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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.

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Acknowledgements

We thank R Rassia for helping us in stopped-flow studies, J Monti for surgical assistance and A Martínez for immunohistochemistry assays. This work was supported by Grant PIP 0244 from Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) to RAM.

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Correspondence to R A Marinelli.

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Marrone, J., Lehmann, G., Soria, L. et al. Adenoviral transfer of human aquaporin -1 gene to rat liver improves bile flow in estrogen-induced cholestasis. Gene Ther 21, 1058–1064 (2014). https://doi.org/10.1038/gt.2014.78

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