Abstract
The aryl hydrocarbon receptor (AHR) mediates biological responses to toxic chemicals. An unexpected role for AHR in vascularization was suggested when mice lacking AHR displayed impaired closure of the ductus venosus after birth, as did knockout mice for aryl hydrocarbon receptor interacting protein (AIP) and aryl hydrocarbon receptor nuclear translocator (ARNT). The resulting intrahepatic portosystemic shunts (IHPSS) are frequently diagnosed in specific dog breeds, such as the Irish wolfhound. We compared the expression of components of the AHR pathway in healthy Irish wolfhounds and dogs with IHPSS. To this end, we analyzed the mRNA expression in the liver of AHR,AIP, ARNT, and other genes involved in this pathway, namely, those for aryl hydrocarbon receptor nuclear translocator 2 (ARNT2), hypoxia inducible factor 1alpha (HIF1A), heat shock protein 90AA1 (HSP90AA1), cytochromes P450 (CYP1A1, CYP1A2, and CYP1B1), vascular endothelial growth factor A (VEGFA), nitric oxide synthesase 3 (NOS3), and endothelin (EDN1). The observed low expression of AHR mRNA in the Irish wolfhounds is in associated with a LINE-1 insertion in intron 2, for which these dogs were homozygous. Down regulation in Irish wolfhounds was observed for AIP, ARNT2, CYP1A2, CYP1B1 and HSP90AA1 expression, whereas the expression of HIF1A was increased. Immunohistochemistry revealed lower levels of AHR, HIF1A, and VEGFA protein in the nucleus and lower levels of ARNT and HSP90AA1 protein in the cytoplasm of the liver cells of Irish wolfhounds. The impaired expression of HSP90AA1 could trigger the observed differences in mRNA and protein levels and therefore explain the link between two very different functions of AHR: regulation of the closure of the ductus venosus and the response to toxins.
Highlights
The ductus venosus is an embryonic vessel connecting the vena porta and vena cava and allows blood to flow from the placenta to the lungs and heart without traversing the liver sinusoids
Rearrangement of aryl hydrocarbon receptor (AHR) As a first step to investigate the role of AHR in intrahepatic portosystemic shunt (IHPSS) we analyzed the exons of the gene in affected dogs
Linkage Analysis On the basis of test matings of Irish wolfhounds with an IHPSS, we previously proposed a digenic, triallelic mode of inheritance, two interacting loci in which a total of at least three risk alleles should be present [7]
Summary
The ductus venosus is an embryonic vessel connecting the vena porta and vena cava and allows blood to flow from the placenta to the lungs and heart without traversing the liver sinusoids. The vessel closes within a few days after birth, thereby ensuring that the liver becomes fully functional [1]. In some purebred dogs, especially large and giant dogs such as Irish wolfhounds, the ductus venosus sometimes fails to close because of a genetic disorder [3]. A permanently patent ductus venosus, called an intrahepatic portosystemic shunt (IHPSS), leads to portosystemic bypass of venous hepatic perfusion, resulting in impaired growth and function of the liver and no clearance of intestinal metabolites, such as ammonia, from portal blood [4]. The prevalence of IHPSS in Irish wolfhounds is 2.1–3.4% [5,6] and the disease has a polygenic mode of inheritance [7]. IHPSS is a rare disease in humans, with only 89 cases reported to date (listed in [3])
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
