{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T00:22:40Z","timestamp":1780532560207,"version":"3.54.1"},"reference-count":52,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,1,27]],"date-time":"2022-01-27T00:00:00Z","timestamp":1643241600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: Acute kidney injury (AKI) is common in advanced liver cirrhosis, a consequence of reduced kidney perfusion due to splanchnic arterial vasodilation and intrarenal vasoconstriction. It clinically manifests as hepatorenal syndrome type 1, type 2, or as acute tubular necrosis. Beyond hemodynamic factors, an additional mechanism may be hypothesized to explain the renal dysfunction during liver cirrhosis. Recent evidence suggest that such mechanisms may be closely related to obstructive jaundice. Methods: Given the not completely elucidated role of bile acids in kidney tissue damage, this study developed a rat model of AKI with liver cirrhosis induction by carbon tetrachloride (CCl4) inhalation for 12 weeks. Histological analyses of renal and liver biopsies were performed at sacrifice. Organic anion tubular transporter distribution and apoptosis in kidney cells were analyzed by immunohistochemistry. Circulating and urinary markers of inflammation and tubular injury were assayed in 21 treated rats over time (1, 2, 4, 8, and 12 weeks of CCl4 administration) and 5 controls. Results: No renal histopathological alterations were found at sacrifice. Comparing treated rats with controls, organic anion transporters were differentially expressed and localized. High serum bile acid values were detected in cirrhotic animals, while caspase-3 staining was negative in both groups. Increased levels of serum inflammatory and urinary tubular injury biomarkers were observed during cirrhosis progression, with a peak after 4 and 8 weeks of treatment. Conclusions: These findings suggest possible adaptive tubular mechanisms for bile acid transporters in response to cirrhosis-induced AKI.<\/jats:p>","DOI":"10.3390\/jcm11030636","type":"journal-article","created":{"date-parts":[[2022,1,27]],"date-time":"2022-01-27T22:00:56Z","timestamp":1643320856000},"page":"636","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Adaptive Mechanisms of Renal Bile Acid Transporters in a Rat Model of Carbon Tetrachloride-Induced Liver Cirrhosis"],"prefix":"10.3390","volume":"11","author":[{"given":"Chiara","family":"Donadei","sequence":"first","affiliation":[{"name":"Nephrology, Dialysis and Renal Transplant Unit, IRCCS\u2014Azienda Ospedaliero-Universitaria di Bologna, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6121-5326","authenticated-orcid":false,"given":"Andrea","family":"Angeletti","sequence":"additional","affiliation":[{"name":"Nephrology, Dialysis and Renal Transplant Unit, IRCCS\u2014Azienda Ospedaliero-Universitaria di Bologna, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy"},{"name":"Division of Nephrology, Dialysis and Transplantation, IRCCS Istituto Giannina Gaslini, Genoa Largo Gaslini, 16148 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2592-9532","authenticated-orcid":false,"given":"Maria","family":"Cappuccilli","sequence":"additional","affiliation":[{"name":"Nephrology, Dialysis and Renal Transplant Unit, IRCCS\u2014Azienda Ospedaliero-Universitaria di Bologna, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimiliano","family":"Conti","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diletta","family":"Conte","sequence":"additional","affiliation":[{"name":"Nephrology, Dialysis and Renal Transplant Unit, IRCCS\u2014Azienda Ospedaliero-Universitaria di Bologna, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fulvia","family":"Zappulo","sequence":"additional","affiliation":[{"name":"Nephrology, Dialysis and Renal Transplant Unit, IRCCS\u2014Azienda Ospedaliero-Universitaria di Bologna, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessio","family":"De Giovanni","sequence":"additional","affiliation":[{"name":"Department of Experimental, Diagnostic and Specialty Medicine\u2014DIMES, \u201cF. Addarii\u201d Institute of Oncology and Transplant Pathology, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah","family":"Malvi","sequence":"additional","affiliation":[{"name":"Department of Experimental, Diagnostic and Specialty Medicine\u2014DIMES, \u201cF. Addarii\u201d Institute of Oncology and Transplant Pathology, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita","family":"Aldini","sequence":"additional","affiliation":[{"name":"Department of Chemistry \u201cG. Ciamician\u201d, Alma Mater Studiorum University