title: Adenoviral transfer of human aquaporin-1 gene to rat liver improves bile flow in estrogen-induced cholestasis.
abstract: Estrogens can cause liver cholestatic disease. As downregulation of hepatocyte canalicular aquaporin-8 (AQP8) water channels has been involved in estrogen-induced bile secretory failure, we tested whether the archetypal water channel AQP1 improves 17α-ethinylestradiol (EE)-induced cholestasis. EE administration to rats reduced bile flow by 50%. A recombinant adenoviral (Ad) vector encoding human AQP1 (hAQP1), AdhAQP1, or a control vector was administered by retrograde bile ductal infusion. Hepatocyte canalicular hAQP1 expression was confirmed by liver immunostaining and immunoblotting in purified membrane fractions. Accordingly, canalicular osmotic water permeability was markedly increased. Bile flow, either basal or bile salt-stimulated was significantly augmented by over 50%. The choleretic efficiency of endogenous bile salts (that is, volume of bile per μmol of excreted bile salt) was significantly increased by 45% without changes in the biliary bile salt composition. Our data suggest that the adenoviral transfer of hAQP1 gene to the livers of EE-induced cholestatic rats improves bile flow by enhancing the AQP-mediated bile salt-induced canalicular water secretion. This novel finding might have potential therapeutic implications for cholestatic diseases.
authors.affiliation: Instituto de Fisiología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, Argentina.
authors.forename: J
authors.initials: J
authors.lastname: Marrone
authors.affiliation: Margaret Dyson Vision Research Institute, Weill Cornell Medical College, New York, NY, USA.
authors.forename: G L
authors.initials: GL
authors.lastname: Lehmann
authors.affiliation: Instituto de Fisiología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, Argentina.
authors.forename: L R
authors.initials: LR
authors.lastname: Soria
authors.affiliation: Instituto de Fisiología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, Argentina.
authors.forename: J M
authors.initials: JM
authors.lastname: Pellegrino
authors.affiliation: Instituto de Fisiología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, Argentina.
authors.forename: S
authors.initials: S
authors.lastname: Molinas
authors.affiliation: Instituto de Fisiología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, Argentina.
authors.forename: R A
authors.initials: RA
authors.lastname: Marinelli
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D051398:Aquaporin 1 / Q000235:genetics* / Q000378:metabolism; D020346:Aquaporins / Q000235:genetics / Q000378:metabolism; D001219:Aspartate Aminotransferases / Q000097:blood; D001646:Bile / Q000378:metabolism*; D002779:Cholestasis / Q000139:chemically induced / Q000235:genetics / Q000628:therapy*; D004195:Disease Models, Animal; D015536:Down-Regulation; D004967:Estrogens / Q000009:adverse effects*; D004997:Ethinyl Estradiol / Q000008:administration & dosage / Q000009:adverse effects; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D006836:Hydro-Lyases / Q000097:blood; D008099:Liver / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar
chemical_list: C496020:AQP1 protein, human; D020346:Aquaporins; D004967:Estrogens; C108330:aquaporin 8; D051398:Aquaporin 1; D004997:Ethinyl Estradiol; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; D006836:Hydro-Lyases; C045581:lactate dehydratase