic-liver-disease: PCLD) were randomized into 3 groups and treatment was started at 16 wk, at the moment of extensive hepatomegaly (comparable to what is done in the human disease). Animals received: controls (n = 14), lanreotide (LAN: 3 mg/kg per 2 wk) (n = 10) or everolimus (EVR: 1 mg/kg per day) (n = 7). LV was measured at week 16, 24, 28. At week 28, all rats were sacrificed and liver tissue was harvested. Fibrosis was evaluated using quantitative image analysis. In addition, gene (quantitative RT-PCR) and protein expression (by Western blot) of the PI3K/AkT/mTOR signaling pathway was investigated.RESULTSLV determination by MRI correlated excellent with the ex vivo measurements (r = 0.99, P < 0.001). The relative changes in LV at the end of treatment were: (controls) +31.8%; (LAN) +5.1% and (EVR) +8.8%, indicating a significantly halt of LV progression compared with controls (respectively, P = 0.01 and P = 0.04). Furthermore, EVR significantly reduced the amount of liver fibrosis (P = 0.004) thus might also prevent the development of portal hypertension. There was no difference in phosphorylation of Akt (Threonine 308) between LAN-treated PCK rats control PCK rats, whereas S6 was significantly more phosphorylated in the LAN group. Phosphorylation of Akt was not different between controls and EVR treated rats, however, for S6 there was significantly less phosphorylation in the EVR treated rats. Thus, both drugs interact with the PI3K/AkT/mTOR signaling cascade but acting at different molecular levels.CONCLUSIONEverolimus halts cyst growth comparable to lanreotide and reduces the development of fibrosis. mTOR-inhibition should be further explored in PCLD patients especially those that need immunosuppression.

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“…Further experimental studies on PCK rats highlighted the cyst disconnection from the biliary system with advancing age, consistent with the human disease features [107]. However, in contrast with the Pkhd1 del4/del4 mouse, the PCK rat shows some critical differences, including a more pronounced development of the hepatic cysts, the renal involvement with cyst lesions affecting the outer medullary-collecting ducts, and the mild degree of portal fibrosis, without formation of fibrous septa or development of portal hypertension [108,109]. Overall, these characteristics make the PCK rat a less coherent model of the human CHF, at least with respect to the liver phenotype.…”

Section: Genetic Mouse Models Of Cholangiocyte Dysfunctionmentioning

confidence: 86%

Animal models of biliary injury and altered bile acid metabolism

Mariotti

Strazzabosco

Fabris

et al. 2018

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

131

102

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In the last 25 years, a number of animal models, mainly rodents, have been generated with the goal to mimic cholestatic liver injuries and, thus, to provide in vivo tools to investigate the mechanisms of biliary repair and, eventually, to test the efficacy of innovative treatments. Despite fundamental limitations applying to these models, such as the distinct immune system and the different metabolism regulating liver homeostasis in rodents when compared to humans, multiple approaches, such as surgery (bile duct ligation), chemical-induced (3,5-diethoxycarbonyl-1,4-dihydrocollidine, DDC, α-naphthylisothiocyanate, ANIT), viral infections (Rhesus rotavirustype A, RRV-A), and genetic manipulation (Mdr2, Cftr, Pkd1, Pkd2, Prkcsh, Sec63, Pkhd1) have been developed. Overall, they have led to a range of liver phenotypes recapitulating the main features of biliary injury and altered bile acid metabolisms, such as ductular reaction, peribiliary inflammation and fibrosis, obstructive cholestasis and biliary dysgenesis. Although with a limited translability to the human setting, these mouse models have provided us with the ability to probe over time the fundamental mechanisms promoting cholestatic disease progression. Moreover, recent studies from genetically engineered mice have unveiled ‘core’ pathways that make the cholangiocyte a pivotal player in liver repair. In this review, we will highlight the main phenotypic features, the more interesting peculiarities and the different drawbacks of these mouse models.

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Disease Stage Characterization of Hepatorenal Fibrocystic Pathology in the PCK Rat Model of ARPKD

Cited by 29 publications

References 29 publications

Ursodeoxycholic acid inhibits hepatic cystogenesis in experimental models of polycystic liver disease

Ursodeoxycholic acid inhibits hepatic cystogenesis in experimental models of polycystic liver disease

Everolimus halts hepatic cystogenesis in a rodent model of polycystic-liver-disease

Animal models of biliary injury and altered bile acid metabolism

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