of Bologna, 40126 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7649-4797","authenticated-orcid":false,"given":"Aldo","family":"Roda","sequence":"additional","affiliation":[{"name":"Department of Chemistry \u201cG. Ciamician\u201d, Alma Mater Studiorum University of Bologna, 40126 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaetano","family":"La Manna","sequence":"additional","affiliation":[{"name":"Nephrology, Dialysis and Renal Transplant Unit, IRCCS\u2014Azienda Ospedaliero-Universitaria di Bologna, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1002\/hep.26980","article-title":"Kidney biomarkers and differential diagnosis of patients with cirrhosis and acute kidney injury","volume":"60","author":"Belcher","year":"2013","journal-title":"Hepatology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"195","DOI":"10.14218\/JCTH.2015.00015","article-title":"Acute Kidney Injury in Patients with Cirrhosis","volume":"3","author":"Russ","year":"2015","journal-title":"J. Clin. Transl. Hepatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2064","DOI":"10.1002\/hep.22605","article-title":"Acute kidney injury in cirrhosis","volume":"48","author":"Parikh","year":"2008","journal-title":"Hepatology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.1002\/hep.29915","article-title":"Disruption of R enal A rginine M etabolism P romotes K idney I njury in H epatorenal S yndrome in M ice","volume":"68","author":"Varga","year":"2018","journal-title":"Hepatology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1111\/liv.13023","article-title":"A model of acute kidney injury in mice with cirrhosis and infection","volume":"36","author":"Carl","year":"2016","journal-title":"Liver Int."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1002\/hep.1840080532","article-title":"Peripheral arterial vasodilation hypothesis: A proposal for the initiation of renal sodium and water retention in cirrhosis","volume":"8","author":"Schrier","year":"1988","journal-title":"Hepatology"},{"key":"ref_7","first-page":"723","article-title":"Familial progressive tubulo-interstitial nephropathy and cholestatic liver disease\u2014A newly recognized entity?","volume":"156","author":"Neuhaus","year":"1997","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1007\/BF00857550","article-title":"Progressive tubulointerstitial nephritis and chronic cholestatic liver disease","volume":"7","author":"Jovanovic","year":"1993","journal-title":"Pediatr. Nephrol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/0002-9343(86)90205-6","article-title":"Progressive tubulointerstitial renal disease in infancy with associated hepatic abnormalities","volume":"81","author":"Harris","year":"1986","journal-title":"Am. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Perreault, M., Bia\u0142ek, A., Trottier, J., Verreault, M., Caron, P., Milkiewicz, P., and Barbier, O. (2013). Role of Glucuronidation for Hepatic Detoxification and Urinary Elimination of Toxic Bile Acids during Biliary Obstruction. PLoS ONE, 8, Erratum in PLoS ONE 2014, 9, https:\/\/doi.org\/10.1371\/annotation\/ef13ed51-6848-419d-94d8-1bb62e7bcf52.","DOI":"10.1371\/annotation\/ef13ed51-6848-419d-94d8-1bb62e7bcf52"},{"key":"ref_11","first-page":"549","article-title":"Bile acids, oxidative stress, and renal function in biliary obstruction","volume":"17","author":"Bomzon","year":"1997","journal-title":"Semin. Nephrol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.1016\/j.jhep.2015.07.004","article-title":"Mechanisms of decompensation and organ failure in cirrhosis: From peripheral arterial vasodilation to systemic inflammation hypothesis","volume":"63","author":"Bernardi","year":"2015","journal-title":"J. Hepatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1046\/j.1523-1755.2001.0600031047.x","article-title":"Acute cholestatic liver disease protects against glycerol-induced acute renal failure in the rat","volume":"60","author":"Leung","year":"2001","journal-title":"Kidney Int."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.mam.2013.10.001","article-title":"Chronic cholestatic liver diseases: Clues from histopathology for pathogenesis","volume":"37","author":"Pollheimer","year":"2014","journal-title":"Mol. Asp. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2905","DOI":"10.12659\/MSM.894232","article-title":"Abnormal Expression of Urea Transporter Protein in a Rat Model of Hepatorenal Syndrome Induced by Succinylated Gelatin","volume":"21","author":"Song","year":"2015","journal-title":"Med. Sci. Monit."