Basic Study
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Mar 28, 2016; 22(12): 3363-3371
Published online Mar 28, 2016. doi: 10.3748/wjg.v22.i12.3363
Tolvaptan regulates aquaporin-2 and fecal water in cirrhotic rats with ascites
Chao Chen, Ren-Pin Chen, Hai-Hua Lin, Wen-You Zhang, Xie-Lin Huang, Zhi-Ming Huang
Chao Chen, Ren-Pin Chen, Hai-Hua Lin, Wen-You Zhang, Xie-Lin Huang, Zhi-Ming Huang, Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
Xie-Lin Huang, Ren-Ji College of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
Author contributions: Chen RP and Huang ZM designed the study; Chen C, Lin HH and Zhang WY performed the research; Chen RP provided analytic tools; Chen C and Huang XL analyzed the data; Chen C and Chen RP wrote the paper.
Supported by The Crosswise Project, No. KJHX1310.
Institutional review board statement: The study was reviewed and approved by the Wenzhou Medical University Institutional Review Board.
Institutional animal care and use committees statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Wenzhou Medical University in 2013 (NO. wydw2013-0071).
Conflict-of-interest statement: The authors declare that there is no conflict of interest related to this study.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Dr. Zhi-Ming Huang, Professor, Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Shangcai Village, Ouhai District, Wenzhou 325000, Zhejiang Province, China. wyyyhzm@126.com
Telephone: +86-577-55578033 Fax: +86-577-55578033
Received: August 7, 2015
Peer-review started: August 10, 2015
First decision: November 13, 2015
Revised: November 19, 2015
Accepted: December 8, 2015
Article in press: December 8, 2015
Published online: March 28, 2016
Processing time: 229 Days and 7.2 Hours
Abstract

AIM: To investigate the role of tolvaptan in regulating aquaporin (AQP)-2 expression and fecal water content in cirrhotic rats with ascites.

METHODS: Cirrhosis with ascites was induced in rats by repetitive dorsal injection of CCl4 for 14 wk. In total, 84 cirrhotic rats with ascites divided into three groups (vehicle, 3 mg/kg and 5 mg/kg tolvaptan), and then further divided into five subgroups (days 1, 2, 3, 4, and 5). Blood samples were obtained to measure vasopressin and sodium concentrations. Rats were killed and colonic mucosa was scraped for analysis of protein expression and AQP-2 transcriptional level. The whole layer was fixed for hematoxylin&eosin (HE) staining and feces were collected for determination of fecal water content.

CONCLUSION: Compared with vehicle, vasopressin decreased significantly in the tolvaptan groups from day 2 to a similar level in each treatment group. AQP-2 showed significant upregulation in cirrhotic rats with ascites compared with an untreated control group (100% ± 22.9% vs 22.2% ± 10.23%, P < 0.01). After administration of tolvaptan, AQP-2 expression began to decrease significantly from day 2 in each treatment group, but no significant difference was finally found between the treatment groups. Fecal water content in the distal colon was increased by 5 mg/kg tolvaptan on day 1 (66.8% ± 9.3% vs 41.4% ± 6.3%, in the vehicle group, P < 0.05). Fecal water content returned to baseline at day 4 at the latest in both treatment groups, and did not correspond to the change in AQP-2 expression. HE staining of the colonic mucosa showed no mucosal damage related to tolvaptan.

CONCLUSION: Upregulation of AQP-2 in the distal colon is found in cirrhotic rats with ascites. Tolvaptan inhibits its expression and may decrease water reabsorption and induce diarrhea.

Keywords: Tolvaptan; Aquaporin-2; Cirrhosis; Ascites

Core tip: Aquaporin (AQP)-2 is mainly expressed in the kidneys, although it has been detected in the distal colon. We confirmed its expression in the distal colon and its upregulation in cirrhotic rats with ascites. Tolvaptan is a highly potent and selective AQP-2 antagonist and is used to treat cirrhotic ascites and hyponatremia. It blocked AQP-2 expression in the distal colon after oral administration, and temporarily increased fecal water content. Fecal water content returned to baseline quickly. The results suggest that tolvaptan inhibited AQP-2 expression in the distal colon and may induce diarrhea to clear water.