{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T15:34:58Z","timestamp":1775144098884,"version":"3.50.1"},"reference-count":24,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2023,6,2]],"date-time":"2023-06-02T00:00:00Z","timestamp":1685664000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002923","name":"Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas","doi-asserted-by":"publisher","award":["PUE 0089"],"award-info":[{"award-number":["PUE 0089"]}],"id":[{"id":"10.13039\/501100002923","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002923","name":"Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas","doi-asserted-by":"publisher","award":["PICT 2018-02643"],"award-info":[{"award-number":["PICT 2018-02643"]}],"id":[{"id":"10.13039\/501100002923","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Agencia Nacional de Promoci\u00f3n Cient\u00edfica y Tecnol\u00f3gica","award":["PUE 0089"],"award-info":[{"award-number":["PUE 0089"]}]},{"name":"Agencia Nacional de Promoci\u00f3n Cient\u00edfica y Tecnol\u00f3gica","award":["PICT 2018-02643"],"award-info":[{"award-number":["PICT 2018-02643"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>We previously reported that, in cultured hepatocytes, mitochondrial aquaporin-8 (AQP8) channels facilitate the conversion of ammonia to urea and that the expression of human AQP8 (hAQP8) enhances ammonia-derived ureagenesis. In this study, we evaluated whether hepatic gene transfer of hAQP8 improves detoxification of ammonia to urea in normal mice as well as in mice with impaired hepatocyte ammonia metabolism. A recombinant adenoviral (Ad) vector encoding hAQP8, AdhAQP8, or a control Ad vector was administered via retrograde infusion into the bile duct of the mice. Hepatocyte mitochondrial expression of hAQP8 was confirmed using confocal immunofluorescence and immunoblotting. The normal hAQP8-transduced mice showed decreased plasma ammonia and increased liver urea. Enhanced ureagenesis was confirmed via the NMR studies assessing the synthesis of 15N-labeled urea from 15N-labeled ammonia. In separate experiments, we made use of the model hepatotoxic agent, thioacetamide, to induce defective hepatic metabolism of ammonia in mice. The adenovirus-mediated mitochondrial expression of hAQP8 was able to restore normal ammonemia and ureagenesis in the liver of the mice. Our data suggest that hAQP8 gene transfer to mouse liver improves detoxification of ammonia to urea. This finding could help better understand and treat disorders with defective hepatic ammonia metabolism.<\/jats:p>","DOI":"10.3390\/cells12111535","type":"journal-article","created":{"date-parts":[[2023,6,2]],"date-time":"2023-06-02T08:50:31Z","timestamp":1685695831000},"page":"1535","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Adenoviral Transfer of Human Aquaporin-8 Gene to Mouse Liver Improves Ammonia-Derived Ureagenesis"],"prefix":"10.3390","volume":"12","author":[{"given":"Alejo M.","family":"Capiglioni","sequence":"first","affiliation":[{"name":"Instituto de Fisiolog\u00eda Experimental, Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas, Facultad de Ciencias Bioqu\u00edmicas y Farmac\u00e9uticas, Universidad Nacional de Rosario, Rosario 2000, Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda C.","family":"Capitani","sequence":"additional","affiliation":[{"name":"Instituto de Fisiolog\u00eda Experimental, Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas, Facultad de Ciencias Bioqu\u00edmicas y Farmac\u00e9uticas, Universidad Nacional de Rosario, Rosario 2000, Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julieta","family":"Marrone","sequence":"additional","affiliation":[{"name":"Instituto de Fisiolog\u00eda Experimental, Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas, Facultad de Ciencias Bioqu\u00edmicas y Farmac\u00e9uticas, Universidad Nacional de Rosario, Rosario 2000, Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ra\u00fal A.","family":"Marinelli","sequence":"additional","affiliation":[{"name":"Instituto de Fisiolog\u00eda Experimental, Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas, Facultad de Ciencias Bioqu\u00edmicas y Farmac\u00e9uticas, Universidad Nacional de Rosario, Rosario 2000, Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/bs.acc.2014.09.002","article-title":"Ammonia Metabolism and Hyperammonemic Disorders","volume":"Volume 67","author":"Walker","year":"2014","journal-title":"Advances in Clinical Chemistry"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1002\/hep.31274","article-title":"Functional Consequences of Metabolic Zonation in Murine Livers: Insights for an Old Story","volume":"73","author":"Berndt","year":"2021","journal-title":"Hepatology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1042\/BC20050026","article-title":"Purification and Functional Characterization of Aquaporin-8","volume":"98","author":"Liu","year":"2006","journal-title":"Biol. 