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1016\/j.jhep.2009.09.008","article-title":"A novel model of CCl4-induced cirrhosis with ascites in the mouse","volume":"51","author":"Domenicali","year":"2009","journal-title":"J. Hepatol."},{"key":"ref_17","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_18","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1111\/j.1365-2362.2006.01620.x","article-title":"A stable model of cirrhotic portal hypertension in the rat: Thioacetamide revisited","volume":"36","author":"Laleman","year":"2006","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1111\/j.1476-5381.2010.00872.x","article-title":"Animal research: Reporting in vivo experiments: The ARRIVE guidelines","volume":"160","author":"Kilkenny","year":"2010","journal-title":"Br. J. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1111\/j.1440-1746.1992.tb00940.x","article-title":"Carbon tetrachloride induced cirrhosis in rats: A useful tool for investigating the pathogenesis of ascites in chronic liver disease","volume":"7","author":"Arroyo","year":"1992","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.jhep.2005.01.034","article-title":"A novel sodium overload test predicting ascites decompensation in rats with CCl4-induced cirrhosis","volume":"43","author":"Domenicali","year":"2005","journal-title":"J. Hepatol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1016\/S0168-8278(01)00097-6","article-title":"Effect of phenobarbital on the expression of bile salt and organic anion transporters of rat liver","volume":"34","author":"Hagenbuch","year":"2001","journal-title":"J. Hepatol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"114","DOI":"10.5114\/fn.2016.60088","article-title":"Assessment of candidate immunohistochemical prognostic markers of meningioma recurrence","volume":"2","author":"Csonka","year":"2016","journal-title":"Folia Neuropathol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1016\/0168-8278(95)80226-6","article-title":"Histological grading and staging of chronic hepatitis","volume":"22","author":"Ishak","year":"1995","journal-title":"J. Hepatol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1002\/hep.510240201","article-title":"An algorithm for the grading of activity in chronic hepatitis C","volume":"24","author":"Bedossa","year":"1996","journal-title":"Hepatology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"511","DOI":"10.5527\/wjn.v4.i5.511","article-title":"Hepatorenal syndrome: Update on diagnosis and treatment","volume":"4","author":"Baraldi","year":"2015","journal-title":"World J. Nephrol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1038\/s41581-019-0218-4","article-title":"Reappraising the spectrum of AKI and hepatorenal syndrome in patients with cirrhosis","volume":"16","author":"Velez","year":"2019","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1016\/S0168-8278(03)00324-6","article-title":"Systemic and regional hemodynamics in pre-ascitic cirrhosis: Effects of posture","volume":"39","author":"Bernardi","year":"2003","journal-title":"J. Hepatol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1016\/0016-5085(93)90025-8","article-title":"Renal sodium retention during upright posture in preascitic cirrhosis","volume":"105","author":"Bernardl","year":"1993","journal-title":"Gastroenterology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/0163-7258(89)90050-8","article-title":"Mechanisms of carbon tetrachloride toxicity","volume":"43","author":"Recknagel","year":"1989","journal-title":"Pharmacol. Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1016\/S0022-5347(17)67968-0","article-title":"The Histologic Lesion of Cholemic Nephrosis","volume":"70","author":"Holmes","year":"1953","journal-title":"J. Urol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1084\/jem.35.4.533","article-title":"The Renal Elimination of Bilirubin","volume":"35","author":"Haessler","year":"1922","journal-title":"J. Exp. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"F516","DOI":"10.1152\/ajprenal.1983.244.5.F516","article-title":"Renal response to four hours of biliary obstruction in the dog","volume":"244","author":"Levy","year":"1983","journal-title":"Am. J. Physiol. Physiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1056\/NEJM196604072741402","article-title":"Effect of Bile Infusion on the Dog Kidney","volume":"274","author":"Topuzlu","year":"1966","journal-title":"N. Engl. J. Med."