Aberrant Gene Expression in Dogs with Portosystemic Shunts

Frank G Van Steenbeek,Lindsay Van Den Bossche,Frank C P Holstege,Louis C Penning,Marian J A Groot Koerkamp,Jan Rothuizen,Anne Kummeling,Peter A J Leegwater,Ingrid H M Van Gils,Bart Spee,Dik Van Leenen,Guy C M Grinwis,Erica Villa

doi:10.1371/journal.pone.0057662

Frank G Van Steenbeek, Lindsay Van Den Bossche + Show 11 more

Open Access

https://doi.org/10.1371/journal.pone.0057662

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Journal: PLoS ONE	Publication Date: Feb 25, 2013
Citations: 66	License type: CC BY 4.0

Affiliation: Utrecht University, University Medical Center Utrecht

Abstract

Congenital portosystemic shunts are developmental anomalies of the splanchnic vascular system that cause portal blood to bypass the liver. Large-breed dogs are predisposed for intrahepatic portosystemic shunts (IHPSS) and small-breed dogs for extrahepatic portosystemic shunts (EHPSS). While the phenotype resulting from portal bypass of the liver of the two types of shunt is identical, the genotype and molecular pathways involved are probably different. The aim of this study was to gain insight into the pathways involved in the different types of portosystemic shunting. Microarray analysis of mRNA expression in liver tissue from dogs with EHPSS and IHPSS revealed that the expression of 26 genes was altered in either IHPSS or EHPSS samples compared with that in liver samples from control dogs. Quantitative real-time PCR of these genes in 14 IHPSS, 17 EHPSS, and 8 control liver samples revealed a significant differential expression of ACBP, CCBL1, GPC3, HAMP, PALLD, VCAM1, and WEE1. Immunohistochemistry and Western blotting confirmed an increased expression of VCAM1 in IHPSS but its absence in EHPSS, an increased WEE1 expression in IHPSS but not in EHPSS, and a decreased expression of CCBL1 in both shunt types. Regarding their physiologic functions, these findings may indicate a causative role for VCAM1 in IHPSS and WEE1 for IHPSS. CCBL1 could be an interesting candidate to study not yet elucidated aspects in the pathophysiology of hepatic encephalopathy.

Highlights

Congenital portosystemic shunts (CPSS) are vascular anomalies by which portal blood circumvents the liver, flowing directly into the systemic circulation
Intrahepatic portosystemic shunts (IHPSS) are usually embryological shunts in the liver that failed to close after birth, whereas extrahepatic shunts (EHPSS) are developmental vascular anomalies by which the extrahepatic portal system is connected with the caudal vena cava orazygos vein [7]
19 and 6 annotated genes were specific to liver samples from dogs with either IHPSS or EHPSS, respectively (Table 4)

Summary

Introduction

Congenital portosystemic shunts (CPSS) are vascular anomalies by which portal blood circumvents the liver, flowing directly into the systemic circulation. Portal blood does not undergo hepatic metabolism through the liver parenchyma [1,2,3]. Two anatomically different types of shunt have been described. Intrahepatic portosystemic shunts (IHPSS) are usually embryological shunts (ductus venosus) in the liver that failed to close after birth, whereas extrahepatic shunts (EHPSS) are developmental vascular anomalies by which the extrahepatic portal system is connected with the caudal vena cava or (hemi)azygos vein [7]. The functional consequences, virtual absence of portal perfusion of the liver parenchyma, and clinical signs are identical for both types of shunt [8,9]

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