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Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.bbrc.2010.01.104","article-title":"Aquaporin-8-Facilitated Mitochondrial Ammonia Transport","volume":"393","author":"Soria","year":"2010","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2061","DOI":"10.1002\/hep.26236","article-title":"Ammonia Detoxification via Ureagenesis in Rat Hepatocytes Involves Mitochondrial Aquaporin-8 Channels","volume":"57","author":"Soria","year":"2013","journal-title":"Hepatology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4331","DOI":"10.1002\/bit.27901","article-title":"Enhanced Ammonia Detoxification to Urea in Hepatocytes Transduced with Human Aquaporin-8 Gene","volume":"118","author":"Capiglioni","year":"2021","journal-title":"Biotechnol. 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Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1016\/j.stem.2018.10.018","article-title":"In Vitro Expansion of Primary Human Hepatocytes with Efficient Liver Repopulation Capacity","volume":"23","author":"Zhang","year":"2018","journal-title":"Cell Stem Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1038\/gt.2014.78","article-title":"Adenoviral Transfer of Human Aquaporin-1 Gene to Rat Liver Improves Bile Flow in Estrogen-Induced Cholestasis","volume":"21","author":"Marrone","year":"2014","journal-title":"Gene Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1002\/hep.510280301","article-title":"Suppression of Proliferative Cholangitis in a Rat Model with Direct Adenovirus-Mediated Retinoblastoma Gene Transfer to the Biliary Tract","volume":"28","author":"Terao","year":"1998","journal-title":"Hepatology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5051","DOI":"10.1111\/j.1742-4658.2006.05503.x","article-title":"Differential Gene Expression in Periportal and Perivenous Mouse Hepatocytes","volume":"273","author":"Braeuning","year":"2006","journal-title":"FEBS J."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1136\/gut.2003.013748","article-title":"Repeated Adenoviral Administration into the Biliary Tract Can Induce Repeated Expression of the Original Gene Construct in Rat Livers without Immunosuppressive Strategies","volume":"53","author":"Tominaga","year":"2004","journal-title":"Gut"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1002\/hep.28564","article-title":"Hepatic Gene Transfer of Human Aquaporin-1 Improves Bile Salt Secretory Failure in Rats with Estrogen-Induced Cholestasis","volume":"64","author":"Marrone","year":"2016","journal-title":"Hepatology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1002\/iub.1689","article-title":"Adenovirus-Mediated Human Aquaporin-1 Expression in Hepatocytes Improves Lipopolysaccharide-Induced Cholestasis","volume":"69","author":"Marrone","year":"2017","journal-title":"IUBMB Life"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1089\/nat.2020.0886","article-title":"DNA-Encoded Glutamine Synthetase Enzyme as Ammonia-Lowering Therapeutic for Hyperammonemia","volume":"30","author":"Khoshnejad","year":"2020","journal-title":"Nucleic Acid Ther."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1016\/j.toxrep.2021.04.011","article-title":"Drug-Induced-Acute Liver Failure: A Critical Appraisal of the Thioacetamide Model for the Study of Hepatic Encephalopathy","volume":"8","author":"Sepehrinezhad","year":"2021","journal-title":"Toxicol. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1111\/j.1478-3231.2009.02034.x","article-title":"Experimental Models of Hepatic Encephalopathy: ISHEN Guidelines","volume":"29","author":"Butterworth","year":"2009","journal-title":"Liver Int."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1111\/j.1365-2613.2008.00576.x","article-title":"Single Dose Intravenous Thioacetamide Administration as a Model of Acute Liver Damage in Rats","volume":"89","author":"Chen","year":"2008","journal-title":"Int. J. Exp. Pathol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2097","DOI":"10.1016\/j.tiv.2010.06.011","article-title":"The Toxic Effect of Thioacetamide on Rat Liver In Vitro","volume":"24","author":"Endlicher","year":"2010","journal-title":"Toxicol. 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