},{"key":"ref_35","first-page":"571","article-title":"Ultrastructural changes in the isolated rat kidney induced by conjugated bilirubin and bile acids","volume":"57","author":"Gollan","year":"1976","journal-title":"Br. J. Exp. Pathol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.etp.2006.05.001","article-title":"Renal dysfunction as a consequence of acute liver damage by bile duct ligation in cirrhotic rats","volume":"58","year":"2006","journal-title":"Exp. Toxicol. Pathol."},{"key":"ref_37","first-page":"1458","article-title":"Human kidney histopathology in acute obstructive jaundice","volume":"22","author":"Uslu","year":"2010","journal-title":"Eur. J. Gastroenterol. Hepatol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1038\/ki.2013.78","article-title":"Bile cast nephropathy is a common pathologic finding for kidney injury associated with severe liver dysfunction","volume":"84","author":"Salem","year":"2013","journal-title":"Kidney Int."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1159\/000371689","article-title":"Bile Acid-Induced Cholemic Nephropathy","volume":"33","author":"Krones","year":"2015","journal-title":"Dig. Dis."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1194\/jlr.R054114","article-title":"Intestinal transport and metabolism of bile acids","volume":"56","author":"Dawson","year":"2015","journal-title":"J. Lipid Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1146\/annurev.physiol.64.082201.100300","article-title":"Bile Salt Transporters","volume":"64","author":"Meier","year":"2002","journal-title":"Annu. Rev. Physiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1152\/physrev.00027.2002","article-title":"Bile Salt Transporters: Molecular Characterization, Function, and Regulation","volume":"83","author":"Trauner","year":"2003","journal-title":"Physiol. Rev."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1270","DOI":"10.1002\/hep.20961","article-title":"OST\u03b1-OST\u03b2: A major basolateral bile acid and steroid transporter in human intestinal, renal, and biliary epithelia","volume":"42","author":"Ballatori","year":"2005","journal-title":"Hepatology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1055\/s-2000-9426","article-title":"Hepatic Transport of Bile Salts","volume":"20","author":"Stieger","year":"2000","journal-title":"Semin. Liver Dis."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.cld.2007.11.010","article-title":"Mechanisms of Cholestasis","volume":"12","author":"Zollner","year":"2008","journal-title":"Clin. Liver Dis."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1172\/JCI103450","article-title":"Bile Acid Content of Human Serum. I. Serum Bile Acids in Patients with Hepatic Disease","volume":"36","author":"Rudman","year":"1957","journal-title":"J. Clin. Investig."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/j.jhep.2005.03.017","article-title":"Enterohepatic transport of bile salts and genetics of cholestasis","volume":"43","author":"Stieger","year":"2005","journal-title":"J. Hepatol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"15211","DOI":"10.1074\/jbc.271.25.15211","article-title":"Multiple Factors Regulate the Rat Liver Basolateral Sodium-dependent Bile Acid Cotransporter Gene Promoter","volume":"271","author":"Karpen","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1053\/jhep.2003.50317","article-title":"Effects of proinflammatory cytokines on rat organic anion transporters during toxic liver injury and cholestasis","volume":"38","author":"Geier","year":"2003","journal-title":"Hepatology"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1016\/S0022-2275(20)31482-6","article-title":"Regulation of cholesterol-7\u03b1-hydroxylase: BAREly missing a SHP","volume":"43","author":"Davis","year":"2002","journal-title":"J. Lipid Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1016\/j.jhep.2011.11.024","article-title":"Prevention of acute kidney injury in a rodent model of cirrhosis following selective gut decontamination is associated with reduced renal TLR4 expression","volume":"56","author":"Shah","year":"2012","journal-title":"J. Hepatol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.jcma.2011.08.002","article-title":"Kinetics of cytokine expression in cirrhotic rats","volume":"74","author":"Hsieh","year":"2011","journal-title":"J. Chin. Med. Assoc."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/11\/3\/636\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:08:36Z","timestamp":1760134116000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/11\/3\/636"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,27]]},"references-count":52,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["jcm11030636"],"URL":"https:\/\/doi.org\/10.3390\/jcm11030636","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,27]]}}}